Dr Malcolm Starkey

Dr Malcolm Starkey

NHMRC Early Career Fellow

School of Biomedical Sciences and Pharmacy (Immunology and Microbiology)

Mice for mankind

Dr Malcolm Starkey is a National Health and Medical Research Council (NHMRC) Early Career Postdoctoral Fellow who is using transgenic animal technology to investigate – and manipulate – the immunological mechanisms underpinning the onset and progression of multiple chronic illnesses.

Dr Malcolm Starkey

Giving weight to time-honoured truisms of science and philosophy, Dr Malcolm Starkey's research is clear proof that little things can make a big difference. The immunologist is using mouse models in experimental studies that seek to cement a mechanistic understanding of the early-life origins of chronic lung diseases.

"It can be difficult to recruit humans, particularly young children, for clinical trials," he concedes.

"So you need to have a strong rationale as to why you're going to do these studies."

"Our models provide pivotal preclinical evidence to justify this clinical work."

Straddling the microbiological and immunological fields, Malcolm's projects stress the "multifactorial" nature of several airway conditions. His work also emphasise the urgent need to identify the roles played by bacteria and viruses in the onset and progression of respiratory diseases.

"Using mouse models, we have learnt that just one respiratory infection in early life can trigger asthma and/or emphysema in adulthood."

"We've learnt that early life infections can cause irreparable damage to the lung and alter the way the immune system develops."

"It's really quite incredible."

Acutely aware of the lack of therapeutic options available for these chronic illnesses, Malcolm is hoping his research will be used to inform the development of new therapeutic targets for patients.

"If we can't breathe, we can't function."

"We want people to breathe easy."

Of mice, men and molecules

Malcolm's research career began in 2008, when he undertook a PhD with Professor Phil Hansbro at the Hunter Medical Research Institute. Chiefly focusing on understanding the 'why' behind the 'what is,' the duo looked to figure out how infections predispose people to disease.

"There's emerging evidence that some chronic lung diseases such as asthma and emphysema may originate from infections – contracted either as a newborn or an infant."

Examining multiple molecular pathways during the six-year probe, Malcolm sought to elucidate the effects of the transfer of Chlamydia from mother to baby during childbirth.

"There is a cohort of neonates that are susceptible to this vertical transmission," he explains.

"We used mouse models to replicate this phenotype seen in humans."

"It's a vital stage because the lung is still developing."

"If the lung doesn't develop properly, overall health can be negatively affected."

Going viral

Malcolm expanded upon this work after his PhD was conferred in early 2014, exploring the relationships between chronic airway diseases and infections. Concentrating research efforts on infections contracted in an early window post-birth, he is also studying the long-term effects of influenza, Streptococcus pneumoniae and nontypeable Haemophilus influenzae.

"Neonates are particularly vulnerable," he describes.

"The fetal immune system is altered in utero to prevent the mother's immune system rejecting the fetus during pregnancy."

"This contributes to an unbalanced and immature immune system in early life."

"If you happen to be unfortunate enough to contract a series of respiratory infections in early life, you are more likely to experience lung problems in the long term."

With recent clinical data showing some bacteria are important in this regard, Malcolm duly pursued this avenue of contemporary interest.

"For some time it was thought that viruses cause this predisposition to asthma," he states.

"As it turns out though, it probably doesn't matter whether it's viruses or bacteria – it can be both."

"It depends on many circumstances coming together, such as genetics, age of infection and environment."

"We have found that early life infections cause the production of disease inducing factors. These factors promote long term effects by altering the immune system as well as the structure and function of the lung."

Malcolm's research has shown that therapies that target these factors may be effective new treatments for infection-induced chronic lung diseases.

Parts of a whole

Still dedicated to investigating the interplay between early life infections and acute airway conditions, Malcolm is working to address his evolving, specialist area from multiple angles.

The NHMRC fellow is aiming to examine links between these insults (infections) and autoimmune diseases as well.

"What we also want to do in the near future is look at predisposition to diabetes," Malcolm divulges.

"Clinical evidence suggests that infections can alter the way the immune system develops so that it attacks itself."

"We're in the process of putting models in place for this study."

Hypothesising that certain bacteria and viruses have an impact on the whole body, Malcolm and his team are after scientific proof of long-term systemic effects, such as changes in lung structure and development, and inappropriate immune system responses.

"There is already evidence linking respiratory Chlamydia infections to atherosclerosis and arthritis," he acknowledges.

"We believe that early life insults might cause changes in the brain and pancreas too."

"Early life infections may be a common cause of many chronic diseases."

Raising hope and raising awareness

Recognised as a leading young researcher in the field of paediatric respiratory medicine after winning the internationally competitive Klosterfrau Grant for research of airway diseases in childhood in 2015, Malcolm points to "tailor-made, personalised medicine" as the science of the not-so-distant future, hoping to pinpoint more discrete subsets of patients and how he can better treat them.

"A critical goal of our research is to understand what factors drive the development of chronic diseases and devise strategies to stop this from occurring."

More about Malcolm's Career

Malcolm Starkey

Mice for mankind

Dr Malcolm Starkey is a National Health and Medical Research Council (NHMRC) Early Career Postdoctoral Fellow who is using transgenic animal technology to inv

Read more

Career Summary

Biography

Dr Starkey is an NHMRC early career post-doctoral fellow (Peter Doherty Biomedical Fellow) and ARC DECRA fellow at the Priority Research Centre's for GrowUpWell and Lung Health and School of Biomedical Science and Pharmacy. He is a member of Professor Phil Hansbro's research team based at the Hunter Medical Research Institute.

Dr Starkey is an immunologist and microbiologist interested in how respiratory challenges in early-life impair the normal development of the lung and a healthy immune system and how this may predispose to chronic diseases such as asthma, emphysema and kidney disease. His work is substantially contributing to understanding the basic molecular and cellular mechanisms driving chronic diseases. Indeed his work has made important contributions and led to the identification of novel therapeutic strategies that are under further investigation. Dr Starkey uses novel mouse models that recapitulate the hallmark features of human disease, including infections, asthma and acute kidney injury. He employs these models to understand how the immune system works, and to advance knowledge on the fundamental processes for underpinning respiratory dysfunction. His work has substantially furthered the understanding of the deleterious effects of infection in early life and how these infections have long-term consequences for the respiratory and immune systems. More recently he has modeled infection-induced severe asthma and emphysema and is identifying strategies for treating these severe forms of disease. This has been achieved using mouse models of human disease and specifically he has shown that:

*1. Chlamydia respiratory tract infection (RTI) in early life differentially suppress (neonates) or enhance (infants) allergic inflammation depending on the age infection. Nevertheless infection at either age increases asthma severity. Published in 2xJ Allergy Clin Immunol IF=12, ERA=A*

*2. Constitutive IL-13 promotes Chlamydia RTI in early life and associated asthma. Published in Mucosal Immunol IF=7.5, ERA=A*

*3. TRAIL and its receptors are required for neonatal Chlamydia RTI-induced asthma. Published in Mucosal Immunol IF=7.5, ERA=A*

