Dr Nathan Bartlett

Dr Nathan Bartlett

Senior Lecturer

School of Biomedical Sciences and Pharmacy

Career Summary

Biography

Dr Nathan Bartlett is a Senior Lecturer in the new Viral Immunology and Respiratory Disease group and is based at the Hunter Medical Research Institute. He also retains an honorary academic appointment within the National Heart and Lung Institute, at Imperial College London, UK  where he continues to be involved in ongoing research. 

Following the award of PhD, Dr Bartlett undertook a 5 year Postdoctoral research position with Professor Geoffrey Smith (FRS) - first at the Sir William Dunn School of Pathology, University of Oxford, then in the Department of Virology, Imperial College London. Dr Bartlett then undertook a second Postdoctoral position with Professor Sebastian Johnston in the Department of Respiratory Medicine within the National Heart and Lung Institute (NHLI), also at Imperial.

After joining the NHLI, Dr Bartlett continued to build on his virology training and investigated the interaction of respiratory viral infection with type-2 immunity to uncover pathogenic mechanisms in asthma exacerbations. He is a co-applicant on several successful project and program grants and since his Lecturer appointment at Imperial in 2011 was successful as the Lead Investigator in achieving an MRC project grant to study the role of IL-25 in asthma exacerbations, the research from which was published as the featured cover story in Science Translational Medicine (October 2014). Bartlett et al, Nat Med 2008, the world's first mouse rhinovirus infection model which received extensive media coverage (TV, radio and newspaper). Dr Bartlett was interviewed on radio by BBC World and ABC Canberra, Australia and has been highlighted by Asthma UK as an important researcher in their magazine. Dr Bartlett has contributed to several scholarly books including the Rhinovirus chapter for the Encyclopaedia of Virology (Elsevier). Dr Bartlett is considered a world expert on in vivo models of rhinovirus infection and consults for a number companies that seek to develop novel anti-viral therapies.He is also an Associate Editor for the American Journal of Physiology - Lung, Cellular and Molecular Physiology (AJP-LUNG).

In 2015 Dr Bartlett accepted an academic appointment at the University of Newcastle where he has received funding from HMRI, Asthma Australia, NHMRC and multiple companies to continue researching the pathogenesis of rhinovirus infections and development of new treatment approaches for respiratory virus infections, asthma and COPD exacerbations. 


Qualifications

  • PhD, Deakin University
  • Bachelor of Science (Honours), Deakin University

Keywords

  • Asthma
  • Epithelium
  • Respiratory virus
  • Rhinovirus
  • Type 2 immunity
  • allergy
  • anti-viral immunity
  • innate immunity

Fields of Research

Code Description Percentage
110707 Innate Immunity 20
110799 Immunology not elsewhere classified 50
060599 Microbiology not elsewhere classified 30

Professional Experience

UON Appointment

Title Organisation / Department
Senior Lecturer University of Newcastle
School of Biomedical Sciences and Pharmacy
Australia

Academic appointment

Dates Title Organisation / Department
20/03/2011 -  Lecturer Imperial College London
United Kingdom
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Publications

For publications that are currently unpublished or in-press, details are shown in italics.


Chapter (3 outputs)

Year Citation Altmetrics Link
2015 Bartlett NW, Singanayagam A, Johnston SL, 'Mouse models of rhinovirus infection and airways disease', Rhinoviruses: Methods and Protocols, Springer, New York 181-188 (2015) [B1]
DOI 10.1007/978-1-4939-1571-2_14
Citations Scopus - 2
2014 Bartlett NW, Johnston SL, 'Rhinoviruses', Reference Module in Biomedical Research (2014)

© 2014 Elsevier Inc. All rights reserved.Human rhinovirus (HRV) infections are the most frequent cause of the common cold, the most common illness affecting mankind with cases do... [more]

© 2014 Elsevier Inc. All rights reserved.Human rhinovirus (HRV) infections are the most frequent cause of the common cold, the most common illness affecting mankind with cases documented as far back in human history as the ancient Egyptians. Morbidity associated with the illness is a major cause of lost productivity through absenteeism from school or work. More recently, rhinoviruses have been shown to play a significant role in precipitating severe respiratory disease syndromes such as acute exacerbations of asthma. Rhinoviruses belong to the family Picornaviridae. Initially 102 HRV serotypes were identified. Subsequent molecular-based genetic identification has extended the number to over 160 viruses which are divided into 3 species (HRV-A, -B and -C). The immense antigenic variation arising from such a large number of virus types has thwarted efforts to date to develop an anti-HRV vaccine. Viral replication occurs in the cytoplasm and the virions are small non-enveloped icosahedral particles which contain a single-stranded positive-sense RNA genome. The single polyprotein encoded by the RNA genome is cleaved by viral proteases to yield mature proteins. The majority of HRV serotypes require intercellular adhesion molecule 1 for cell binding and entry. Rhinoviruses exhibit a narrow host range infecting only humans and some primates although recently mouse infection models have been developed. Sensitive molecular assays such as polymerase chain reaction (PCR) have significantly increased the ability to detect HRVs direcetly in infected material. Transmitted by aerosol the virus enters via the nose and replicates in the nasal epithelium, inducing production of pro-inflammatory cytokines that contribute to cold symptoms with involvement of lower respiratory tract in susceptible individuals.

DOI 10.1016/B978-0-12-801238-3.02658-1
2008 Bartlett NW, 'Rhinoviruses', Encyclopedia of Virology, Elsevier, Oxford UK (2008)

Journal article (44 outputs)

Year Citation Altmetrics Link
2017 Toussaint M, Jackson DJ, Swieboda D, Guedán A, Tsourouktsoglou T-D, Ching YM, et al., 'Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation', Nature Medicine, (2017)
DOI 10.1038/nm.4332
2017 Chairakaki A-D, Saridaki M-I, Pyrillou K, Mouratis M-A, Koltsida O, Walton RP, et al., 'Plasmacytoid dendritic cells drive acute exacerbations of asthma', Journal of Allergy and Clinical Immunology, (2017)
2017 Dhariwal J, Cameron A, Trujillo-Torralbo M-B, del Rosario A, Bakhsoliani E, Paulsen M, et al., 'Mucosal Type 2 Innate Lymphoid Cells Are a Key Component of the Allergic Response to Aeroallergens', American Journal of Respiratory and Critical Care Medicine, 195 1586-1596 (2017)
DOI 10.1164/rccm.201609-1846OC
2017 Hansel TT, Tunstall T, Trujillo-Torralbo MB, Shamji B, del-Rosario A, Dhariwal J, et al., 'A Comprehensive Evaluation of Nasal and Bronchial Cytokines and Chemokines Following Experimental Rhinovirus Infection in Allergic Asthma: Increased Interferons (IFN-¿ and IFN-¿) and Type 2 Inflammation (IL-5 and IL-13)', EBioMedicine, 19 128-138 (2017)

© 2017 The Authors Background Rhinovirus infection is a major cause of asthma exacerbations. Objectives We studied nasal and bronchial mucosal inflammatory responses during exper... [more]

© 2017 The Authors Background Rhinovirus infection is a major cause of asthma exacerbations. Objectives We studied nasal and bronchial mucosal inflammatory responses during experimental rhinovirus-induced asthma exacerbations. Methods We used nasosorption on days 0, 2¿5 and 7 and bronchosorption at baseline and day 4 to sample mucosal lining fluid to investigate airway mucosal responses to rhinovirus infection in patients with allergic asthma (n¿=¿28) and healthy non-atopic controls (n¿=¿11), by using a synthetic absorptive matrix and measuring levels of 34 cytokines and chemokines using a sensitive multiplex assay. Results Following rhinovirus infection asthmatics developed more upper and lower respiratory symptoms and lower peak expiratory flows compared to controls (all P¿ < ¿0.05). Asthmatics also developed higher nasal lining fluid levels of an anti-viral pathway (including IFN-¿, IFN-¿/IL-29, CXCL11/ITAC, CXCL10/IP10 and IL-15) and a type 2 inflammatory pathway (IL-4, IL-5, IL-13, CCL17/TARC, CCL11/eotaxin, CCL26/eotaxin-3) (area under curve day 0¿7, all P¿ < ¿0.05). Nasal IL-5 and IL-13 were higher in asthmatics at day 0 (P¿ < ¿0.01) and levels increased by days 3 and 4 (P¿ < ¿0.01). A hierarchical correlation matrix of 24 nasal lining fluid cytokine and chemokine levels over 7¿days demonstrated expression of distinct interferon-related and type 2 pathways in asthmatics. In asthmatics IFN-¿, CXCL10/IP10, CXCL11/ITAC, IL-15 and IL-5 increased in bronchial lining fluid following viral infection (all P¿ < ¿0.05). Conclusions Precision sampling of mucosal lining fluid identifies robust interferon and type 2 responses in the upper and lower airways of asthmatics during an asthma exacerbation. Nasosorption and bronchosorption have potential to define asthma endotypes in stable disease and at exacerbation.

DOI 10.1016/j.ebiom.2017.03.033
Citations Scopus - 1
2017 Petrova NV, Emelyanova AG, Gorbunov EA, Edwards MR, Walton RP, Bartlett NW, et al., 'Efficacy of novel antibody-based drugs against rhinovirus infection: In¿vitro and in¿vivo results', Antiviral Research, 142 185-192 (2017)

© 2017 Elsevier B.V. Rhinoviruses (RVs) cause the common cold and are associated with exacerbations of chronic inflammatory respiratory diseases, especially asthma and chronic ob... [more]

© 2017 Elsevier B.V. Rhinoviruses (RVs) cause the common cold and are associated with exacerbations of chronic inflammatory respiratory diseases, especially asthma and chronic obstructive pulmonary disease (COPD). We have assessed the antiviral drugs Anaferon for Children (AC) and Ergoferon (containing AC as one of the active pharmaceutical ingredients) in in¿vitro and in¿vivo experimental models, in order to evaluate their anti-rhinoviral and immunomodulatory potential. HeLa cells were pretreated with AC, and levels of the interferon-stimulated gene (ISG), 2'-5'-oligoadenylate synthetase 1 (OAS1-A) and viral replication were analyzed. In a mouse model of RV-induced exacerbation of allergic airway inflammation we administered Ergoferon and analyzed its effect on type I (IFN-ß), type II (IFN-¿) and type III (IFN-¿) IFNs induction, cell counts in bronchoalveolar lavage (BAL), cytokine (interleukin (IL)-4; IL-6) and chemokine (CXCL10/IP-10; CXCL1/KC) levels. It was shown that AC increased OAS1-¿ production and significantly decreased viral replication in¿vitro. Increased IFNs expression together with reduced neutrophils/lymphocytes recruitment and correlated IL-4/IL-6 declination was demonstrated for Ergoferon in¿vivo. However, there was no effect on examined chemokines. We conclude that AC and Ergoferon possess effects against RV infection and may have potential as novel therapies against RV-induced exacerbations of asthma.

DOI 10.1016/j.antiviral.2017.03.017
2016 Tay H, Wark PAB, Bartlett NW, 'Advances in the treatment of virus-induced asthma', Expert Review of Respiratory Medicine, 10 629-641 (2016) [C1]

© 2016 Informa UK Limited, trading as Taylor &amp; Francis Group. ABSTRACT: Viral exacerbations continue to represent the major burden in terms of morbidity, mortality and heal... [more]

© 2016 Informa UK Limited, trading as Taylor & Francis Group. ABSTRACT: Viral exacerbations continue to represent the major burden in terms of morbidity, mortality and health care costs associated with asthma. Those at greatest risk for acute asthma are those with more severe airways disease and poor asthma control. It is this group with established asthma in whom acute exacerbations triggered by virus infections remain a serious cause of increased morbidity. A range of novel therapies are emerging to treat asthma and in particular target this group with poor disease control, and in most cases their efficacy is now being judged by their ability to reduce the frequency of acute exacerbations. Critical for the development of new treatment approaches is an improved understanding of virus-host interaction in the context of the asthmatic airway. This requires research into the virology of the disease in physiological models in conjunction with detailed phenotypic characterisation of asthma patients to identify targets amenable to therapeutic intervention.