4. Infection with Streptococcus pneumoniae suppresses allergic airway disease through the induction of regulatory T cells. Published in Eur Respir J IF=7, ERA=A*

5. Chlamydia RTI during asthma in later life drives more severe asthma with similar features to severe asthma in humans that is dominated by Th1/Th17 responses and airway neutrophilia. Published in J Immunol IF=6, ERA=A*

6. TLR2 but not TLR4 is required for effective host defence against neonatal Chlamydia RTI. Published in PLoS One IF=4, ERA=A

*7. Chlamydia RTI in infants but not neonates alters hematopoietic cells to promote asthma. Published in PLoS One IF=4, ERA=A

8. Targeting PI3K-p110α suppresses influenza viral infection in chronic obstructive pulmonary disease. Accepted Am J Respir Crit Care Med IF =12, ERA=A*

9. Antibiotics (macrolides) suppress key features of experimental steroid-sensitive and steroid-insensitive asthma. Published in Thorax IF= 8.5, ERA=A*

10. PD-L1 promotes early-life infection-induced severe asthma. Published in Am J Respir Cell Mol Biol IF=4, ERA=A

11. He has also written (three) and contributed to another four reviews in this field (*Curr Opin Pharmacol (IF=7, ERA=A), Expert Opin Invest Drugs (IF=5, ERA=A), J Devl Orig Health Dis (IF=2, ERA=C), *Clin Obst Gyn (IF=2, ERA=C), *Ann Am Thorac Soc).
Those marked * are as first author. He has an average impact factor of >7 and 12/15 of his manuscripts are in ERA ranked A*/A journals. His work has been cited >200 times since 2010.

His achievements during his studies and early post-doctoral career have been recognised by over 20 awards/fellowships, including the prestigious NHMRC Early Career Post-doctoral Fellowship (Doherty), ARC DECRA fellowship, HMRI Early Career Research education prize, multiple communication awards, the Faculty of Health Honours Research Medal, international laboratory exchange awards, The Peter Phelan Paediatric fellowship, The Janet Elder International Travel award and numerous scholarships. Dr Starkey was recently awarded the internationally competitive Klosterfrau research grant honouring an outstanding young scientist in the field of paediatric pulmonology. He has presented his work at numerous international and national conferences and institutions including Harvard, Imperial College, University of London and Cardiff University.
 

Research Expertise
Our research involves the use of well-established models of respiratory bacterial and viral infections to understand the immunological mechanisms underpinning the development of chronic respiratory diseases such as asthma and emphysema. A particular interest is how infections in early-life predispose to disease in later-life. We are also exploring how respiratory infections exacerbate existing lung disease such as asthma and chronic obstructive pulmonary disease (COPD). We have models of Chlamydia, Streptococcus pneumoniae, Haemophilus influenzae, Influenza, Respiratory syncytial virus, Rhinovirus, and Pseudomonas aeruginosa respiratory infections that we superimpose with models of asthma and emphysema/COPD. We investigate the role of specific molecules in these systems using transgenic animal models (knock-out, knock-in, reporter systems) and inhibitory compounds (monoclonal antibodies, small molecule inhibitors) to identify potential therapeutic targets. We also adopt a translational approach where we take our key observations from our models and look for these molecules/pathways in human tissue.

In more recent studies, we have become interested in the basic process underpinning normal mammalian lung development. We hypothesise that the immune system plays a currently unknown role in regulating stem cell maintenance and lung development. We are also investigating the role of innate lymphoid cells in kidney injury and repair.

Teaching Expertise
Lecturer, laboratory demonstrator and tutor of all levels of the B Biomedical Science program at the University of Newcastle.  The supervisor of several summer scholarship, HUBS3409 (3rd year projects), honours and PhD students. Currently the co-supervisor of 5 PhD students.

Administrative Expertise

Collaborations
University of Newcastle/Hunter Medical Research Institute collaborators; - Prof. Phil Hansbro - Dr Jay Horvat - Prof. Paul Foster - Prof. Peter Wark - Dr Alan Hsu - Prof. Darryl Knight - Dr Fatemeh Moheimani - Prof. Joerg Mattes - Dr Adam Collison - Dr Matt Dun - Dr Jamie Flynn, Prof. Lisa Wood. External Australian collaborators; - Prof. Ranjeny Thomas University of Queensland - Dr. Brendan O'Sullivan University of Queensland - A/Prof. Ray Steptoe University of Queensland - Dr Stavros Selemidis Monash University - Dr Sandra Nicholson Walter and Eliza Hall Institute of Medical Research, Prof. Gabrielle Belz Walter and Eliza Hall Institute of Medical Research,  International collaborators; - Prof. Hideo Yagita Juntendo University Japan - Prof. Ian Adcock Imperial College London - Prof. Mark Inman McMaster University Canada - Dr Jeremy Hirota The University of British Columbia


Qualifications

  • Doctor of Philosophy, University of Newcastle
  • Bachelor of Biomedical Sciences, University of Newcastle
  • Bachelor of Biomedical Sciences (Hons), University of Newcastle

Keywords

  • Acute Kidney Injury
  • Asthma
  • Chlamydia
  • Chronic Obstructive Pulmonary Disease (COPD)
  • Early life infections
  • Emphysema
  • IL-13
  • ILC2
  • Immunology
  • Influenza
  • Innate lymphoid cells
  • Kidney
  • Lung development
  • Lung diseases
  • Neonate
  • PI3K
  • Respiratory infections
  • Stem cells
  • TLR2
  • TRAIL

Languages

  • English (Mother)

Fields of Research

Code Description Percentage
110203 Respiratory Diseases 30
060599 Microbiology not elsewhere classified 20
110799 Immunology not elsewhere classified 50

Professional Experience

UON Appointment

Title Organisation / Department
NHMRC Early Career Fellow University of Newcastle
School of Biomedical Sciences and Pharmacy
Australia

Academic appointment

Dates Title Organisation / Department
1/07/2017 - 30/06/2020 ARC DECRA Fellow

Australian Research Council (ARC) Discovery Early Career Researcher Award (DECRA)

ARC (Australian Research Council)
Australia
1/01/2017 - 30/06/2020 Lecturer

Research only Level B academic/research fellow

The University of Newcastle
Immunology and Microbiology, School of Biomedical Sciences and Pharmacy
Australia
1/01/2014 -  NHMRC Early Career Post-doctoral Fellow University of Newcastle
School of Biomedical Sciences and Pharmacy
Australia
1/01/2014 -  NHMRC early career fellow

NHMRC - Early Career Fellowships (Formerly Postdoctoral Training Fellowships)

University of Newcastle
Australia
1/01/2014 -  Membership - International Cytokine and Interferon Society International Cytokine and Interferon Society
Australia
1/10/2013 - 1/01/2014 Associate Lecturer University of Newcastle
Australia
1/01/2010 - 31/12/2015 Membership - Australian Lung Foundation Lung Foundation Australia
1/01/2010 - 31/12/2015 Membership - Thoracic Society of Australia and New Zealand The Thoracic Society of Australia and New Zealand
Australia
1/01/2010 - 31/12/2013 Conference Chair - Newcastle Asthma Meeting Newcastle Asthma Meeting
Australia
1/01/2008 - 31/12/2015 Membership - Australasian Society of Immunology Australasian Society of Immunology
Australia