DOI 10.1080/17476348.2016.1180249
Citations Scopus - 1Web of Science - 1
Co-authors Peter Wark, Hock Tay
2015 Jackson DJ, Trujillo-Torralbo M-B, del-Rosario J, Bartlett NW, Edwards MR, Mallia P, et al., 'The influence of asthma control on the severity of virus-induced asthma exacerbations', Journal of Allergy and Clinical Immunology, 136 497-500.e3 (2015) [C3]
DOI 10.1016/j.jaci.2015.01.028
Citations Scopus - 4
2015 Hatchwell L, Collison A, Girkin J, Parsons K, Li J, Zhang J, et al., 'Toll-like receptor 7 governs interferon and inflammatory responses to rhinovirus and is suppressed by IL-5-induced lung eosinophilia', Thorax, (2015) [C1]

© 2015 BMJ Publishing Group Ltd &amp; British Thoracic Society.Background Asthma exacerbations represent a significant disease burden and are commonly caused by rhinovirus (RV), ... [more]

© 2015 BMJ Publishing Group Ltd & British Thoracic Society.Background Asthma exacerbations represent a significant disease burden and are commonly caused by rhinovirus (RV), which is sensed by Toll-like receptors (TLR) such as TLR7. Some asthmatics have impaired interferon (IFN) responses to RV, but the underlying mechanisms of this clinically relevant observation are poorly understood. Objectives To investigate the importance of intact TLR7 signalling in vivo during RV exacerbation using mouse models of house dust mite (HDM)-induced allergic airways disease exacerbated by a superimposed RV infection. Methods Wild-type and TLR7-deficient (Tlr7<sup>-/-</sup>) BALB/c mice were intranasally sensitised and challenged with HDM prior to infection with RV1B. In some experiments, mice were administered recombinant IFN or adoptively transferred with plasmacytoid dendritic cells (pDC). Results Allergic Tlr7<sup>-/-</sup> mice displayed impaired IFN release upon RV1B infection, increased virus replication and exaggerated eosinophilic inflammation and airways hyper reactivity. Treatment with exogenous IFN or adoptive transfer of TLR7-competent pDCs blocked these exaggerated inflammatory responses and boosted IFN? release in the absence of host TLR7 signalling. TLR7 expression in the lungs was suppressed by allergic inflammation and by interleukin (IL)-5-induced eosinophilia in the absence of allergy. Subjects with moderate-to-severe asthma and eosinophilic but not neutrophilic airways inflammation, despite inhaled steroids, showed reduced TLR7 and IFN?2/3 expression in endobronchial biopsies. Furthermore, TLR7 expression inversely correlated with percentage of sputum eosinophils. Conclusions This implicates IL-5-induced airways eosinophilia as a negative regulator of TLR7 expression and antiviral responses, which provides a molecular mechanism underpinning the effect of eosinophil-targeting treatments for the prevention of asthma exacerbations.

DOI 10.1136/thoraxjnl-2014-205465
Citations Scopus - 23Web of Science - 23
Co-authors Joerg Mattes, Peter Wark, Darryl Knight, Adam Collison, Paul Foster
2015 Singanayagam A, Glanville N, Walton RP, Aniscenko J, Pearson RM, Pinkerton JW, et al., 'A short-term mouse model that reproduces the immunopathological features of rhinovirus-induced exacerbation of COPD.', Clin Sci (Lond), 129 245-258 (2015) [C1]
DOI 10.1042/CS20140654
Citations Scopus - 10Web of Science - 9
Co-authors Jay Horvat, Philip Hansbro
2015 Girkin J, Hatchwell L, Foster P, Johnston SL, Bartlett N, Collison A, Mattes J, 'CCL7 and IRF-7 mediate hallmark inflammatory and IFN responses following rhinovirus 1B infection', Journal of Immunology, 194 4924-4930 (2015) [C1]

Copyright © 2015 by The American Association of Immunologists, Inc. Rhinovirus (RV) infections are common and have the potential to exacerbate asthma. We have determined the lung... [more]

Copyright © 2015 by The American Association of Immunologists, Inc. Rhinovirus (RV) infections are common and have the potential to exacerbate asthma. We have determined the lung transcriptome in RV strain 1B-infected naive BALB/c mice (nonallergic) and identified CCL7 and IFN regulatory factor (IRF)-7 among the most upregulated mRNA transcripts in the lung. To investigate their roles we employed anti-CCL7 Abs and an IRF-7-targeting small interfering RNA in vivo. Neutralizing CCL7 or inhibiting IRF-7 limited neutrophil and macrophage influx and IFN responses in nonallergic mice. Neutralizing CCL7 also reduced activation of NF-¿B p65 and p50 subunits, as well as airway hyperreactivity (AHR) in nonallergic mice. However, neither NF-¿B subunit activation nor AHR was abolished with infection of allergic mice after neutralizing CCL7, despite a reduction in the number of neutrophils, macrophages, and eosinophils. IRF-7 small interfering RNA primarily suppressed IFN-a and IFN-b levels during infection of allergic mice. Our data highlight a pivotal role of CCL7 and IRF-7 in RV-induced inflammation and IFN responses and link NF-¿B signaling to the development of AHR.

DOI 10.4049/jimmunol.1401362
Citations Scopus - 10Web of Science - 9
Co-authors Adam Collison, Joerg Mattes, Paul Foster
2014 George PM, Oliver E, Dorfmuller P, Dubois OD, Reed DM, Kirkby NS, et al., 'Evidence for the involvement of type I interferon in pulmonary arterial hypertension', Circulation Research, 114 677-688 (2014) [C1]

RATIONALE:: Evidence is increasing of a link between interferon (IFN) and pulmonary arterial hypertension (PAH). Conditions with chronically elevated endogenous IFNs such as syste... [more]

RATIONALE:: Evidence is increasing of a link between interferon (IFN) and pulmonary arterial hypertension (PAH). Conditions with chronically elevated endogenous IFNs such as systemic sclerosis are strongly associated with PAH. Furthermore, therapeutic use of type I IFN is associated with PAH. This was recognized at the 2013 World Symposium on Pulmonary Hypertension where the urgent need for research into this was highlighted. OBJECTIVE:: To explore the role of type I IFN in PAH. METHODS AND RESULTS:: Cells were cultured using standard approaches. Cytokines were measured by ELISA. Gene and protein expression were measured using reverse transcriptase polymerase chain reaction, Western blotting, and immunohistochemistry. The role of type I IFN in PAH in vivo was determined using type I IFN receptor knockout (IFNAR1) mice. Human lung cells responded to types I and II but not III IFN correlating with relevant receptor expression. Type I, II, and III IFN levels were elevated in serum of patients with systemic sclerosis associated PAH. Serum interferon ¿ inducible protein 10 (IP10; CXCL10) and endothelin 1 were raised and strongly correlated together. IP10 correlated positively with pulmonary hemodynamics and serum brain natriuretic peptide and negatively with 6-minute walk test and cardiac index. Endothelial cells grown out of the blood of PAH patients were more sensitive to the effects of type I IFN than cells from healthy donors. PAH lung demonstrated increased IFNAR1 protein levels. IFNAR1 mice were protected from the effects of hypoxia on the right heart, vascular remodeling, and raised serum endothelin 1 levels. CONCLUSIONS:: These data indicate that type I IFN, via an action of IFNAR1, mediates PAH. © 2014 American Heart Association, Inc.

DOI 10.1161/CIRCRESAHA.114.302221
Citations Scopus - 39
2014 Mahmutovic-Persson I, Akbarshahi H, Bartlett NW, Glanville N, Johnston SL, Brandelius A, Uller L, 'Inhaled dsRNA and rhinovirus evoke neutrophilic exacerbation and lung expression of thymic stromal lymphopoietin in allergic mice with established experimental asthma', Allergy: European Journal of Allergy and Clinical Immunology, 69 348-358 (2014)

Background: Rhinovirus infection or dsRNA stimulation increased thymic stromal lymphopoietin (TSLP), an upstream pro-allergic cytokine, in asthmatic bronchial epithelial cells. We... [more]

Background: Rhinovirus infection or dsRNA stimulation increased thymic stromal lymphopoietin (TSLP), an upstream pro-allergic cytokine, in asthmatic bronchial epithelial cells. We hypothesized that dsRNA challenges superimposed on established experimental allergic asthma constitute a useful exacerbation model. We further hypothesized that TSLP is induced at dsRNA- and rhinoviral infection-induced exacerbations. Methods: Allergic mice were challenged with OVA followed by three daily intranasal challenges with dsRNA or saline. Bronchoalveolar lavage fluid (BALF) was analysed for total protein, lactate dehydrogenase (LDH), CXCL1/KC, CCL2/MCP-1 and differential cell counts. Lung tissue histology, neutrophils and TSLP, TNF-a, IFN-ß and IFN-¿ mRNA were examined. Alternatively, allergen-challenged mice received intranasal rhinovirus-(RV)-1B followed by lung TSLP immunostaining. Results: In mice with allergic airway inflammation, dsRNA challenges caused a significant exacerbation increasing lung tissue inflammation score and tissue neutrophilia. Bronchoalveolar lavage fluid neutrophils, total protein, LDH, CXCL1/KC and CCL2/MCP-1 were also increased (P < 0.01), and so were lung tissue expressions of TNF-a, IFN-¿ and TSLP (P < 0.01), but IFN-ß was not increased. TSLP, IFN-¿ and LDH were not increased by allergen or dsRNA challenges alone, but increased exclusively at exacerbations. RV1B infection-induced exacerbation also increased lung tissue TSLP (P < 0.05). Conclusions: dsRNA-induced exacerbation in mice with experimental asthma involved general inflammation, cytokines and interferons, in agreement with previous observations in exacerbating human asthma. Additionally, both dsRNA and RV1B infection increased lung TSLP exclusively at exacerbations. Our data suggest that dsRNA challenges superimposed on allergic inflammation are suited for pharmacological studies of asthma exacerbations including the regulation of lung tissue TSLP, TNF-a, IFN-ß and IFN-¿. © 2013 The Authors. Allergy published by John Wiley & Sons Ltd.

DOI 10.1111/all.12329
Citations Scopus - 19
2014 Jackson DJ, Makrinioti H, Rana BMJ, Shamji BWH, Trujillo-Torralbo MB, Footitt J, et al., 'IL-33-Dependent type 2 inflammation during rhinovirus-induced asthma exacerbations in vivo', American Journal of Respiratory and Critical Care Medicine, 190 1373-1382 (2014)

Copyright © 2014 by the American Thoracic Society. Rationale: Rhinoviruses are the major cause of asthma exacerbations; however, its underlying mechanisms are poorly understood. ... [more]

Copyright © 2014 by the American Thoracic Society. Rationale: Rhinoviruses are the major cause of asthma exacerbations; however, its underlying mechanisms are poorly understood. We hypothesized that the epithelial cell-derived cytokine IL-33 plays a central role in exacerbation pathogenesis through augmentation of type 2 inflammation. Objectives: To assess whether rhinovirus induces a type 2 inflammatory response in asthma in vivo and to define a role for IL-33 in this pathway. Methods: We used a human experimental model of rhinovirus infection and novel airway sampling techniques to measure IL-4, IL-5, IL-13, and IL-33 levels in the asthmatic and healthy airways during a rhinovirus infection. Additionally, we cultured human T cells and type 2 innate lymphoid cells (ILC2s) with the supernatants of rhinovirusinfected bronchial epithelial cells (BECs) to assess type 2 cytokine production in the presence or absence of IL-33 receptor blockade. Measurements and Main Results: IL-4, IL-5, IL-13, and IL-33 are all induced by rhinovirus in the asthmatic airway in vivo and relate to exacerbation severity. Further, induction of IL-33 correlates with viral load and IL-5 and IL-13 levels. Rhinovirus infection of human primary BECs induced IL-33, and culture of human T cells and ILC2s with supernatants of rhinovirus-infected BECs strongly induced type 2 cytokines. This induction was entirely dependent on IL-33. Conclusions: IL-33 and type 2 cytokines are induced during a rhinovirus-induced asthma exacerbation in vivo. Virus-induced IL-33 and IL-33-responsive T cells and ILC2s are key mechanistic links between viral infection and exacerbation of asthma. IL-33 inhibition is a novel therapeutic approach for asthma exacerbations.