Awards

Award

Year Award
2016 Science at The Shine Dome Early Career Travel Award
Australian Academy of Sciences
2016 Monash Department of Immunology and Pathology Travel Bursay
Monash University
2015 Australasian Society Immunology Travel Award
Australasian Society of Immunology

Distinction

Year Award
2008 Faculty of Health and Medicine Medal
University of Newcastle

Nomination

Year Award
2016 Finalist Young Alumni Awards
The University of Newcastle

Recognition

Year Award
2015 Thoracic Society of Australia and New Zealand (TSANZ) conference travel award
Unknown
2014 Priority Research Centre for Asthma and Respiratory Disease early career award
Unknown
2014 University of Newcastle, research conference travel grant
University of Newcastle
2013 Priority Research Centre for Asthma and Respiratory Disease student award
Unknown
2012 Australasian Society of Immunology travel grant
Australasian Society of Immunology
2012 New Investigator Award at Australasian Society of Immunology annual meeting
Unknown
2011 Science communication award at the Australasian Society of Immunology annual meeting
Australasian Society of Immunology

Research Award

Year Award
2016 ARC Discovery Early Career Researcher Award (DECRA)
ARC (Australian Research Council)
2015 Klosterfrau research grant
Unknown
2015 Janet Elder International travel award
Thoracic Society of Australia and New Zealand
2014 The Leo Dintenfass Memorial Award for research excellence
Unknown
2014 Peter Phelan Pediatric Travel Grant
Unknown
2014 International Cytokine and Interferon Society travel award
Unknown
2012 International laboratory exchange award
Unknown
2011 PULSE Education Prize
Unknown
2009 Cooperative Research Council for Asthma and Airways international travel award
Unknown
2008 Australian postgraduate award
Unknown
2008 Asthma Foundation PhD Scholarship
Unknown

Invitations

Speaker

Year Title / Rationale
2015 Early-life infections and the development of asthma
Organisation: Brigham and Women's Hospital and Harvard Medical School
2015 Early-life infections and chronic lung disease
Organisation: Imperial College London
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Publications

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


Journal article (30 outputs)

Year Citation Altmetrics Link
2017 Kim RY, Pinkerton JW, Essilfie AT, Robertson AA, Baines KJ, Brown AC, et al., 'Role for NLRP3 Inflammasome-mediated, IL-1ß-dependent Responses in Severe, Steroid-resistant Asthma.', Am J Respir Crit Care Med, (2017)
DOI 10.1164/rccm.201609-1830OC
Co-authors Katherine Baines, Philip Hansbro, Jodie Simpson, Nicole Hansbro, Lisa Wood, Darryl Knight, Peter Wark, Jay Horvat, Peter Gibson
2017 Kim RY, Horvat JC, Pinkerton JW, Starkey MR, Essilfie AT, Mayall JR, et al., 'MicroRNA-21 drives severe, steroid-insensitive experimental asthma by amplifying phosphoinositide 3-kinase¿mediated suppression of histone deacetylase 2', Journal of Allergy and Clinical Immunology, 139 519-532 (2017)

© 2016 American Academy of Allergy, Asthma & ImmunologyBackground Severe steroid-insensitive asthma is a substantial clinical problem. Effective treatments are urgently required,... [more]

© 2016 American Academy of Allergy, Asthma & ImmunologyBackground Severe steroid-insensitive asthma is a substantial clinical problem. Effective treatments are urgently required, however, their development is hampered by a lack of understanding of the mechanisms of disease pathogenesis. Steroid-insensitive asthma is associated with respiratory tract infections and noneosinophilic endotypes, including neutrophilic forms of disease. However, steroid-insensitive patients with eosinophil-enriched inflammation have also been described. The¿mechanisms that underpin infection-induced, severe steroid-insensitive asthma can be elucidated by using mouse models of disease. Objective We sought to develop representative mouse models of severe, steroid-insensitive asthma and to use them to identify pathogenic mechanisms and investigate new treatment approaches. Methods Novel mouse models of Chlamydia, Haemophilus influenzae, influenza, and respiratory syncytial virus respiratory¿tract infections and ovalbumin-induced, severe, steroid-insensitive allergic airway disease (SSIAAD) in BALB/c mice were developed and interrogated. Results Infection induced increases in the levels of microRNA (miRNA)-21 (miR-21) expression in the lung during SSIAAD, whereas expression of the miR-21 target phosphatase and tensin homolog was reduced. This was associated with an increase in levels of phosphorylated Akt, an indicator of phosphoinositide 3-kinase (PI3K) activity, and decreased nuclear histone deacetylase (HDAC)2 levels. Treatment with an miR-21¿specific antagomir (Ant-21) increased phosphatase and tensin homolog levels. Treatment with Ant-21, or the pan-PI3K inhibitor LY294002, reduced PI3K activity and restored HDAC2 levels. This led to suppression of airway hyperresponsiveness and restored steroid sensitivity to allergic airway disease. These observations were replicated with SSIAAD associated with 4 different pathogens. Conclusion We identify a previously unrecognized role for an¿miR-21/PI3K/HDAC2 axis in SSIAAD. Our data highlight miR-21 as a novel therapeutic target for the treatment of this form of asthma.

DOI 10.1016/j.jaci.2016.04.038
Citations Web of Science - 3
Co-authors Simon Keely, Nicole Hansbro, Philip Hansbro, Paul Foster, Joerg Mattes, Jay Horvat
2017 Al-Kouba J, Wilkinson AN, Starkey MR, Rudraraju R, Werder RB, Liu X, et al., 'Allergen-encoding bone marrow transfer inactivates allergic T cell responses, alleviating airway inflammation.', JCI Insight, 2 (2017)
DOI 10.1172/jci.insight.85742
Co-authors Jay Horvat
2017 Girkin JL, Hatchwell LM, Collison AM, Starkey MR, Hansbro PM, Yagita H, et al., 'TRAIL signaling is proinflammatory and proviral in a murine model of rhinovirus 1B infection', American Journal of Physiology - Lung Cellular and Molecular Physiology, 312 L89-L99 (2017)

© 2017 the American Physiological Society.The aim of this study is to elucidate the role of TRAIL during rhinovirus (RV) infection in vivo. Naïve wild-type and tumor necrosis fa... [more]

© 2017 the American Physiological Society.The aim of this study is to elucidate the role of TRAIL during rhinovirus (RV) infection in vivo. Naïve wild-type and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-deficient (Tnfsf10-/-) BALB/c mice were infected intranasally with RV1B. In separate experiments, Tnfsf10-/-mice were sensitized and challenged via the airway route with house dust mite (HDM) to induce allergic airways disease and then challenged with RVIB or UV-RVIB. Airway hyperreactivity (AHR) was invasively assessed as total airways resistance in response to increasing methacholine challenge and inflammation was assessed in bronchoalveolar lavage fluid at multiple time points postinfection. Chemokines were quantified by ELISA of whole lung lysates and viral load was determined by quantitative RT-PCR and tissue culture infective dose (TCID50). Human airway epithelial cells (BEAS2B) were infected with RV1B and stimulated with recombinant TRAIL or neutralizing anti-TRAIL antibodies and viral titer assessed by TCID50. HDM-challenged Tnfsf10-/-mice were protected against RV-induced AHR and had suppressed cellular infiltration in the airways upon RV infection. Chemokine C-X-C-motif ligand 2 (CXCL2) production was suppressed in naïve Tnfsf10-/-mice infected with RV1B, with less RV1B detected 24 h postinfection. This was associated with reduced apoptotic cell death and a reduction of interferon (IFN)-¿2/3 but not IFN-a or IFN-ß. TRAIL stimulation increased, whereas anti-TRAIL antibodies reduced viral replication in RV1B-infected BEAS2B cells in vitro. In conclusion, TRAIL promotes RV-induced AHR, inflammation and RV1B replication, implicating this molecule and its downstream signaling pathways as a possible target for the amelioration of RV1B-induced allergic and nonallergic lung inflammation and AHR.

DOI 10.1152/ajplung.00200.2016
Co-authors Adam Collison, Philip Hansbro, Paul Foster, Joerg Mattes
2017 Kedzierski L, Tate MD, Hsu AC, Kolesnik TB, Linossi EM, Dagley L, et al., 'Suppressor of cytokine signaling (SOCS)5 ameliorates influenza infection via inhibition of EGFR signaling.', Elife, 6 (2017)
DOI 10.7554/eLife.20444
Co-authors Peter Wark, Philip Hansbro, Alan Hsu
2017 Nair PM, Starkey MR, Haw TJ, Liu G, Horvat JC, Morris JC, et al., 'Targeting PP2A and proteasome activity ameliorates features of allergic airway disease in mice.', Allergy, (2017)
DOI 10.1111/all.13212
Co-authors Jay Horvat, Nikki Verrills
2017 Hansbro PM, Haw TJ, Starkey MR, Miyake K, 'Toll-like receptors in COPD.', Eur Respir J, 49 (2017)
DOI 10.1183/13993003.00739-2017
2017 Ali MK, Kim RY, Karim R, Mayall JR, Martin KL, Shahandeh A, et al., 'Role of iron in the pathogenesis of respiratory disease.', Int J Biochem Cell Biol, 88 181-195 (2017)
DOI 10.1016/j.biocel.2017.05.003
Co-authors Liz Milward, Jay Horvat, Philip Hansbro
2017 Hsu A, Dua K, Starkey MR, Haw TJ, Nair PM, Nichol K, et al., 'MicroRNA-125a and -b inhibit A20 and MAVS to promote inflammation and impair antiviral response in COPD', JOURNAL OF CLINICAL INVESTIGATION (JCI) Insight, (2017)
DOI 10.1172/jci.insight.90443
Co-authors Peter Wark, Paul Foster, Katherine Baines, Philip Hansbro, Alan Hsu
2016 Kim RY, Rae B, Neal R, Donovan C, Pinkerton J, Balachandran L, et al., 'Elucidating novel disease mechanisms in severe asthma', CLINICAL & TRANSLATIONAL IMMUNOLOGY, 5 (2016)
DOI 10.1038/cti.2016.37
Citations Web of Science - 1
Co-authors Chantal Donovan, Philip Hansbro, Jay Horvat, Darryl Knight
2016 Sokulsky LA, Collison AM, Nightingale S, Le Fevre A, Percival E, Starkey MR, et al., 'TRAIL deficiency and PP2A activation with salmeterol ameliorates egg allergen-driven eosinophilic esophagitis', American Journal of Physiology - Gastrointestinal and Liver Physiology, 311 G998-G1008 (2016) [C1]

© 2016 the American Physiological Society.Food antigens are common inflammatory triggers in pediatric eosinophilic esophagitis (EoE). TNFrelated apoptosis-inducing ligand (TRAIL)... [more]

© 2016 the American Physiological Society.Food antigens are common inflammatory triggers in pediatric eosinophilic esophagitis (EoE). TNFrelated apoptosis-inducing ligand (TRAIL) promotes eosinophilic inflammation through the upregulation of the E3 ubiquitin ligase Midline (MID)-1 and subsequent downregulation of protein phosphatase 2A (PP2A), but the role of this pathway in EoE that is experimentally induced by repeated food antigen challenges has not been investigated. Esophageal mucosal biopsies were collected from children with EoE and controls and assessed for TRAIL and MID-1 protein and mRNA transcript levels. Wild-type and TRAIL-deficient (Tnfsf10-/-) mice were administered subcutaneous ovalbumin (OVA) followed by oral OVA challenges. In separate experiments, OVA-challenged mice were intraperitoneally administered salmeterol or dexamethasone. Esophageal biopsies from children with EoE revealed increased levels of TRAIL and MID-1 and reduced PP2A activation compared with controls. Tnfsf10-/- mice were largely protected from esophageal fibrosis, eosinophilic inflammation, and the upregulation of TSLP, IL-5, IL-13, and CCL11 when compared with wild-type mice. Salmeterol administration to wild-type mice with experimental EoE restored PP2A activity and also prevented esophageal eosinophilia, inflammatory cytokine expression, and remodeling, which was comparable to the treatment effect of dexamethasone. TRAIL and PP2A regulate inflammation and fibrosis in experimental EoE, which can be therapeutically modulated by salmeterol.

DOI 10.1152/ajpgi.00151.2016
Co-authors Adam Collison, Philip Hansbro, Paul Foster, Joerg Mattes
2016 Russell KE, Chung KF, Clarke CJ, Durham AL, Mallia P, Footitt J, et al., 'The MIF antagonist ISO-1 attenuates corticosteroid-insensitive inflammation and airways hyperresponsiveness in an ozone-induced model of COPD', PLoS ONE, 11 (2016) [C1]

Copyright © 2016 Russell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distributi... [more]

Copyright © 2016 Russell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Introduction. Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine associated with acute and chronic inflammatory disorders and corticosteroid insensitivity. Its expression in the airways of patients with chronic obstructive pulmonary disease (COPD), a relatively steroid insensitive inflammatory disease is unclear, however. Methods. Sputum, bronchoalveolar lavage (BAL) macrophages and serum were obtained from nonsmokers, smokers and COPD patients. To mimic oxidative stress-induced COPD, mice were exposed to ozone for six-weeks and treated with ISO-1, a MIF inhibitor, and/or dexamethasone before each exposure. BAL fluid and lung tissue were collected after the final exposure. Airway hyperresponsiveness (AHR) and lung function were measured using whole body plethysmography. HIF-1a binding to the Mif promoter was determined by Chromatin Immunoprecipitation assays. Results. MIF levels in sputum and BAL macrophages from COPD patients were higher than those from non-smokers, with healthy smokers having intermediate levels. MIF expression correlated with that of HIF-1a in all patients groups and in ozone-exposed mice. BAL cell counts, cytokine mRNA and protein expression in lungs and BAL, including MIF, were elevated in ozone-exposed mice and had increased AHR. Dexamethasone had no effect on these parameters in the mouse but ISO-1 attenuated cell recruitment, cytokine release and AHR. Conclusion MIF and HIF-1a levels are elevated in COPD BAL macrophages and inhibition of MIF function blocks corticosteroid-insensitive lung inflammation and AHR. Inhibition of MIF may provide a novel anti-inflammatory approach in COPD.