DOI 10.1164/rccm.201406-1039OC
Citations Scopus - 114
2014 Beale J, Jayaraman A, Jackson DJ, Macintyre JDR, Edwards MR, Walton RP, et al., 'Rhinovirus-induced IL-25 in asthma exacerbation drives type 2 immunity and allergic pulmonary inflammation', Science Translational Medicine, 6 (2014)

© 2014, American Association for the Advancement of Science. All rights reserved. Rhinoviruses (RVs), which are the most common cause of virally induced asthma exacerbations, acc... [more]

© 2014, American Association for the Advancement of Science. All rights reserved. Rhinoviruses (RVs), which are the most common cause of virally induced asthma exacerbations, account for much of the burden of asthma in terms of morbidity, mortality, and associated cost. Interleukin-25 (IL-25) activates type 2-driven inflammation and is therefore potentially important in virally induced asthma exacerbations. To investigate this, we examined whether RV-induced IL-25 could contribute to asthma exacerbations. RV-infected cultured asthmatic bronchial epithelial cells exhibited a heightened intrinsic capacity for IL-25 expression, which correlated with donor atopic status. In vivo human IL-25 expression was greater in asthmatics at baseline and during experimental RV infection. In addition, inmice, RV infection induced IL-25 expression and augmented allergen-induced IL-25. Blockade of the IL-25 receptor reduced many RV-induced exacerbation-specific responses including type 2 cytokine expression, mucus production, and recruitment of eosinophils, neutrophils, basophils, and T and non-T type 2 cells. Therefore, asthmatic epithelial cells have an increased intrinsic capacity for expression of a pro-type 2 cytokine in response to a viral infection, and IL-25 is a key mediator of RV-induced exacerbations of pulmonary inflammation.

DOI 10.1126/scitranslmed.3009124
Citations Scopus - 80
2014 Jayaraman A, Jackson DJ, Message SD, Pearson RM, Aniscenko J, Caramori G, et al., 'IL-15 complexes induce NK- and T-cell responses independent of type i IFN signaling during rhinovirus infection', Mucosal Immunology, 7 1151-1164 (2014)

Rhinoviruses are among the most common viruses to infect man, causing a range of serious respiratory diseases including exacerbations of asthma and COPD. Type I IFN and IL-15 are ... [more]

Rhinoviruses are among the most common viruses to infect man, causing a range of serious respiratory diseases including exacerbations of asthma and COPD. Type I IFN and IL-15 are thought to be required for antiviral immunity; however, their function during rhinovirus infection in vivo is undefined. In RV-infected human volunteers, IL-15 protein expression in fluid from the nasal mucosa and in bronchial biopsies was increased. In mice, RV induced type I IFN-dependent expressions of IL-15 and IL-15R, which in turn were required for NK- and CD8 + T-cell responses. Treatment with IL-15-IL-15R complexes (IL-15c) boosted RV-induced expression of IL-15, IL-15Ra, IFN-¿, CXCL9, and CXCL10 followed by recruitment of activated, IFN-¿-expressing NK, CD8 + , and CD4 + T cells. Treating infected IFNAR1 -/- mice with IL-15c similarly increased IL-15, IL-15Ra, IFN-¿, and CXCL9 (but not CXCL10) expression also followed by NK-, CD8 + -, and CD4 + -T-cell recruitment and activation. We have demonstrated that type I IFN-induced IFN-¿ and cellular immunity to RV was mediated by IL-15 and IL-15Ra. Importantly, we also show that IL-15 could be induced via a type I IFN-independent mechanism by IL-15 complex treatment, which in turn was sufficient to drive IFN-¿ expression and lymphocyte responses. © 2014 Society for Mucosal Immunology.

DOI 10.1038/mi.2014.2
Citations Scopus - 9
2014 Toussaint M, Singanayagam A, Johnston SL, Bartlett N, 'Role Of Interleukine-33 In Rhinovirus-Induced Allergic Asthma Exacerbation', Journal of Allergy and Clinical Immunology, 133 AB52-AB52 (2014)
DOI 10.1016/j.jaci.2013.12.211
2014 Jayaraman A, Bartlett N, Johnston SL, 'Innate and Adaptive Lymphocyte Responses In a Mouse Model Of Rhinovirus-Induced Asthma Exacerbation', Journal of Allergy and Clinical Immunology, 133 AB135-AB135 (2014)
DOI 10.1016/j.jaci.2013.12.501
2013 McLean GR, Walton RP, Shetty S, Peel TJ, Paktiawal N, Kebadze T, et al., 'Corrigendum to: "Rhinovirus infections and immunisation induce cross-serotype reactive antibodies to VP1" [Antiviral Res. 95(3) (2012) 193-201]', Antiviral Research, 97 381 (2013)
DOI 10.1016/j.antiviral.2013.02.004
2013 Traub S, Nikonova A, Carruthers A, Dunmore R, Vousden KA, Gogsadze L, et al., 'An Anti-Human ICAM-1 Antibody Inhibits Rhinovirus-Induced Exacerbations of Lung Inflammation', PLoS Pathogens, 9 (2013)

Human rhinoviruses (HRV) cause the majority of common colds and acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Effective therapies are urgently ne... [more]

Human rhinoviruses (HRV) cause the majority of common colds and acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Effective therapies are urgently needed, but no licensed treatments or vaccines currently exist. Of the 100 identified serotypes, ~90% bind domain 1 of human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor, making this an attractive target for development of therapies; however, ICAM-1 domain 1 is also required for host defence and regulation of cell trafficking, principally via its major ligand LFA-1. Using a mouse anti-human ICAM-1 antibody (14C11) that specifically binds domain 1 of human ICAM-1, we show that 14C11 administered topically or systemically prevented entry of two major groups of rhinoviruses, HRV16 and HRV14, and reduced cellular inflammation, pro-inflammatory cytokine induction and virus load in vivo. 14C11 also reduced cellular inflammation and Th2 cytokine/chemokine production in a model of major group HRV-induced asthma exacerbation. Interestingly, 14C11 did not prevent cell adhesion via human ICAM-1/LFA-1 interactions in vitro, suggesting the epitope targeted by 14C11 was specific for viral entry. Thus a human ICAM-1 domain-1-specific antibody can prevent major group HRV entry and induction of airway inflammation in vivo. © 2013 Traub et al.

DOI 10.1371/journal.ppat.1003520
Citations Scopus - 35
2013 Glanville N, Mclean GR, Guy B, Lecouturier V, Berry C, Girerd Y, et al., 'Cross-Serotype Immunity Induced by Immunization with a Conserved Rhinovirus Capsid Protein', PLoS Pathogens, 9 (2013)

Human rhinovirus (RV) infections are the principle cause of common colds and precipitate asthma and COPD exacerbations. There is currently no RV vaccine, largely due to the existe... [more]

Human rhinovirus (RV) infections are the principle cause of common colds and precipitate asthma and COPD exacerbations. There is currently no RV vaccine, largely due to the existence of ~150 strains. We aimed to define highly conserved areas of the RV proteome and test their usefulness as candidate antigens for a broadly cross-reactive vaccine, using a mouse infection model. Regions of the VP0 (VP4+VP2) capsid protein were identified as having high homology across RVs. Immunization with a recombinant VP0 combined with a Th1 promoting adjuvant induced systemic, antigen specific, cross-serotype, cellular and humoral immune responses. Similar cross-reactive responses were observed in the lungs of immunized mice after infection with heterologous RV strains. Immunization enhanced the generation of heterosubtypic neutralizing antibodies and lung memory T cells, and caused more rapid virus clearance. Conserved domains of the RV capsid therefore induce cross-reactive immune responses and represent candidates for a subunit RV vaccine. © 2013 Glanville et al.

DOI 10.1371/journal.ppat.1003669
Citations Scopus - 28
2013 Glanville N, Message SD, Walton RP, Pearson RM, Parker HL, Laza-Stanca V, et al., '¿dT cells suppress inflammation and disease during rhinovirus-induced asthma exacerbations', Mucosal Immunology, 6 1091-1100 (2013)

Most asthma exacerbations are triggered by virus infections, the majority being caused by human rhinoviruses (RV). In mouse models, ¿dT cells have been previously demonstrated to... [more]

Most asthma exacerbations are triggered by virus infections, the majority being caused by human rhinoviruses (RV). In mouse models, ¿dT cells have been previously demonstrated to influence allergen-driven airways hyper-reactivity (AHR) and can have antiviral activity, implicating them as prime candidates in the pathogenesis of asthma exacerbations. To explore this, we have used human and mouse models of experimental RV-induced asthma exacerbations to examine ¿dT-cell responses and determine their role in the immune response and associated airways disease. In humans, airway ¿dT-cell numbers were increased in asthmatic vs. healthy control subjects during experimental infection. Airway and blood ¿dT-cell numbers were associated with increased airways obstruction and AHR. Airway ¿dT-cell number was also positively correlated with bronchoalveolar lavage (BAL) virus load and BAL eosinophils and lymphocytes during RV infection. Consistent with our observations of RV-induced asthma exacerbations in humans, infection of mice with allergic airways inflammation increased lung ¿dT-cell number and activation. Inhibiting ¿dT-cell responses using anti-¿dTCR (anti-¿dT-cell receptor) antibody treatment in the mouse asthma exacerbation model increased AHR and airway T helper type 2 cell recruitment and eosinophilia, providing evidence that ¿dT cells are negative regulators of airways inflammation and disease in RV-induced asthma exacerbations.

DOI 10.1038/mi.2013.3
Citations Scopus - 14
2013 Brignull LM, Czimmerer Z, Saidi H, Daniel B, Villela I, Bartlett NW, et al., 'Reprogramming of lysosomal gene expression by interleukin-4 and Stat6', BMC Genomics, 14 (2013)

Background: Lysosomes play important roles in multiple aspects of physiology, but the problem of how the transcription of lysosomal genes is coordinated remains incompletely under... [more]

Background: Lysosomes play important roles in multiple aspects of physiology, but the problem of how the transcription of lysosomal genes is coordinated remains incompletely understood. The goal of this study was to illuminate the physiological contexts in which lysosomal genes are coordinately regulated and to identify transcription factors involved in this control.Results: As transcription factors and their target genes are often co-regulated, we performed meta-analyses of array-based expression data to identify regulators whose mRNA profiles are highly correlated with those of a core set of lysosomal genes. Among the ~50 transcription factors that rank highest by this measure, 65% are involved in differentiation or development, and 22% have been implicated in interferon signaling. The most strongly correlated candidate was Stat6, a factor commonly activated by interleukin-4 (IL-4) or IL-13. Publicly available chromatin immunoprecipitation (ChIP) data from alternatively activated mouse macrophages show that lysosomal genes are overrepresented among Stat6-bound targets. Quantification of RNA from wild-type and Stat6-deficient cells indicates that Stat6 promotes the expression of over 100 lysosomal genes, including hydrolases, subunits of the vacuolar H + ATPase and trafficking factors. While IL-4 inhibits and activates different sets of lysosomal genes, Stat6 mediates only the activating effects of IL-4, by promoting increased expression and by neutralizing undefined inhibitory signals induced by IL-4.Conclusions: The current data establish Stat6 as a broadly acting regulator of lysosomal gene expression in mouse macrophages. Other regulators whose expression correlates with lysosomal genes suggest that lysosome function is frequently re-programmed during differentiation, development and interferon signaling. © 2013 Brignull et al.; licensee BioMed Central Ltd.

DOI 10.1186/1471-2164-14-853
Citations Scopus - 8
2013 Collison AM, Hatchwell LM, Verrills NM, Wark PA, Pereira De Siqueira AL, Tooze MK, et al., 'The E3 ubiquitin ligase midline 1 promotes allergen and rhinovirus-induced asthma by inhibiting protein phosphatase 2A activity', Nature Medicine, 19 232-237 (2013) [C1]
Citations Scopus - 65Web of Science - 63
Co-authors Peter Wark, Adam Collison, Nikki Verrills, Joerg Mattes, Paul Foster
2012 McLean GR, Walton RP, Shetty S, Paktiawal N, Kebadze T, Gogsadze L, et al., 'Rhinovirus infections and immunisation induce cross-serotype reactive antibodies to VP1', Antiviral Research, 95 193-201 (2012)

Rhinoviruses (RVs) are ubiquitous human respiratory viruses, the major cause of common colds, acute exacerbations of asthma and other respiratory diseases. The development of anti... [more]

Rhinoviruses (RVs) are ubiquitous human respiratory viruses, the major cause of common colds, acute exacerbations of asthma and other respiratory diseases. The development of antibodies to RV following primary infection is poorly understood and there is currently no RV vaccine available. We therefore used mouse models of intranasal RV infection and immunisation to determine the induction, magnitude and specificity of antibody responses. Strong cross-serotype RV-specific IgG responses in serum and bronchoalveolar lavage were induced towards the RV capsid protein VP1. IgA responses were weaker, requiring two infections to generate detectable RV-specific binding. Similarly two or more RV infections were necessary to induce neutralising antibodies. Immunisation strategies boosted homotypic as well as inducing cross-serotype neutralising IgG responses. We conclude that VP1 based antigens combined with adjuvants may permit successful antibody-mediated vaccine design and development. © 2012 Elsevier B.V.