DOI 10.1371/journal.pone.0146102
Citations Scopus - 4Web of Science - 4
Co-authors Philip Hansbro
2016 Haw TJ, Starkey MR, Nair PM, Pavlidis S, Liu G, Nguyen DH, et al., 'A pathogenic role for tumor necrosis factor-related apoptosis-inducing ligand in chronic obstructive pulmonary disease', Mucosal Immunology, 9 859-872 (2016) [C1]

Chronic obstructive pulmonary disease (COPD) is a life-Threatening inflammatory respiratory disorder, often induced by cigarette smoke (CS) exposure. The development of effective ... [more]

Chronic obstructive pulmonary disease (COPD) is a life-Threatening inflammatory respiratory disorder, often induced by cigarette smoke (CS) exposure. The development of effective therapies is impaired by a lack of understanding of the underlining mechanisms. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine with inflammatory and apoptotic properties. We interrogated a mouse model of CS-induced experimental COPD and human tissues to identify a novel role for TRAIL in COPD pathogenesis. CS exposure of wild-Type mice increased TRAIL and its receptor messenger RNA (mRNA) expression and protein levels, as well as the number of TRAIL + CD11b + monocytes in the lung. TRAIL and its receptor mRNA were also increased in human COPD. CS-exposed TRAIL-deficient mice had decreased pulmonary inflammation, pro-inflammatory mediators, emphysema-like alveolar enlargement, and improved lung function. TRAIL-deficient mice also developed spontaneous small airway changes with increased epithelial cell thickness and collagen deposition, independent of CS exposure. Importantly, therapeutic neutralization of TRAIL, after the establishment of early-stage experimental COPD, reduced pulmonary inflammation, emphysema-like alveolar enlargement, and small airway changes. These data provide further evidence for TRAIL being a pivotal inflammatory factor in respiratory diseases, and the first preclinical evidence to suggest that therapeutic agents that target TRAIL may be effective in COPD therapy.

DOI 10.1038/mi.2015.111
Citations Scopus - 6Web of Science - 9
Co-authors Philip Hansbro, Paul Foster, Joerg Mattes, Jay Horvat, Darryl Knight, Peter Wark, Alan Hsu, Adam Collison
2016 Gold MJ, Hiebert PR, Park HY, Stefanowicz D, Le A, Starkey MR, et al., 'Mucosal production of uric acid by airway epithelial cells contributes to particulate matter-induced allergic sensitization', Mucosal Immunology, 9 809-820 (2016) [C1]

Exposure to particulate matter (PM), a major component of air pollution, contributes to increased morbidity and mortality worldwide. PM induces innate immune responses and contrib... [more]

Exposure to particulate matter (PM), a major component of air pollution, contributes to increased morbidity and mortality worldwide. PM induces innate immune responses and contributes to allergic sensitization, although the mechanisms governing this process remain unclear. Lung mucosal uric acid has also been linked to allergic sensitization. The links among PM exposure, uric acid, and allergic sensitization remain unexplored. We therefore investigated the mechanisms behind PM-induced allergic sensitization in the context of lung mucosal uric acid. PM 10 and house dust mite exposure selectively induced lung mucosal uric acid production and secretion in vivo, which did not occur with other challenges (lipopolysaccharide, virus, bacteria, or inflammatory/fibrotic stimuli). PM 10 -induced uric acid mediates allergic sensitization and augments antigen-specific T-cell proliferation, which is inhibited by uricase. We then demonstrate that human airway epithelial cells secrete uric acid basally and after stimulation through a previously unidentified mucosal secretion system. Our work discovers a previously unknown mechanism of air pollution-induced, uric acid-mediated, allergic sensitization that may be important in the pathogenesis of asthma.

DOI 10.1038/mi.2015.104
Citations Scopus - 5Web of Science - 7
Co-authors Jay Horvat, Darryl Knight, Philip Hansbro
2016 Starkey MR, Nguyen DH, Brown AC, Essilfie AT, Kim RY, Yagita H, et al., 'PD-L1 Promotes Early-life Chlamydia Respiratory Infection-induced Severe Allergic Airway Disease.', American journal of respiratory cell and molecular biology, (2016) [C1]
Citations Scopus - 2Web of Science - 3
Co-authors Jay Horvat, Philip Hansbro
2015 Essilfie A, Horvat JC, Kim RY, Mayall JR, Pinkerton JW, Beckett EL, et al., 'Macrolide therapy suppresses key features of experimental steroid-sensitive and steroid-insensitive asthma', Thorax Journal, 70 458-467 (2015) [C1]
DOI 10.1136/thoraxjnl-2014-206067
Citations Scopus - 23Web of Science - 24
Co-authors Emma Beckett, Paul Foster, Jodie Simpson, Peter Gibson, Philip Hansbro, Jay Horvat
2015 Hsu ACY, Starkey MR, Hanish I, Parsons K, Haw TJ, Howland LJ, et al., 'Targeting PI3K-p110a suppresses influenza virus infection in chronic obstructive pulmonary disease', American Journal of Respiratory and Critical Care Medicine, 191 1012-1023 (2015) [C1]

Copyright © 2015 by the American Thoracic Society.Rationale: Chronic obstructive pulmonary disease (COPD) and influenza virus infections are major global health issues. Patients ... [more]

Copyright © 2015 by the American Thoracic Society.Rationale: Chronic obstructive pulmonary disease (COPD) and influenza virus infections are major global health issues. Patients with COPD are more susceptible to infection, which exacerbates their condition and increases morbidity and mortality. The mechanisms of increased susceptibility remain poorly understood, and current preventions and treatments have substantial limitations. Objectives: To characterize the mechanisms of increased susceptibility to influenza virus infection in COPD and the potential for therapeutic targeting. Methods: We used a combination of primary bronchial epithelial cells (pBECs) from COPD and healthy control subjects, a mouse model of cigarette smoke-induced experimental COPD, and influenza infection. The role of the phosphoinositide-3-kinase (PI3K) pathway was characterized using molecular methods, and its potential for targeting assessed using inhibitors. Measurements and Main Results: COPDpBECs were susceptible to increased viral entry and replication. Infected mice with experimental COPD also had more severe infection (increased viral titer and pulmonary inflammation, and compromised lung function). These processes were associated with impaired antiviral immunity, reduced retinoic acid-inducible gene-I, and IFN/cytokine and chemokine responses. Increased PI3K-p110a levels and activity inCOPDpBECs and/or mice were responsible for increased infection and reduced antiviral responses. Global PI3K, specific therapeutic p110a inhibitors, or exogenous IFN-b restored protective antiviral responses, suppressed infection, and improved lung function. Conclusions: The increased susceptibility of individuals with COPD to influenza likely results from impaired antiviral responses, which are mediated by increased PI3K-p110a activity. This pathway may be targeted therapeutically in COPD, or in healthy individuals, during seasonal or pandemic outbreaks to prevent and/or treat influenza.