DOI 10.1016/j.antiviral.2012.06.006
Citations Scopus - 22
2012 Edwards MR, Bartlett NW, Hussell T, Openshaw P, Johnston SL, 'The microbiology of asthma', Nature Reviews Microbiology, 10 459-471 (2012)

Asthma remains an important human disease that is responsible for substantial worldwide morbidity and mortality. The causes of asthma are multifactorial and include a complex mix ... [more]

Asthma remains an important human disease that is responsible for substantial worldwide morbidity and mortality. The causes of asthma are multifactorial and include a complex mix of environmental, immunological and host genetic factors. In addition, epidemiological studies show strong associations between asthma and infection with respiratory pathogens, including common respiratory viruses such as rhinoviruses, human respiratory syncytial virus, adenoviruses, coronaviruses and influenza viruses, as well as bacteria (including atypical bacteria) and fungi. In this Review, we describe the many roles of microorganisms in the risk of developing asthma and in the pathogenesis of and protection against the disease, and we discuss the mechanisms by which infections affect the severity and prevalence of asthma. © 2012 Macmillan Publishers Limited. All rights reserved.

DOI 10.1038/nrmicro2801
Citations Scopus - 69
2012 Bartlett NW, Slater L, Glanville N, Haas JJ, Caramori G, Casolari P, et al., 'Defining critical roles for NF-¿B p65 and type I interferon in innate immunity to rhinovirus', EMBO Molecular Medicine, 4 1244-1260 (2012)

The importance of NF-¿B activation and deficient anti-viral interferon induction in the pathogenesis of rhinovirus-induced asthma exacerbations is poorly understood. We provide t... [more]

The importance of NF-¿B activation and deficient anti-viral interferon induction in the pathogenesis of rhinovirus-induced asthma exacerbations is poorly understood. We provide the first in vivo evidence in man and mouse that rhinovirus infection enhanced bronchial epithelial cell NF-¿B p65 nuclear expression, NF-¿B p65 DNA binding in lung tissue and NF-¿B-regulated airway inflammation. In vitro inhibition of NF-¿B reduced rhinovirus-induced pro-inflammatory cytokines but did not affect type I/III interferon induction. Rhinovirus-infected p65-deficient mice exhibited reduced neutrophilic inflammation, yet interferon induction, antiviral responses and virus loads were unaffected, indicating that NF-¿B p65 is required for pro-inflammatory responses, but redundant in interferon induction by rhinoviruses in vivo. Conversely, IFNAR1 -/- mice exhibited enhanced neutrophilic inflammation with impaired antiviral immunity and increased rhinovirus replication, demonstrating that interferon signalling was critical to antiviral immunity. We thus provide new mechanistic insights into rhinovirus infection and demonstrate the therapeutic potential of targeting NF-¿B p65 (to suppress inflammation but preserve anti-viral immunity) and type I IFN signalling (to enhance deficient anti-viral immunity) to treat rhinovirus-induced exacerbations of airway diseases. © 2012 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

DOI 10.1002/emmm.201201650
Citations Scopus - 36
2012 Hewson CA, Haas JJ, Bartlett NW, Message SD, Laza-Stanca V, Kebadze T, et al., 'Rhinovirus induces MUC5AC in a human infection model and in vitro via NF-¿B and EGFR pathways (European Respiratory Journal (2010) 36, (1425-1435))', European Respiratory Journal, 39 793 (2012)
DOI 10.1183/09031936.50026910
2012 Kuo C, Lim S, King NJC, Bartlett NW, Walton RP, Zhu J, et al., 'Erratum: Rhinovirus infection induces expression of airway remodelling factors in vitro and in vivo (Respirology (2011) 16 (367-377))', Respirology, 17 192 (2012)
DOI 10.1111/j.1440-1843.2011.02110.x
2011 Telcian AG, Laza-Stanca V, Edwards MR, Harker JA, Wang H, Bartlett NW, et al., 'RSV-induced bronchial epithelial cell PD-L1 expression inhibits CD8

Respiratory syncytial virus (RSV) is a major cause of bronchiolitis in infants. It is also responsible for high morbidity and mortality in the elderly. Programmed death ligands (P... [more]

Respiratory syncytial virus (RSV) is a major cause of bronchiolitis in infants. It is also responsible for high morbidity and mortality in the elderly. Programmed death ligands (PD-Ls) on antigen-presenting cells interact with receptors on T cells to regulate immune responses. The programmed death receptor-ligand 1/programmed death receptor 1 (PD-L1-PD-1) pathway is inhibitory in chronic viral infections, but its role in acute viral infections is unclear. We hypothesized that bronchial epithelial cell (BEC) expression of PD-Ls would inhibit local effector CD8 + T cell function. We report that RSV infection of primary human BECs strongly induces PD-L1 expression. In a co-culture system of BECs with purified CD8 + T cells, we demonstrated that RSV-infected BECs increased CD8 + T cell activation, proliferation, and antiviral function. Blocking PD-L1 on RSV-infected BECs cocultured with CD8 + T cells enhanced CD8 + T cell IFN-¿, IL-2, and granzyme B production. It also decreased the virus load of the BECs. Based on our findings, we believe therapeutic strategies that target the PD-L1-PD-1 pathway might increase antiviral immune responses to RSV and other acute virus infections. © The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.

DOI 10.1093/infdis/jiq020
Citations Scopus - 33
2011 Kuo C, Lim S, King NJC, Bartlett NW, Walton RP, Zhu J, et al., 'Rhinovirus infection induces expression of airway remodelling factors in vitro and in vivo', Respirology, 16 367-377 (2011)

Background and objective: A hallmark of asthma is airway remodelling, which includes increased deposition of extracellular matrix (ECM) protein. Viral infections may promote the d... [more]

Background and objective: A hallmark of asthma is airway remodelling, which includes increased deposition of extracellular matrix (ECM) protein. Viral infections may promote the development of asthma and are the most common causes of asthma exacerbations. We evaluated whether rhinovirus (RV) infection induces airway remodelling, as assessed by ECM deposition. Methods: Primary human bronchial epithelial cells and lung parenchymal fibroblasts were infected with RV-2 or RV-16, or treated with RV-16 RNA, imiquimod (Toll-like receptor (TLR) 7/8 agonist) or polyinosinic: polycytidylic acid (poly I: C) (activator of TLR 3, retinoic-acid-inducible protein I and melanoma-differentiated-associated gene 5). Changes in ECM proteins and their transcription were measured by ELISA and quantitative real-time PCR. In addition, gene expression for ECM proteins was assessed in a mouse model of RV infection. Results: RV infection increased deposition of the ECM protein, perlecan, by human bronchial epithelial cells, and collagen V and matrix-bound vascular endothelial growth factor were increased in both human bronchial epithelial cell and fibroblast cultures. Purified RV-16 RNA, poly I: C and imiquimod induced similar increases in ECM deposition to those observed with RV-infected fibroblasts. However, only poly I: C induced ECM deposition by bronchial epithelial cells, suggesting that RV-induced ECM deposition is mediated through TLR. Furthermore, gene expression for fibronectin and collagen I was increased in lung homogenates of mice infected with RV-1b. Conclusions: RV infection and TLR ligands promote ECM deposition in isolated cell systems and RV induces ECM gene expression in vivo, thus demonstrating that RV has the potential to contribute to remodelling of the airways through induction of ECM deposition. Airway remodelling, as indicated by increased extracellular matrix production, was induced by rhinovirus in both in vitro and in vivo models. This study provides important information on the aetiology of asthmatic airway remodelling, which is integral to the pathogenesis of asthma. © 2011 Asian Pacific Society of Respirology.

DOI 10.1111/j.1440-1843.2010.01918.x
Citations Scopus - 27
2010 Hewson CA, Haas JJ, Bartlett NW, Message SD, Laza-Stanca V, Kebadze T, et al., 'Rhinovirus induces MUC5AC in a human infection model and in vitro via NF-¿B and EGFR pathways', European Respiratory Journal, 36 1425-1435 (2010)

Rhinovirus (RV) infections are the major cause of asthma exacerbations, the major cause of morbidity and mortality in asthma. MUC5AC is the major mucin produced by bronchial epith... [more]

Rhinovirus (RV) infections are the major cause of asthma exacerbations, the major cause of morbidity and mortality in asthma. MUC5AC is the major mucin produced by bronchial epithelial cells. Whether RV infection upregulates MUC5AC in vivo is unknown and the molecular mechanisms involved are incompletely understood. We investigated RV induction of MUC5AC in vivo and in vitro to identify targets for development of new therapies for asthma exacerbations. RV infection increased MUC5AC release in normal and asthmatic volunteers experimentally infected with RV-16, and in asthmatic, but not normal, subjects, this was related to virus load. Bronchial epithelial cells were confirmed a source of MUC5AC in vivo. RV induction of MUC5AC in bronchial epithelial cells in vitro occurred via nuclear factor-kB-dependent induction of matrix metalloproteinase-mediated transforming growth factor-a release, thereby activating an epidermal growth factor receptor-dependent cascade culminating, via mitogen-activated protein kinase activation, in specificity protein-1 transactivation of the MUC5AC promoter. RV induction of MUC5AC may be an important mechanism in RV-induced asthma exacerbations in vivo. Revealing the complex serial signalling cascade involved identifies targets for development of pharmacologic intervention to treat mucus hypersecretion in RV-induced illness. Copyright©ERS 2010.

DOI 10.1183/09031936.00026910
Citations Scopus - 48
2010 Slater L, Bartlett NW, Haas JJ, Zhu J, Message SD, Walton RP, et al., 'Co-ordinated role of TLR3, RIG-I and MDA5 in the innate response to rhinovirus in bronchial epithelium', PLoS Pathogens, 6 (2010)

The relative roles of the endosomal TLR3/7/8 versus the intracellular RNA helicases RIG-I and MDA5 in viral infection is much debated. We investigated the roles of each pattern re... [more]

The relative roles of the endosomal TLR3/7/8 versus the intracellular RNA helicases RIG-I and MDA5 in viral infection is much debated. We investigated the roles of each pattern recognition receptor in rhinovirus infection using primary bronchial epithelial cells. TLR3 was constitutively expressed; however, RIG-I and MDA5 were inducible by 8-12 h following rhinovirus infection. Bronchial epithelial tissue from normal volunteers challenged with rhinovirus in vivo exhibited low levels of RIG-I and MDA5 that were increased at day 4 post infection. Inhibition of TLR3, RIG-I and MDA5 by siRNA reduced innate cytokine mRNA, and increased rhinovirus replication. Inhibition of TLR3 and TRIF using siRNA reduced rhinovirus induced RNA helicases. Furthermore, IFNAR1 deficient mice exhibited RIG-I and MDA5 induction early during RV1B infection in an interferon independent manner. Hence anti-viral defense within bronchial epithelium requires co-ordinated recognition of rhinovirus infection, initially via TLR3/TRIF and later via inducible RNA helicases. © 2010 Slater et al.

DOI 10.1371/journal.ppat.1001178
Citations Scopus - 131
2009 Edwards MR, Bartlett NW, Clarke D, Birrell M, Belvisi M, Johnston SL, 'Targeting the NF-¿B pathway in asthma and chronic obstructive pulmonary disease', Pharmacology and Therapeutics, 121 1-13 (2009)

Asthma and chronic obstructive pulmonary disease are inflammatory lung disorders responsible for significant morbidity and mortality worldwide. While the importance of allergic re... [more]

Asthma and chronic obstructive pulmonary disease are inflammatory lung disorders responsible for significant morbidity and mortality worldwide. While the importance of allergic responses in asthma is well known, respiratory viral and bacterial infections and pollutants especially cigarette smoke are important factors in the pathogenesis of both diseases. Corticosteroid treatment remains the first preference of treatment in either disease, however these therapies are not always completely effective, and are associated with side effects and steroid resistance. Due to such limitations, development of new treatments represents a major goal for both the pharmaceutical industry and academic researchers. There are now excellent reasons to promote NF-¿B signalling intermediates and Rel family proteins as potential therapeutic targets for both asthma and chronic obstructive pulmonary disease. This notion is supported by the fact that much of the underlying inflammation of both diseases independent of stimuli, is mediated at least in part, by NF-¿B mediated signalling events in several cell types. Also, a range of inhibitors of NF-¿B signalling intermediates are now available, including DNA oligonucleotides and DNA-peptide molecules that act as NF-¿B decoy sequences, small molecule inhibitors such as IKK-ß inhibitors, and proteasome inhibitors affecting NF-¿B signalling, that have either shown promise in animal models or have begun clinical trials in other disorders. This review will focus on the role of NF-¿B in both diseases, will discuss its suitability as a target, and will highlight recent key studies that support the potential of NF-¿B as a therapeutic target in these two important inflammatory lung diseases. © 2008 Elsevier Inc. All rights reserved.