DOI 10.1164/rccm.201501-0188OC
Citations Scopus - 23Web of Science - 24
Co-authors Darryl Knight, Philip Hansbro, Alan Hsu, Peter Wark, Paul Foster
2014 Starkey MR, Nguyen DH, Essilfie AT, Kim RY, Hatchwell LM, Collison AM, et al., 'Tumor necrosis factor-related apoptosis-inducing ligand translates neonatal respiratory infection into chronic lung disease.', Mucosal Immunol, 7 478-488 (2014) [C1]
DOI 10.1038/mi.2013.65
Citations Scopus - 11Web of Science - 11
Co-authors Paul Foster, Adam Collison, Philip Hansbro, Jay Horvat, Joerg Mattes
2014 Hansbro PM, Starkey MR, Mattes J, Horvat JC, 'Pulmonary immunity during respiratory infections in early life and the development of severe asthma', Annals of the American Thoracic Society, 11 S297-S302 (2014) [C1]

Copyright © 2014 by the American Thoracic SocietyAsthma affects 10% of the population in Westernized countries, being most common in children. It is a heterogeneous condition cha... [more]

Copyright © 2014 by the American Thoracic SocietyAsthma affects 10% of the population in Westernized countries, being most common in children. It is a heterogeneous condition characterized by chronic allergic airway inflammation, mucus hypersecretion, and airway hyperresponsiveness (AHR) to normally innocuous antigens. Combination therapies with inhaled corticosteroids and bronchodilators effectively manage mild to moderate asthma, but there are no cures, and patients with severe asthma do not respond to these treatments. The inception of asthma is linked to respiratory viral (respiratory syncytial virus, rhinovirus) and bacterial (Chlamydia, Mycoplasma) infections. The examination of mouse models of early-life infections and allergic airway disease (AAD) provides valuable insights into the mechanisms of disease inception that may lead to the development of more effective therapeutics. For example, early-life, but not adult, Chlamydia respiratory infections in mice permanently modify immunity and lung physiology. This increases the severity of AAD by promoting IL-13 expression, mucus hypersecretion, and AHR. We have identified novel roles for tumor necrosis factor-related apoptosisinducing ligand (TRAIL) and IL-13 in promoting infection-induced pathology in early life and subsequent chronic lung disease. Genetic deletion of TRAIL or IL-13 variously protected against neonatal infection-induced inflammation, mucus hypersecretion, altered lung structure, AHR, and impaired lung function. Therapeutic neutralization of these factors prevented infection-induced severe AAD. Other novel mechanisms and avenues for intervention are also being explored. Such studies indicate the immunological mechanisms that may underpin the association between early-life respiratory infections and the development of more severe asthma and may facilitate the development of tailored preventions and treatments.

DOI 10.1513/AnnalsATS.201402-086AW
Citations Scopus - 5
Co-authors Joerg Mattes, Philip Hansbro, Jay Horvat
2013 Starkey MR, Nguyen DH, Kim RY, Nair PM, Brown AC, Essifie A-T, et al., 'Programming of the Lung in Early Life by Bacterial Infections Predisposes to Chronic Respiratory Disease', CLINICAL OBSTETRICS AND GYNECOLOGY, 56 566-576 (2013) [C1]
DOI 10.1097/GRF.0b013e3182993a0c
Citations Scopus - 5Web of Science - 3
Co-authors Jay Horvat, Philip Hansbro
2013 Hansbro PM, Scott GV, Essilfie A-T, Kim RY, Starkey MR, Nguyen D, et al., 'Th2 cytokine antagonists: Potential treatments for severe asthma', Expert Opinion on Investigational Drugs, 22 49-69 (2013) [C1]
Citations Scopus - 23Web of Science - 20
Co-authors Jay Horvat, Ming Yang, Philip Hansbro, Paul Foster
2013 Starkey MR, Jarnicki AG, Essilfie A-T, Gellatly SL, Kim RY, Brown AC, et al., 'Murine models of infectious exacerbations of airway inflammation', CURRENT OPINION IN PHARMACOLOGY, 13 337-344 (2013) [C1]
DOI 10.1016/j.coph.2013.03.005
Citations Scopus - 21Web of Science - 22
Co-authors Paul Foster, Philip Hansbro, Jay Horvat
2013 Starkey MR, Essilfie A-T, Horvat JC, Kim RY, Nguyen DH, Beagley KW, et al., 'Constitutive production of IL-13 promotes early-life Chlamydia respiratory infection and allergic airway disease', Mucosal Immunology, 6 569-579 (2013) [C1]
Citations Scopus - 17Web of Science - 15
Co-authors Jay Horvat, Paul Foster, Joerg Mattes, Philip Hansbro
2012 Beckett EL, Phipps S, Starkey MR, Horvat JC, Beagley KW, Foster PS, Hansbro PM, 'TLR2, but not TLR4, is required for effective host defence against chlamydia respiratory tract infection in early life', PLOS One, 7 e39460-e39460 (2012) [C1]
DOI 10.1371/journal.pone.0039460
Citations Scopus - 30Web of Science - 23
Co-authors Emma Beckett, Jay Horvat, Philip Hansbro, Paul Foster
2012 Starkey MR, Kim RY, Beckett EL, Schilter HC, Shim D, Essilfie A-T, et al., 'Chlamydia muridarum lung infection in infants alters hematopoietic cells to promote allergic airway disease in mice', PLoS One, 7 e42588-e42588 (2012) [C1]
DOI 10.1371/journal.pone.0042588
Citations Scopus - 14Web of Science - 13
Co-authors Jay Horvat, Joerg Mattes, Emma Beckett, Philip Hansbro
2012 Hansbro PM, Starkey MR, Kim RY, Stevens RL, Foster PS, Horvat JC, 'Programming of the lung by early-life infection', Journal of Developmental Origins of Health and Disease, 3 153-158 (2012) [C1]
Citations Scopus - 7Web of Science - 5
Co-authors Paul Foster, Philip Hansbro, Jay Horvat
2011 Preston JA, Thorburn AN, Starkey MR, Beckett EL, Horvat JC, Wade MA, et al., 'Streptococcus pneumoniae infection suppresses allergic airways disease by inducing regulatory T-cells', European Respiratory Journal, 37 53-64 (2011) [C1]
DOI 10.1183/09031936.00049510
Citations Scopus - 43Web of Science - 38
Co-authors Peter Gibson, Jay Horvat, Paul Foster, Emma Beckett, Philip Hansbro
2010 Horvat JC, Starkey MR, Kim RY, Beagley KW, Preston JA, Gibson PG, et al., 'Chlamydial respiratory infection during allergen sensitization drives neutrophilic allergic airways disease', Journal of Immunology, 184 4159-4169 (2010) [C1]
DOI 10.4049/jimmunol.0902287
Citations Scopus - 50Web of Science - 46
Co-authors Philip Hansbro, Jay Horvat, Peter Gibson, Paul Foster
2010 Horvat JC, Starkey MR, Kim RY, Phipps S, Gibson PG, Beagley KW, et al., 'Early-life chlamydial lung infection enhances allergic airways disease through age-dependent differences in immunopathology', Journal of Allergy and Clinical Immunology, 125 617-625 (2010) [C1]
DOI 10.1016/j.jaci.2009.10.018
Co-authors Jay Horvat, Peter Gibson, Paul Foster, Philip Hansbro
2010 Starkey MR, Horvat JC, Kim RY, Hansbro PM, 'Reply', Journal of Allergy and Clinical Immunology, 125 1415 (2010) [C3]
DOI 10.1016/j.jaci.2010.03.033
Co-authors Philip Hansbro, Jay Horvat
Show 27 more journal articles