DOI 10.1016/j.pharmthera.2008.09.003
Citations Scopus - 193
2009 Bartlett NW, McLean GR, Chang YS, Johnston SL, 'Genetics and epidemiology: Asthma and infection', Current Opinion in Allergy and Clinical Immunology, 9 395-400 (2009)

PURPOSE OF REVIEW: This review will consider how recent epidemiological studies have helped reveal the role of respiratory infection in asthma inception early in life. We will als... [more]

PURPOSE OF REVIEW: This review will consider how recent epidemiological studies have helped reveal the role of respiratory infection in asthma inception early in life. We will also review the importance of respiratory infections and exacerbations of asthma and will discuss genetic factors controlling host immune responses to respiratory infection and the influence these may exert on asthma pathogenesis. RECENT FINDINGS: Birth cohort studies have demonstrated bidirectional relationships between early life severe respiratory infections and asthma development; however, whether there is a clear causal role for severe respiratory infection early in life leading directly to asthma development remains unknown. The role of rhinovirus infection in asthma exacerbations has been investigated experimentally, with asthmatic patients exhibiting greater clinical illness severity, which was related to increased virus load and lower airways inflammation. Polymorphisms in genes involved in innate, antiviral and Th1 and Th2 immune responses have been linked to asthma as well as to early life severe respiratory infections, suggesting that host factors are likely to play an important role in their association. SUMMARY: Early in life, such genetic factors contribute to the risk of severe lower respiratory tract viral infection as well as later development of wheezing illness and asthma. Respiratory viruses are also the most frequent cause of asthma exacerbations at all ages. © 2009 Lippincott Williams & Wilkins, Inc.

DOI 10.1097/ACI.0b013e32833066fa
Citations Scopus - 35
2008 Jacobs N, Bartlett NW, Clark RH, Smith GL, 'Vaccinia virus lacking the Bcl-2-like protein N1 induces a stronger natural killer cell response to infection', Journal of General Virology, 89 2877-2881 (2008)

The vaccinia virus (VACV) N1 protein is an intracellular virulence factor that has a Bcl-2-like structure and inhibits both apoptosis and signalling from the interleukin 1 recepto... [more]

The vaccinia virus (VACV) N1 protein is an intracellular virulence factor that has a Bcl-2-like structure and inhibits both apoptosis and signalling from the interleukin 1 receptor, leading to nuclear factor kappa B activation. Here, we investigated the immune response to intranasal infection with a virus lacking the N1L gene (v¿N1L) compared with control viruses expressing N1L. Data presented show that deletion of N1L did not affect the proportion of CD4 + and CD8 + T cells infiltrating the lungs or the cytotoxic T-cell activity of these cells. However, v¿N1L induced an increased local natural killer cell activity between days 4 and 6 post-infection. In addition, in the absence of N1 the host inflammatory infiltrate was characterized by a reduced proportion of lymphocytes bearing the early activation marker CD69. Notably, there was a good correlation between the level of CD69 expression and weight loss. The implications of these findings are discussed. © 2008 SGM.

DOI 10.1099/vir.0.2008/004119-0
Citations Scopus - 19
2008 Bartlett NW, Walton RP, Edwards MR, Aniscenko J, Caramori G, Zhu J, et al., 'Mouse models of rhinovirus-induced disease and exacerbation of allergic airway inflammation', Nature Medicine, 14 199-204 (2008)

Rhinoviruses cause serious morbidity and mortality as the major etiological agents of asthma exacerbations and the common cold. A major obstacle to understanding disease pathogene... [more]

Rhinoviruses cause serious morbidity and mortality as the major etiological agents of asthma exacerbations and the common cold. A major obstacle to understanding disease pathogenesis and to the development of effective therapies has been the lack of a small-animal model for rhinovirus infection. Of the 100 known rhinovirus serotypes, 90% (the major group) use human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor and do not bind mouse ICAM-1; the remaining 10% (the minor group) use a member of the low-density lipoprotein receptor family and can bind the mouse counterpart. Here we describe three novel mouse models of rhinovirus infection: minor-group rhinovirus infection of BALB/c mice, major-group rhinovirus infection of transgenic BALB/c mice expressing a mouse-human ICAM-1 chimera and rhinovirus-induced exacerbation of allergic airway inflammation. These models have features similar to those observed in rhinovirus infection in humans, including augmentation of allergic airway inflammation, and will be useful in the development of future therapies for colds and asthma exacerbations. © 2008 Nature Publishing Group.

DOI 10.1038/nm1713
Citations Scopus - 201
2007 Cooray S, Bahar MW, Abrescia NGA, McVey CE, Bartlett NW, Chen RAJ, et al., 'Functional and structural studies of the vaccinia virus virulence factor N1 reveal a Bcl-2-like anti-apoptotic protein', Journal of General Virology, 88 1656-1666 (2007)

Vaccinia virus (VACV) encodes many immunomodulatory proteins, including inhibitors of apoptosis and modulators of innate immune signalling. VACV protein N1 is an intracellular hom... [more]

Vaccinia virus (VACV) encodes many immunomodulatory proteins, including inhibitors of apoptosis and modulators of innate immune signalling. VACV protein N1 is an intracellular homodimer that contributes to virus virulence and was reported to inhibit nuclear factor (NF)-¿B signalling. However, analysis of NF-¿B signalling in cells infected with recombinant viruses with or without the N1L gene showed no difference in NF-¿B-dependent gene expression. Given that N1 promotes virus virulence, other possible functions of N1 were investigated and this revealed that N1 is an inhibitor of apoptosis in cells transfected with the N1L gene and in the context of VACV infection. In support of this finding virally expressed N1 co-precipitated with endogenous pro-apoptotic Bcl-2 proteins Bid, Bad and Bax as well as with Bad and Bax expressed by transfection. In addition, the crystal structure of N1 was solved to 2.9 Å resolution (0.29 nm). Remarkably, although N1 shows no sequence similarity to cellular proteins, its three-dimensional structure closely resembles Bcl-x L and other members of the Bel-2 protein family. The structure also reveals that N1 has a constitutively open surface groove similar to the grooves of other anti-apoptotic Bcl-2 proteins, which bind the BH3 motifs of pro-apoptotic Bcl-2 family members. Molecular modelling of BH3 peptides into the N1 surface groove, together with analysis of their physico-chemical properties, suggests a mechanism for the specificity of peptide recognition. This study illustrates the importance of the evolutionary conservation of structure, rather than sequence, in protein function and reveals a novel anti-apoptotic protein from orthopoxviruses. © 2007 SGM.

DOI 10.1099/vir.0.82772-0
Citations Scopus - 115
2006 Contoli M, Message SD, Laza-Stanca V, Edwards MR, Wark PA, Bartlett N, et al., 'Role of eficient type III interferon-lambda production in asthma exacerbations', Nature Medicine, 12 1023-1026 (2006) [C1]
DOI 10.1038/nm1462
Citations Scopus - 620Web of Science - 561
Co-authors Peter Wark
2006 Clark RH, Kenyon JC, Bartlett NW, Tscharke DC, Smith GL, 'Detection of gene A41L enhances vaccinia virus immunogenicity and vaccine efficacy', Journal of General Virology, 87 29-38 (2006)

Vaccinia virus (VACV) is the vaccine that was used to eradicate smallpox and is being developed as a recombinant vaccine for other pathogens. Removal of genes encoding immunomodul... [more]

Vaccinia virus (VACV) is the vaccine that was used to eradicate smallpox and is being developed as a recombinant vaccine for other pathogens. Removal of genes encoding immunomodulatory proteins expressed by VACV may enhance virus immunogenicity and improve its potential as a vaccine. Protein A41 is a candidate for removal, having sequence similarity to the VACV chemokine-binding protein, vCKBP, and an association with reduced inflammation during dermal infection. Here, it is shown that, at low doses, VACV strain Western Reserve (WR) lacking A41L (v¿A41L) was slightly more virulent than wild-type and revertant controls after intranasal infection of BALB/c mice. The primary immune response to v¿A41L was marked by an increase in the percentage of VACV-specific gamma interferon-producing CD8 + T cells and enhancement of cytotoxic T-cell responses in the spleen. However, this augmentation of cellular response was not seen in lung infiltrates. Splenic CD8 + T-cell responses were also enhanced when VACV strain modified vaccinia virus Ankara (MVA) lacking A41L was used to immunize mice. Lastly, immunization with VACV MVA lacking A41L provided better protection than control viruses to subsequent challenge with a 300 LD 50 dose of VACV WR. This study provides insight into the immunomodulatory role of A41 and suggests that MVA lacking A41 may represent a more efficacious vaccine. © 2006 SGM.

DOI 10.1099/vir.0.81417-0
Citations Scopus - 49
2005 Stack J, Haga IR, Schröder M, Bartlett NW, Maloney G, Reading PC, et al., 'Vaccinia virus protein A46R targets multiple Toll-like-interleukin-1 receptor adaptors and contributes to virulence', Journal of Experimental Medicine, 201 1007-1018 (2005)

Viral immune evasion strategies target key aspects of the host antiviral response. Recently, it has been recognized that Toll-like receptors (TLRs) have a role in innate defense a... [more]

Viral immune evasion strategies target key aspects of the host antiviral response. Recently, it has been recognized that Toll-like receptors (TLRs) have a role in innate defense against viruses. Here, we define the function of the vaccinia virus (W) protein A46R and show it inhibits intracellular signalling by a range of TLRs. TLR signalling is triggered by homotypic interactions between the Toll-like-interleukin-1 resistance (TIR) domains of the receptors and adaptor molecules. A46R contains a TIR domain and is the only viral TIR domain-containing protein identified to date. We demonstrate that A46R targets the host TIR adaptors myeloid differentiation factor 88 (MyD88), MyD88 adaptor-like, TIR domain-containing adaptor inducing IFN-ß (TRIF), and the TRIF-related adaptor molecule and thereby interferes with downstream activation of mitogen-activated protein kinases and nuclear factor ¿B. TRIF mediates activation of interferon (IFN) regulatory factor 3 (IRF3) and induction of IFN-ß by TLR3 and TLR4 and suppresses VV replication in macrophages. Here, A46R disrupted TRIF-induced IRF3 activation and induction of the TRIF-dependent gene regulated on activation, normal T cell expressed and secreted. Furthermore, we show that A46R is functionally distinct from another described VV TLR inhibitor, A52R. Importantly, VV lacking the A46R gene was attenuated in a murine intranasal model, demonstrating the importance of A46R for VV virulence.

DOI 10.1084/jem.20041442
Citations Scopus - 263
2005 Bartlett NW, Buttigieg K, Kotenko SV, Smith GL, 'Murine interferon lambdas (type III interferons) exhibit potent antiviral activity in vivo in a poxvirus infection model', Journal of General Virology, 86 1589-1596 (2005)

Human interferon lambdas (IFN-¿s) (type III IFNs) exhibit antiviral activity in vitro by binding to a receptor complex distinct from that used by type I and type II IFNs, and sub... [more]

Human interferon lambdas (IFN-¿s) (type III IFNs) exhibit antiviral activity in vitro by binding to a receptor complex distinct from that used by type I and type II IFNs, and subsequent signalling through the Janus kinase signal transducers and activators of transcription (STAT) pathway. However, evidence for a function of type III IFNs during virus infection in vivo is lacking. Here, the expression of murine IFN-¿s by recombinant vaccinia virus (VACV) is described and these proteins are shown to have potent antiviral activity in vivo. VACV expressing murine IFN-¿2 (vIFN-¿2) and IFN-¿3 (vIFN-¿3) showed normal growth in tissue culture and expressed N-glycosylated IFN-¿ in infected cell extracts and culture supernatants. The role that murine IFN-¿s play during virus infection was assessed in two different mouse models. vIFN-¿2 and vIFN-¿3 were avirulent for mice infected intranasally and induced no signs of illness or weight loss, in contrast to control viruses. Attenuation of vIFN-¿2 was associated with increases in lymphocytes in bronchial alveolar lavages and CD4 + T cells in total-lung lymphocyte preparations. In addition, vIFN-¿2 was cleared more rapidly from infected lungs and, in contrast to control viruses, did not disseminate to the brain. Expression of IFN-¿2 also attenuated VACV in an intradermal-infection model, characterized by a delay in lesion onset and reduced lesion size. Thus, by characterizing murine IFN-¿s within a mouse infection model, the potent antiviral and immunostimulatory activity of IFN-¿s in response to poxvirus infection has been demonstrated. © 2005 SGM.

DOI 10.1099/vir.0.80904-0
Citations Scopus - 82
2004 Bartlett NW, Dumoutier L, Renauld JC, Kotenko SV, McVey CE, Lee HJ, Smith GL, 'A new member of the interleukin 10-related cytokine family encoded by a poxvirus', Journal of General Virology, 85 1401-1412 (2004)

Poxviruses express numerous proteins involved in manipulating the host immune response. Analysis of the primary sequence and predicted structure of the 134R protein of Yaba-like d... [more]

Poxviruses express numerous proteins involved in manipulating the host immune response. Analysis of the primary sequence and predicted structure of the 134R protein of Yaba-like disease virus (Y134R) indicated that it is similar to cellular proteins of the IL-10 family, specifically IL-19, IL-20 and IL-24. A flag-tagged Y134R was expressed from mammalian cells and identified as a secreted, monomer ic glycoprotein that stimulated signal transduction from class II cytokine receptors IL-20Ra/IL-20Rß (IL-20R type1) and IL-22R/IL-20Rß (IL-20R type 2). Y134R induced phosphorylation of signal transducers and activators of transcription, their translocation to the nucleus and the induction of reporter gene expression. In contrast, Y134R was unable to induce similar responses from either the IL-22 or IFN-¿ (IL-28A, IL-28B, IL-29) class II cytokine receptors. To examine the role Y134R plays during a poxvirus infection, a vaccinia virus recombinant expressing Y134R was constructed and tested in a murine intranasal infection model. Compared with control viruses, the virus expressing Y134R had a reduced virulence, manifested by reduced weight loss, signs of illness and virus titres in infected organs. These results demonstrate that Y134R is a new viral member of the IL-10-related cytokine family and that its activity in vivo affects virus virulence. © 2004 SGM.

DOI 10.1099/vir.0.79980-0
Citations Scopus - 20
2003 Harte MT, Haga IR, Maloney G, Gray P, Reading PC, Bartlett NW, et al., 'The poxvirus protein A52R targets toll-like receptor signaling complexes to suppress host defense', Journal of Experimental Medicine, 197 343-351 (2003)

Toll-like receptors (TLRs) are crucial in the innate immune response to pathogens, in that they recognize and respond to pathogen associated molecular patterns, which leads to act... [more]

Toll-like receptors (TLRs) are crucial in the innate immune response to pathogens, in that they recognize and respond to pathogen associated molecular patterns, which leads to activation of intracellular signaling pathways and altered gene expression. Vaccinia virus (VV), the poxvirus used to vaccinate against smallpox, encodes proteins that antagonize important components of host antiviral defense. Here we show that the VV protein A52R blocks the activation of the transcription factor nuclear factor ¿B (NF-¿B) by multiple TLRs, including TLR3, a recently identified receptor for viral RNA. A52R associates with both interleukin 1 receptor-associated kinase 2 (IRAK2) and tumor necrosis factor receptor-associated factor 6 (TRAF6), two key proteins important in TLR signal transduction. Further, A52R could disrupt signaling complexes containing these proteins. A virus deletion mutant lacking the A52R gene was attenuated compared with wild-type and revertant controls in a murine intranasal model of infection. This study reveals a novel mechanism used by VV to suppress the host immunity. We demonstrate viral disabling of TLRs, providing further evidence for an important role for this family of receptors in the antiviral response.

DOI 10.1084/jem.20021652
Citations Scopus - 271
2002 Bartlett N, Symons JA, Tscharke DC, Smith GL, 'The vaccinia virus N1L protein is an intracellular homodimer that promotes virulence', Journal of General Virology, 83 1965-1976 (2002)

The vaccinia virus (VV) N1L gene encodes a protein of 14 kDa that was identified previously in the concentrated supernatant of virus-infected cells. Here we show that the protein ... [more]

The vaccinia virus (VV) N1L gene encodes a protein of 14 kDa that was identified previously in the concentrated supernatant of virus-infected cells. Here we show that the protein is present predominantly ( > 90%) within cells rather than in the culture supernatant and it exists as a non-glycosylated, non-covalent homodimer. The N1L protein present in the culture supernatant was uncleaved at the N terminus and was released from cells more slowly than the VV A41L gene product, a secreted glycoprotein that has a conventional signal peptide. Bioinformatic analyses predict that the N1L protein is largely alpha-helical and show that it is conserved in many VV strains, in other orthopoxviruses and in members of other chordopoxvirus genera. However, database searches found no non-poxvirus proteins with significant amino acid similarity to N1L. A deletion mutant lacking the N1L gene replicated normally in cell culture, but was attenuated in intranasal and intradermal murine models compared to wild-type and revertant controls. The conservation of the N1L protein and the attenuated phenotype of the deletion mutant indicate an important role in the virus life-cycle.

Citations Scopus - 90
Show 41 more journal articles

Conference (9 outputs)

Year Citation Altmetrics Link
2017 Loo S-L, Hsu A, Bartlett N, Wark P, 'AIRWAY EPITHELIAL INNATE IMMUNE RESPONSES TO CORONAVIRUSES', RESPIROLOGY (2017)
Co-authors Peter Wark, Alan Hsu
2017 Veerati P, Bartlett N, Parsons K, Moheimani F, Wark P, Knight D, Grainge C, 'MECHANICAL FORCES ATTENUATE ANTI-VIRAL IMMUNITY IN PRIMARY HUMAN AIRWAY EPITHELIAL CELLS FROM ASTHMATIC DONORS', RESPIROLOGY (2017)
Co-authors Darryl Knight, Peter Wark, Christopher Grainge, Fatemeh Moheimani
2017 Reid A, Moheimani F, Nichol K, Bartlett N, Wark P, Grainge C, Knight D, 'ACUTE INHIBITION OF NOTCH SIGNALLING ABLATES MUC5AC PRODUCTION IN HUMAN AIRWAY EPITHELIAL CELLS FROM ASTHMATIC, NON-ASTHMATIC AND COPD DONORS.', RESPIROLOGY (2017)
Co-authors Peter Wark, Christopher Grainge, Fatemeh Moheimani, Darryl Knight
2017 Reid AT, Moheimani F, Nichol K, Bartlett N, Wark PAB, Grainge C, et al., 'Short-Term Inhibition Of Notch Signalling Ablates Muc5ac Production In Human Airway Epithelial Cells From Asthmatic, Non-Asthmatic And COPD Donors', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE (2017)
Co-authors Christopher Grainge, Peter Wark, Fatemeh Moheimani, Darryl Knight, Philip Hansbro
2016 Tay H, Yang M, Hsu A, Nguyen T-H, Plank M, Maltby S, et al., 'Role of interleukin-36 gamma in regulating lung inflammation', EUROPEAN JOURNAL OF IMMUNOLOGY (2016)
Co-authors Ming Yang, Philip Hansbro, Alan Hsu, Steven Maltby
2014 Collison A, Hatchwell L, Girkin J, Parsons K, Li J, Zhang J, et al., 'Late-breaking abstract: IL-5-induced airways eosinophilia as a negative regulator of TLR7 expression may impair the interferon response to rhinovirus in allergic airways', EUROPEAN RESPIRATORY JOURNAL (2014)
Co-authors Joerg Mattes, Paul Foster, Peter Wark, Adam Collison
2012 Collison AM, Hatchwell LM, Siqueira AP, Bartlett NW, Johnston SL, Foster PS, Mattes J, 'Antagonism of microRNA-122 is comparible to azithromycin treatment in a mouse model of rhinovirus-induced exacerbation of allergic airways disease', Respirology (2012) [E3]
Co-authors Joerg Mattes, Paul Foster, Adam Collison
2012 Hatchwell LM, Collison AM, Siqueira AP, Bartlett NW, Johnston SL, Foster PS, Mattes J, 'Toll-like receptor 7 mediates anti-viral responses to rhinovirus while suppressing exacerbation of asthma', Respirology (2012) [E3]
Co-authors Paul Foster, Joerg Mattes, Adam Collison
2012 Hatchwell LM, Collison AM, Siqueira AP, Bartlett NW, Johnston SL, Foster PS, Mattes J, 'TRAIL regulates inflammatory responses to rhinovirus and rhinovirus-induced exacerbation of asthma', Respirology (2012) [E3]
Co-authors Adam Collison, Paul Foster, Joerg Mattes
Show 6 more conferences
Edit

Grants and Funding

Summary

Number of grants 12
Total funding $17,056,102

Click on a grant title below to expand the full details for that specific grant.


20173 grants / $1,384,564

Shared innate immune mechanisms underpin-steroid resistant pathogen-induced asthma exacerbations$826,893

Funding body: NHMRC (National Health & Medical Research Council)

Funding body NHMRC (National Health & Medical Research Council)
Project Team Laureate Professor Paul Foster, Doctor Ming Yang, Doctor Nathan Bartlett
Scheme Project Grant
Role Investigator
Funding Start 2017
Funding Finish 2020
GNo G1600084
Type Of Funding Aust Competitive - Commonwealth
Category 1CS
UON Y

Pre-clinical studies with REG3500 and dupilumab$421,307

Funding body: Sanofi US Services Inc.

Funding body Sanofi US Services Inc.
Project Team Doctor Nathan Bartlett, Conjoint Professor Peter Wark
Scheme Research Project
Role Lead
Funding Start 2017
Funding Finish 2021
GNo G1701373
Type Of Funding International - Non Competitive
Category 3IFB
UON Y

Novel epithelial targets and targeting strategies to prevent asthma exacerbations$136,364

Funding body: Asthma Australia

Funding body Asthma Australia
Project Team Doctor Nathan Bartlett, Conjoint Professor Peter Wark, Doctor Roger Liang, Professor Darryl Knight
Scheme National Research Program
Role Lead
Funding Start 2017
Funding Finish 2018
GNo G1601217
Type Of Funding Grant - Aust Non Government
Category 3AFG
UON Y

20163 grants / $997,734

Inhibition of rhinovirus-induced disease by TLR2 agonist$474,632

Funding body: Innavac

Funding body Innavac
Project Team Doctor Nathan Bartlett, Conjoint Professor Peter Wark
Scheme Research Grant
Role Lead
Funding Start 2016
Funding Finish 2017
GNo G1600747
Type Of Funding Grant - Aust Non Government
Category 3AFG
UON Y

Collaborative Research Agreement: New pathways and targets in severe asthma and COPD$411,172

Funding body: Boehringer Ingelheim

Funding body Boehringer Ingelheim
Project Team Professor Darryl Knight, Conjoint Associate Professor Christopher Grainge, Conjoint Professor Peter Wark, Doctor Nathan Bartlett
Scheme Research Project
Role Investigator
Funding Start 2016
Funding Finish 2017
GNo G1601257
Type Of Funding International - Non Competitive
Category 3IFB
UON Y

Efficacy of ABM109 in blocking rhinovirus induced asthma exacerbation: preclinical proof of concept$111,930

Funding body: Abeome Corporation

Funding body Abeome Corporation
Project Team Doctor Nathan Bartlett
Scheme Research Grant
Role Lead
Funding Start 2016
Funding Finish 2016
GNo G1600775
Type Of Funding International - Non Competitive
Category 3IFB
UON Y

20152 grants / $50,238

Novel anti-viral agent for rhinovirus infection$25,238

Determining the efficacy of a novel anti-viral compound for rhinovirus infection.