Conference (27 outputs)

Year Citation Altmetrics Link
2017 Kim RY, Pinkerton JW, Rae B, Mayall JR, Brown AC, Ali M, et al., 'Impaired Induction Of Slc26a4 Promotes Respiratory Acidosis And Severe, Steroid-Insensitive Asthma', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE (2017)
Co-authors Jay Horvat
2017 Starkey MR, Dua K, Hsu AC, Nair PM, Haw TJ, Nguyen DH, et al., 'Interleukin-13 Predisposes To More Severe Influenza Infection In Mice And Human Epithelial Cells By Suppressing Interferon Responses And Activating The Microrna-21/pi3k Signaling Pathway', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE (2017)
Co-authors Jay Horvat, Alan Hsu
2017 Starkey MR, Nguyen DH, Kim RY, Nair PM, Haw TJ, Horvat JC, et al., 'Early Life Respiratory Bacterial Infection-Induced Chronic Lung Disease Is Driven By A Novel Tlr2/il-13/mir-21/pi3k Signaling Pathway', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE (2017)
Co-authors Jay Horvat
2017 Collison A, Li J, De Siqueira AP, Lv X, Toop HD, Morris JC, et al., 'THE E3 UBIQUITIN LIGASE MID1 PROMOTES IDIOPATHIC PULMONARY FIBROSIS', RESPIROLOGY (2017)
Co-authors Adam Collison, Philip Hansbro
2016 Kim RY, Pinkerton JW, Essilfie A-T, Robertson AA, Baines KJ, Mayall JR, et al., 'Nlrp3 Inflammasome-Mediated, Il-1 beta-Dependent Inflammatory Responses Drive Severe, Steroid-Insensitive Asthma', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE (2016)
Co-authors Katherine Baines, Peter Wark, Jay Horvat, Philip Hansbro, Peter Gibson
2016 Starkey MR, Dua K, Hsu AC, Nair PM, Haw TJ, Nguyen DH, et al., 'Interleukin-13 predisposes to more severe influenza infection in mice and human epithelial cells by suppressing interferon responses and activating the microRNA-21/PI3K signaling pathway', EUROPEAN JOURNAL OF IMMUNOLOGY (2016)
Co-authors Peter Wark, Paul Foster, Jay Horvat, Alan Hsu, Philip Hansbro
2016 Starkey MR, Nguyen DH, Kim RY, Haw TJ, Nair PM, Essilfie AT, et al., 'Early-life respiratory bacterial infection-induced chronic lung disease is driven by a novel TLR2/IL-13/miR-21/PI3K signaling pathway', EUROPEAN JOURNAL OF IMMUNOLOGY (2016)
Co-authors Paul Foster, Jay Horvat, Philip Hansbro
2016 Collison A, Sokulsky LA, Starkey MR, Nightingale S, Le Fevre A, Percival E, et al., 'TRAIL regulates egg-allergen induced eosinophilic oesophagitis', EUROPEAN JOURNAL OF IMMUNOLOGY (2016)
Co-authors Philip Hansbro, Joerg Mattes, Paul Foster, Adam Collison
2015 Kim R, Horvat J, Pinkerton J, Starkey M, Essilfie A, Mayall J, et al., 'INFECTION-INDUCED MICRORNA-21 DRIVES SEVERE, STEROID-INSENSITIVE EXPERIMENTAL ASTHMA BY AMPLIFYING PI3K-MEDIATED SUPPRESSION OF HDAC2', RESPIROLOGY (2015) [E3]
Co-authors Simon Keely, Philip Hansbro, Paul Foster, Jay Horvat, Joerg Mattes
2015 Hansbro PM, Kim RY, Pinkerton JW, Starkey MR, Essilfie AT, Mayall JR, et al., 'Infection-Induced Microrna-21 Drives Severe, Steroid-Insensitive Experimental Asthma By Amplifying PhosphoINOSitide-3-Kinase (pi3k)-Mediated Suppression Of Histone Deacetylase (hdac)2', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE (2015)
Co-authors Simon Keely, Philip Hansbro, Joerg Mattes, Jay Horvat, Paul Foster
2014 Hansbro PM, Horvat JC, Kim RY, Mayall JR, Pinkerton JW, Essilfie A-T, et al., 'Antioxidant Treatment Suppresses The Progression Of Early-Life Infection-Induced Severe Asthma And Pathology In Later-Life', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE (2014)
Citations Web of Science - 1
Co-authors Philip Hansbro, Lisa Wood, Jay Horvat
2014 Starkey M, Hanish I, Dua K, Nair P, Haw T, Hsu A, et al., 'Interleukin-13 predisposes mice to more severe influenza infection by suppressing interferon responses and activating microRNA-21/PI3K', CYTOKINE (2014) [E3]
DOI 10.1016/j.cyto2014.07.182
Citations Web of Science - 1
Co-authors Jay Horvat, Paul Foster, Philip Hansbro, Darryl Knight, Alan Hsu, Peter Wark
2014 Horvat J, Kim R, Mayall J, Pinkerton J, Starkey M, Essilfie A, et al., 'ANTIOXIDANT-BASED THERAPY FOR THE SUPPRESSION OF EARLY- LIFE INFECTION-INDUCED SEVERE ASTHMA', RESPIROLOGY (2014) [E3]
DOI 10.1111/resp.12263_2
Co-authors Philip Hansbro, Jay Horvat, Lisa Wood
2014 Girkin J, Sokulsky L, Hatchwell L, Starkey M, Collison A, Hansbro P, Mattes J, 'IDENTIFICATION OF A NOVEL INTERLEUKIN-13 SIGNALLING PATHWAY', RESPIROLOGY (2014) [E3]
Co-authors Adam Collison, Joerg Mattes, Philip Hansbro
2014 Starkey MR, Hanish I, Dua K, Hsu A, Monogar P, Foster PS, et al., 'Interleukin-13 Predisposes Mice To More Severe Influenza Infection And Exacerbated Allergic Airways Disease', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE (2014)
Co-authors Alan Hsu, Darryl Knight, Paul Foster, Philip Hansbro, Peter Wark
2013 Hansbro PM, Horvat JC, Essilfie A-T, Kim RY, Mayall J, Starkey MR, et al., 'Immunomodulatory Effects Of Macrolide Treatment On Experimental Models Of Steroid-Sensitive And Steroid-Resistant Asthma', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE (2013)
Co-authors Paul Foster, Philip Hansbro, Jay Horvat
2013 Kim RY, Horvat JC, Starkey MR, Essilfie A, Foster PS, Hansbro PM, 'Inhibition Of Early-Life Chlamydia Lung Infection-Induced Micrornas Prevents Infection-Induced Lung Pathologies In Later Life', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE (2013)
Co-authors Philip Hansbro, Paul Foster, Jay Horvat
2013 Hansbro P, Horvat J, Essilfie A-T, Kim R, Mayall J, Starkey M, Foster P, 'Macrolides suppress key features of experimental steroid-sensitive and steroid-resistant asthma', JOURNAL OF IMMUNOLOGY (2013) [E3]
Co-authors Paul Foster, Philip Hansbro, Emma Beckett, Jay Horvat
2013 Kim RY, Horvat JC, Starkey MR, Essilfie A-T, Foster PS, Hansbro PM, 'MICRORNA INHIBITION IN NEONATAL CHLAMYDIA LUNG INFECTION PREVENTS INFECTION-INDUCED LUNG PATHOLOGY IN LATER LIFE', RESPIROLOGY (2013) [E3]
Co-authors Philip Hansbro, Jay Horvat, Paul Foster
2013 Horvat JC, Essilfie A-T, Kim RY, Mayall JR, Starkey MR, Beckett EL, et al., 'MACROLIDES SUPPRESS KEY FEATURES OF EXPERIMENTAL STEROID-SENSITIVE AND STEROID-RESISTANT ASTHMA', RESPIROLOGY (2013) [E3]
Co-authors Jay Horvat, Philip Hansbro, Peter Gibson, Emma Beckett, Paul Foster, Jodie Simpson
2012 Horvat JC, Essilfie A-T, Kim RY, Mayall JR, Starkey MR, Beckett EL, et al., 'Efficacy of antibiotic-based therapeutic strategies for the treatment of infection-induced, steroid-resistant allergic airways disease', Respirology (2012) [E3]
Co-authors Emma Beckett, Paul Foster, Jay Horvat, Philip Hansbro
2012 Starkey MR, Kim RY, Horvat JC, Essilfie A-T, Beagley KW, Mattes J, et al., 'Constitutive IL-13 promotes respiratory chlamydial infection-induced chronic airway hyperresponsiveness', Respirology (2012) [E3]
Co-authors Joerg Mattes, Jay Horvat, Paul Foster, Philip Hansbro
2009 Hansbro PM, Starkey MR, Horvat JC, Kim RY, Phipps S, Gibson PG, Foster PS, 'Early life chlamydial infection enhances allergic airways disease through age-dependent differences in immunopathology', Journal of Immunology (2009) [E3]
DOI 10.1016/j.jaci.2009.10.018
Co-authors Paul Foster, Jay Horvat, Philip Hansbro, Peter Gibson
2009 Horvat JC, Starkey MR, Beagley KW, Gibson PG, Foster PS, Hansbro PM, 'Chlamydial respiratory infection predisposes to neutrophil dominated allergic airways disease (AAD)', Journal of Immunology (2009) [E3]
Co-authors Paul Foster, Jay Horvat, Philip Hansbro, Peter Gibson
2009 Horvat JC, Starkey MR, Beagley KW, Preston JA, Gibson PG, Foster PS, Hansbro PM, 'Neutrophil influx during chlamydial lung infection determines the phenotype of allergic airways disease (AAD)', Respirology (2009) [E3]
DOI 10.1111/j.1440-1843.2009.01503_1.x
Co-authors Philip Hansbro, Peter Gibson, Jay Horvat, Paul Foster
2009 Starkey MR, Horvat JC, Kim RY, Phipps S, Gibson PG, Beagley KW, et al., 'Early life chlamydial lung infection enhances allergic airways disease through age-dependent differences in immunopathology', Respirology (2009) [E3]
DOI 10.1016/j.jaci.2009.10.018
Citations Scopus - 60Web of Science - 57
Co-authors Peter Gibson, Jay Horvat, Philip Hansbro, Paul Foster
2008 Starkey MR, Horvat JC, Kim RY, Phipps S, Gibson PG, Beagley KW, et al., 'Early life chlamydial lung infection enhances allergic airways disease through age-dependent differences in immunopathology', Australasian Society for Immunology 38th Annual Scientific Meeting: Delegate Book (2008) [E3]
Co-authors Paul Foster, Jay Horvat, Philip Hansbro, Peter Gibson
Show 24 more conferences
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Grants and Funding