Funding body: 3E Therapeutics

Funding body 3E Therapeutics
Project Team

Nathan Bartlett

Scheme Commercial
Role Lead
Funding Start 2015
Funding Finish 2015
GNo
Type Of Funding External
Category EXTE
UON N

Specifically targeting the airways to prevent virus-induced asthma attacks$25,000

Funding body: Hunter Medical Research Institute

Funding body Hunter Medical Research Institute
Project Team Doctor Nathan Bartlett, Professor Darryl Knight
Scheme Project Grant
Role Lead
Funding Start 2015
Funding Finish 2016
GNo G1501378
Type Of Funding Grant - Aust Non Government
Category 3AFG
UON Y

20141 grants / $23,566

Miltenyi Biotec GentleMACS Octo Dissociator with Heaters $23,566

Funding body: NHMRC (National Health & Medical Research Council)

Funding body NHMRC (National Health & Medical Research Council)
Project Team Professor Phil Hansbro, Laureate Professor Paul Foster, Professor Darryl Knight, Professor Dirk Van Helden, Professor Joerg Mattes, Professor Jodie Simpson, Professor Lisa Wood, Associate Professor Liz Milward, Dr NATHAN Bartlett, Associate Professor Simon Keely, Doctor Steven Maltby, Doctor Andrew Jarnicki, Doctor Malcolm Starkey, Doctor Adam Collison, Doctor Shaan Gellatly
Scheme Equipment Grant
Role Investigator
Funding Start 2014
Funding Finish 2014
GNo G1500861
Type Of Funding Other Public Sector - Commonwealth
Category 2OPC
UON Y

20122 grants / $4,600,000

Mechanisms of interplay between allergy and viruses in asthma$4,000,000

We apply to form an Alliance between GSK and the MRC & Asthma UK Centre in Allergic Mechanisms of Asthma to discover and develop new approaches for prevention/treatment of asthma and asthma attacks. We will integrate research in areas of major strength for the Centre with the strengths in asthma drug discovery at GSK. The overall aim is to investigate mechanisms of interplay between allergy and virus infection in development of asthma and in acute asthma attacks. 
The major cause of asthma attacks are human rhinovirus (RV) infections, these are also related to development of asthma when they occur in early life. We will investigate gene expression and how expression is regulated in lung cells during RV infection to identify molecules/pathways induced by RV infection that are implicated in promoting allergic responses.
We will determine whether RV induction/modification of these molecules/processes are related to pre-existing allergic responses, virus load and clinical severity of asthma exacerbation. 
A major cause of asthma is failure of development of immunological tolerance to allergens. We have shown that tolerance can be reversed by a virus infection, but the mechanisms are unknown. We will purify lung cells from the virus-induced breakdown of tolerance model to identify genes implicated in tolerance breakdown and determine whether these are replicated in lung cells in the human.
Finally we will determine whether blocking or inducing molecules implicated in virus induced worsening of allergic responses/breakdown of tolerance, determines severity of RV induced allergic airway inflammation.
Accomplishment of these aims will identify targets for development of novel therapies for asthma and asthma attacks.

Funding body: Medical Research Council of the United Kingdom

Funding body Medical Research Council of the United Kingdom
Project Team

Sebastian Johnston, Nathan Bartlett, CIs in MRC Centre for Allergic Mechanisms in Asthma

Scheme Program Grant
Role Investigator
Funding Start 2012
Funding Finish 2017
GNo
Type Of Funding International - Competitive
Category 3IFA
UON N

Defining the importance of IL-25 in rhinovirus induced asthma exacerbations$600,000

Rhinovirus infection induces production of IL-25, augmenting Th2-type immune responses and exacerbating allergic airways inflammation. Thus IL-25 plays a central role in the pathogenesis of RV-induced asthma exacerbations and is a good candidate target for the development of new therapies for asthma aexacerbations. 

The aim of this application is to investigate rhinovirus-induced IL-25 and define its role in RV-induced asthma exacerbations using a combination of patient tissue analysis and experimental mouse models. If IL-25 expression is induced and related to disease outcomes in the human model, AND causally related to Th2 mediated disease outcomes in the mouse in vivo models this cytokine will be a very strong candidate for immediate translation of approaches to inhibit expression or function in pivotal proof of concept human intervention studies. 

Funding body: Medical Research Council of the United Kingdom

Funding body Medical Research Council of the United Kingdom
Project Team

Nathan Bartlett, Sebastian Johnston

Scheme Project Grant
Role Lead
Funding Start 2012
Funding Finish 2014
GNo
Type Of Funding International - Competitive
Category 3IFA
UON N

20101 grants / $10,000,000

Post infectious immune reprogramming and its association with persistence and chronicity of respiratory allergic diseases (PreDicta)$10,000,000

The PreDicta project is based on the observation that childhood asthma usually occurs after a viral respiratory tract infection. Thus, the central hypothesis of this programme is that repeated, acute infection-mediated events may reprogram the innate, adaptive and/or regulatory immune responses to predispose towards a chronic inflammation pattern.

To analyze the relationship between these infections with persistence of asthma, Predicta will employ the latest technologies of molecular biology, virology, and cytology.  The Consortium is privileged to include groups with an excellent track record in clinical research and cohort-based studies that have significantly contributed to the field of allergy and asthma research internationally.

Funding body: European Commission, European Union

Funding body European Commission, European Union
Project Team

Nikolaos Papadopoulos, Sebastian Johnston, Nathan Bartlett, PreDicta Consortium

Scheme 7th Research Framework Programme
Role Investigator
Funding Start 2010
Funding Finish 2016
GNo
Type Of Funding International - Competitive
Category 3IFA
UON N
Edit

Research Supervision

Number of supervisions

Completed5
Current8

Total current UON EFTSL

PhD3.5

Current Supervision

Commenced Level of Study Research Title Program Supervisor Type
2017 PhD Changes in Development of Tight Junction Components in Response to Pathological Infections in Healthy and Diseased Airway Epithelia PhD (Immunology & Microbiol), Faculty of Health and Medicine, The University of Newcastle Principal Supervisor
2017 PhD Epithelial Interaction with Type 2 Innate Lymphoid Cells in Asthma and Rhinovirus Infection PhD (Medicine), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor
2017 PhD Functional characterisation of Calcium-sensing Receptor within differentiated human airway epithelial cells PhD (Medical Biochemistry), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor
2016 PhD Novel Targeted Therapy for Airway Remodeling in Asthma PhD (Pharmacy), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor
2016 PhD Rhinovirus Replication in Differentiated Airway Epithelium PhD (Immunology & Microbiol), Faculty of Health and Medicine, The University of Newcastle Principal Supervisor
2016 PhD Viral Infection Effects on IL-25 Expression on Airway Epithelium in Respiratory Diseases PhD (Immunology & Microbiol), Faculty of Health and Medicine, The University of Newcastle Principal Supervisor
2015 PhD Role of Mechanical Forces in Asthma Pathogenesis PhD (Medicine), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor
2013 PhD Innate anti-viral responses of airway epithelial cells to infection with rhinovirus and coronavirus PhD (Medicine), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor

Past Supervision

Year Level of Study Research Title Program Supervisor Type
2015 PhD Innate Th2 and anti-viral immune responses in rhinovirus-induced asthma exacerbations
&lt;p style="margin-bottom:0cm;margin-bottom:.0001pt;text-autospace:none;"&gt;&lt;span lang="EN-US" style="font-family:Arial, Helvetica, sans-serif;font-size:small;"&gt;W&lt;/span&gt;&lt;span lang="EN-US" style="font-family:Arial, Helvetica, sans-serif;font-size:small;"&gt;&lt;span style="font-size:small;font-family:Arial, Helvetica, sans-serif;"&gt;e recently used type I IFN receptor knockout (IFNAR1KO) mice to show that IFN signalling regulates both allergic and innate anti-viral immune responses in a model of RV-induced exacerbation of allergic airways inflammation. In the absence of type I IFN signalling, RV infection profoundly exacerbated allergen-induced Th2 cell activation (Figure 1). This suggests that type I IFN signalling regulates Th2 immune responses during RV infection. However, RV infection did not exacerbate allergic airways inflammation in strain-matched wild type C57 Bl/6 mice, which is in contrast to the model established in the Th2-biased Balb/c strain whereby RV increases allergen-driven inflammation (Bartlett &lt;/span&gt;&lt;em&gt;et al&lt;/em&gt;&lt;span style="font-size:small;font-family:Arial, Helvetica, sans-serif;"&gt;., 2008). Together, this suggests that RV-induced exacerbation of allergic airways inflammation may be dependent on impaired type I IFN signalling and augmented Th2 immunity.&amp;nbsp;&lt;/span&gt;&lt;/span&gt;&lt;/p&gt;&lt;p style="margin-bottom:0cm;margin-bottom:.0001pt;text-autospace:none;"&gt;&lt;strong&gt;&lt;span lang="EN-US" style="font-family:Arial, Helvetica, sans-serif;font-size:small;"&gt;Hypothesis:&lt;/span&gt;&lt;/strong&gt;&lt;/p&gt;&lt;p style="margin-bottom:0cm;margin-bottom:.0001pt;text-autospace:none;"&gt;&lt;strong&gt;&lt;span lang="EN-US" style="font-family:Arial, Helvetica, sans-serif;font-size:small;"&gt;Type I IFN signalling modulates Th2-mediated allergic airways inflammation during RV-induced asthma exacerbations. &lt;/span&gt;&lt;/strong&gt;&lt;/p&gt;&lt;p style="margin-bottom:0cm;margin-bottom:.0001pt;text-autospace:none;"&gt;&lt;strong&gt;&lt;span lang="EN-US" style="font-family:Arial, Helvetica, sans-serif;font-size:small;"&gt;Aims:&lt;/span&gt;&lt;/strong&gt;&lt;strong&gt;&lt;span lang="EN-US" style="font-family:'Times New Roman',serif;"&gt;&lt;/span&gt;&lt;/strong&gt;&lt;/p&gt;&lt;p style="margin-bottom:0cm;margin-bottom:.0001pt;"&gt;&lt;span lang="EN-US" style="font-family:Arial, Helvetica, sans-serif;font-size:small;"&gt;Mouse models of OVA-induced allergic airways inflammation and RV-induced exacerbation of allergic airways inflammation will be used to determine the role of type I IFN signalling in RV-induced asthma exacerbations. &lt;/span&gt;&lt;/p&gt;&lt;p style="margin-bottom:0cm;margin-bottom:.0001pt;text-indent:-18.0pt;"&gt;&lt;span lang="EN-US" style="font-family:'Times New Roman',serif;"&gt;&lt;span style="font-size:small;font-family:Arial, Helvetica, sans-serif;"&gt;-&lt;/span&gt;&lt;span style="font-variant-numeric:normal;font-size:7pt;line-height:normal;font-family:'Times New Roman';"&gt;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp; &lt;/span&gt;&lt;/span&gt;&lt;span lang="EN-US" style="font-family:Arial, Helvetica, sans-serif;font-size:small;"&gt;To characterise and compare innate anti-viral and early Th2 responses in a model of RV-induced asthma exacerbation in both wild type Balb/C and C57 Bl/6 mouse strains.&lt;/span&gt;&lt;/p&gt;&lt;p style="margin-bottom:0cm;margin-bottom:.0001pt;text-indent:-18.0pt;"&gt;&lt;span lang="EN-US" style="font-family:'Times New Roman',serif;"&gt;&lt;span style="font-size:small;font-family:Arial, Helvetica, sans-serif;"&gt;-&lt;/span&gt;&lt;span style="font-variant-numeric:normal;font-size:7pt;line-height:normal;font-family:'Times New Roman';"&gt;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp; &lt;/span&gt;&lt;/span&gt;&lt;span lang="EN-US" style="font-family:Arial, Helvetica, sans-serif;font-size:small;"&gt;To use type I IFN receptor knock out (IFNAR1KO) mice in a model of RV-induced asthma exacerbation to determine how type I IFN regulates Th2 immune responses during allergen challenge and RV infection. &lt;/span&gt;&lt;/p&gt;&lt;p style="margin-bottom:0cm;margin-bottom:.0001pt;text-indent:-18.0pt;"&gt;&lt;span lang="EN-US" style="font-family:'Times New Roman',serif;"&gt;&lt;span style="font-size:small;font-family:Arial, Helvetica, sans-serif;"&gt;-&lt;/span&gt;&lt;span style="font-variant-numeric:normal;font-size:7pt;line-height:normal;font-family:'Times New Roman';"&gt;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp; &lt;/span&gt;&lt;/span&gt;&lt;span lang="EN-US" style="font-family:Arial, Helvetica, sans-serif;font-size:small;"&gt;To investigate the effects of recombinant mouse IFN&amp;beta; treatment in mouse models of asthma and RV-induced asthma exacerbation to determine whether type I IFN signalling can inhibit Th2 immune responses in both the absence and presence of RV infection. &lt;/span&gt;&lt;/p&gt;&lt;p style="margin-bottom:0cm;margin-bottom:.0001pt;"&gt;&lt;span lang="EN-US" style="font-family:'Times New Roman',serif;"&gt;&lt;span style="font-family:Arial, Helvetica, sans-serif;font-size:small;"&gt;&lt;/span&gt;&lt;/span&gt;&lt;/p&gt;&lt;p style="margin-bottom:0cm;margin-bottom:.0001pt;"&gt;&lt;span lang="EN-US" style="font-family:Arial, Helvetica, sans-serif;font-size:small;"&gt;&lt;span style="font-family:Arial, Helvetica, sans-serif;font-size:small;"&gt;Human &lt;/span&gt;&lt;em style="font-family:Arial, Helvetica, sans-serif;font-size:small;"&gt;in vitro&lt;/em&gt;&lt;span style="font-family:Arial, Helvetica, sans-serif;font-size:small;"&gt; cell-based assays will be used to investigate the molecular mechanisms of type I IFN signalling.&amp;nbsp;&lt;/span&gt;&lt;/span&gt;&lt;/p&gt;&lt;p style="margin-bottom:0cm;margin-bottom:.0001pt;text-indent:-18.0pt;"&gt;&lt;span lang="EN-US" style="font-family:'Times New Roman',serif;"&gt;&lt;span style="font-size:small;font-family:Arial, Helvetica, sans-serif;"&gt;-&lt;/span&gt;&lt;span style="font-variant-numeric:normal;font-size:7pt;line-height:normal;font-family:'Times New Roman';"&gt;&amp;nbsp;&amp;nbsp;&amp;nbsp;&lt;/span&gt;&lt;/span&gt;&lt;span lang="EN-US" style="font-family:Arial, Helvetica, sans-serif;font-size:small;"&gt;TTo determine the role of type I IFN signalling on epithelial-mediated Th2 immune responses in a model of RV- and IL-4-stimulated bronchial epithelial cell culture. &lt;/span&gt;&lt;/p&gt;&lt;p style="margin-bottom:0cm;margin-bottom:.0001pt;text-indent:-18.0pt;"&gt;&lt;span lang="EN-US" style="font-family:'Times New Roman',serif;"&gt;&lt;span style="font-size:small;font-family:Arial, Helvetica, sans-serif;"&gt;-&lt;/span&gt;&lt;span style="font-variant-numeric:normal;font-size:7pt;line-height:normal;font-family:'Times New Roman';"&gt;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp;&amp;nbsp; &lt;/span&gt;&lt;/span&gt;&lt;span lang="EN-US" style="font-family:Arial, Helvetica, sans-serif;font-size:small;"&gt;To investigate the mechanisms of type I IFN-mediated regulation Th2 cells in a Th2 polarised CD4+ T cell model.&lt;/span&gt;&lt;/p&gt;
Medical Science, Imperial College London Principal Supervisor
2014 PhD Effect of inhaled corticosteroids on viral and bacterial infection in chronic obstructive pulmonary disease
Rhinovirus (RV) infections trigger exacerbations of chronic obstructive pulmonary disease (COPD) exacerbations and may precipitate secondary bacterial infections. Inhaled corticosteroids (ICS) are used commonly in COPD but are relatively ineffective in the context of virus-induced exacerbations and may also increase the risk of pneumonia. We hypothesised that, in a mouse model, ICS would suppress anti-viral and anti-bacterial immune responses leading to alteration of the airway microbiota and secondary bacterial infection following RV-induced exacerbation of COPD.<br />Despite extensive optimisation, we were unable to define a representative mouse model of the deficient anti-viral and anti-bacterial responses that are indicative of human COPD. For this reason, and because of difficulties in measuring the airway microbiota in mice, we employed models of primary RV1B and Streptococcus pneumoniae infection as surrogates for viral exacerbation and bacterial colonisation in COPD. Fluticasone propionate (FP) administration prior to RV1B infection suppressed innate and adaptive immune responses leading to impaired virus control, in a dose dependent manner. This effect was causally related to suppression of type I interferon (IFN) as administration of recombinant IFN-&beta; reconstituted IFN-stimulated gene expression and restored virus control. FP suppressed RV-induced airway inflammation but led to enhanced airway mucin production, effects that were unaltered by recombinant IFN-&beta;. FP administration also suppressed innate responses to S. pneumoniae including expression of anti-bacterial cytokines and cathelicidin-related anti-microbial peptide. High dose FP increased lung tissue bacterial loads with the opposite effect observed with lower dose FP despite similar anti-inflammatory effects.<br />Our findings demonstrate beneficial anti-inflammatory effects of ICS during virus-induced COPD exacerbations but reveal some previously unrecognised detrimental effects including increased virus replication and enhanced mucin production. Additionally, we show that high dose ICS administration may increase bacterial loads and thus increase pneumonia risk but lower doses may conversely reduce bacterial loads and therefore could be safer in COPD.
Medical Science, Imperial College London Co-Supervisor
2012 PhD The role of IL-25 in rhinovirus-induced asthma exacerbations
Background and hypothesis: Rhinovirus (RV) infections are the principal cause of asthma exacerbations. While Th2-mediated inflammation is clearly implicated in the asthmatic response, it is unknown how the immune response to RV infection interacts with Th2 immunity to enhance disease pathogenesis. The epithelial-derived cytokine, IL-25, has been identified as an initiator and regulator of Th2 immunity and plays a role in asthma pathogenesis. Based on the fact that bronchial epithelial cells are the primary site of RV infection, we hypothesized that RV induces IL-25 production providing a link between infection and Th2 driven allergic inflammation. Aims and methods: RV-induced IL-25 expression was measured in human bronchial epithelial cells (HBECs) obtained from bronchoscopic brushings from atopic asthmatics and healthy patients. Mouse models of RV infection and RV-induced allergic airways disease were also employed to examine IL-25 induction in response to RV infection and/or OVA sensitisation and challenge. Finally, to define a mechanistic role for RV-induced IL-25, signalling mediated by IL-25 was blocked in our model of RV-induced allergic airways disease by neutralising the IL-25 receptor. Results: RV-infected HBECs from asthmatics expressed significantly greater IL-25 gene and protein compared with cells from healthy controls. Furthermore, RV infection of mice induced IL-25 expression in the airway epithelium as well as in inflammatory cells in the airway lamina propia. Using a mouse model of RV-induced allergic disease, we demonstrated that RV enhanced allergen-driven IL-25 gene and protein expression which was associated with increased Th2 inflammation in the lung. Finally, by blocking IL-25 signalling in an RV-infected and OVA-sensitised and challenged mouse, several key features of the exacerbation phenotype were significantly reduced including airway leukocyte infiltration, BAL Th2 cytokines and chemokines and Th2 cells. Conclusions: These novel findings indicate that RV-induced IL-25 plays an important role in enhancing Th2 inflammation associated with the exacerbation phenotype which is mediated by binding to the IL-25 receptor.
Medical Science, Imperial College London Principal Supervisor
2011 PhD The role of IL-15 in response to rhinovirus infections
Rhinoviruses (RV) cause the common cold and are major precipitants of asthma exacerbations. The underlying mechanisms of RV-induced airways disease are unclear. IL-15 is a proinflammatory cytokine produced during viral infections and plays a key role in the regulation of NK cells. Using mouse models of RV infection and RV-induced asthma exacerbation we examined the role of IL-15 and its importance for NK cell responses during RV infections in allergic and non-allergic airways. We demonstrate RV-induced IL-15 upregulation in the airway and lungs of BALB/c mice at day 1 after infection and accumulation of NK cells in the airway and lungs at days 1-2 and 2-4 respectively. The NK cells exhibited an activated phenotype characterised by upregulated CD69, IFN-&gamma; and GranzymeB expression. Blocking IL-15 upon intranasal administration of an IL-15 neutralising antibody inhibited the NK cell response to RV infection, which was associated with deficient IFN-&gamma; production and increased expression of Th2 mediators. IL-15R&alpha; knockout mice lack NK cells and also demonstrated deficient IFN-&gamma; and increased Th2 responses to RV infection; these mice also exhibited deficient CD8+ T cell responses and an increased viral load. Similar results were observed in RV infected IFNAR1 ko mice, which was associated with deficient IL-15 upregulation. We suggest that RV-induced IL-15 is mediated by type I interferon signalling, and is necessary for NK cell responses and early IFN-&gamma; production during RV-1B infection, which drives development of appropriate Th1 antiviral responses. In the absence of this pathway, Th2 responses result and are associated with impaired antiviral immunity. To examine the interaction between allergen driven Th2 immunity and RV infection, we employed a RV-induced asthma exacerbation model. Unexpectedly, RV infected allergen challenged mice, despite having increased viral load, demonstrated increased IL-15 expression and NK cell responses, revealing a novel interaction between allergic responses and antiviral immunity.
Microbiology, Imperial College London Co-Supervisor
2010 PhD T cell responses in models of rhinovirus-induced airways disease
<p style="text-align:justify;line-height:150%;"><span lang="EN-GB" style="font-family:'Arial',sans-serif;">Human Rhinoviruses (HRV) cause the common cold and are associated wtih more severe respiratory diseases such as asthma exacerbations. There is good evidence that T lymphocytes (T cells) play a central role in the pathogenesis of atopic asthma however little is known about T cell responses to HRV infection or how HRV infection modulates T cell responses in asthma. One T cell subset expresses the &gamma;&delta; TCR and are capable of modulating inflammation &amp; AHR in mouse models of infection and asthma. Furthermore we have observed increased &gamma;&delta; T cells in the airways of human atopic asthmatics following experimental HRV infection which was associated with worse symptoms, enhanced airway inflammation and diminished lung function. Despite the association of &gamma;&delta; T cells with disease in asthma the functional role of these cells is unknown (Message et al., unpublished data). The aims of this thesis were to use recently developed mouse models and characterise the T cell responses to HRV infection in healthy and in ovalbumin (OVA) sensitised &amp; challenged (asthmatic) mice, and to define a role for &gamma;&delta; T cells in RV infection and RV-induced asthma exacerbations... </span></p><p style="line-height:150%;"><span lang="EN-GB">Consistent with observations in human studies, mouse HRV infection was characterised by neutrophilic and lymphocytic airways inflammation. The airway and lung-tissue lymphocyte response to HRV infection was composed of activated CD4+, CD8+ and CD4<sup>-</sup>/CD8<sup>-</sup> &gamma;&delta; TCR+ T cells<span style="color:#999999;"> </span>and was weakly Th1 orientated.<span style="color:#999999;"> </span>In HRV induced asthma exacerbation, HRV infection modestly enhanced numbers of multiple T cell populations in the airway and lung tissue as well as levels of Th2 cytokines such as IL-4. Systemic depletion of &gamma;&delta; T cells with a monoclonal anti-TCR&gamma;&delta; antibody in the HRV infection model modestly enhanced some aspects of airways inflammation such as neutrophil recruitment but had no effect on AHR. In both the asthma and the HRV induced asthma exacerbation models, &gamma;&delta; T cell depletion enhanced AHR at 48hrs post allergen challenge/ HRV infection. In the allergic asthma model &gamma;&delta; T cell depletion also enhanced some aspects of airways inflammation such as&hellip; </span></p><p style="text-align:justify;line-height:150%;"><span lang="EN-GB" style="font-family:'Arial',sans-serif;">This thesis has demonstrated that HRV infection is capable of increasing multiple T cell populations and associated cytokine production in the lung, Antibody-mediated depletion studies specifically defined a function in disease for &gamma;&delta; T cells indicating that they perform a regulatory function, limiting both virus and allergen induced airway inflammation and, in asthma and asthma exacerbation models, also limiting AHR.</span></p>
Medical Studies, Imperial College London Co-Supervisor
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Dr Nathan Bartlett

Position

Senior Lecturer
Bartlett Lab
School of Biomedical Sciences and Pharmacy
Faculty of Health and Medicine

Contact Details

Email nathan.bartlett@newcastle.edu.au
Phone (02) 4042 0171

Office

Room HMRI2405
Building HMRI
Location New Lambton Heights

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