Summary

Number of grants 14
Total funding $894,843

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


20173 grants / $407,000

Understanding how innate lymphoid cells regulate mammalian lung development$372,000

Funding body: ARC (Australian Research Council)

Funding body ARC (Australian Research Council)
Project Team Doctor Malcolm Starkey
Scheme Discovery Early Career Researcher Award (DECRA)
Role Lead
Funding Start 2017
Funding Finish 2019
GNo G1600344
Type Of Funding Aust Competitive - Commonwealth
Category 1CS
UON Y

Understanding how immune cells repair the kidney$20,000

Funding body: Hunter Medical Research Institute

Funding body Hunter Medical Research Institute
Project Team Doctor Malcolm Starkey, Dr Aniruddh Deshpande
Scheme Project Grant
Role Lead
Funding Start 2017
Funding Finish 2017
GNo G1700006
Type Of Funding Grant - Aust Non Government
Category 3AFG
UON Y

DVC(RI) Research Support for DECRA (DE17)$15,000

Funding body: University of Newcastle

Funding body University of Newcastle
Project Team Doctor Malcolm Starkey
Scheme DECRA Support
Role Lead
Funding Start 2017
Funding Finish 2019
GNo G1701000
Type Of Funding Internal
Category INTE
UON Y

20154 grants / $99,827

Nose only inhalation smoke exposure system for mice$54,698

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, Doctor Jay Horvat, Doctor Janet Bristow, Doctor Malcolm Starkey, Doctor Rebecca Vanders
Scheme Equipment Grant
Role Investigator
Funding Start 2015
Funding Finish 2015
GNo G1501551
Type Of Funding Other Public Sector - Commonwealth
Category 2OPC
UON Y

Early-life infections and the development of chronic disease$28,129

Funding body: Klosterfrau Healthcare Group

Funding body Klosterfrau Healthcare Group
Project Team Doctor Malcolm Starkey
Scheme Klosterfrau Research Grant
Role Lead
Funding Start 2015
Funding Finish 2015
GNo G1500307
Type Of Funding International - Competitive
Category 3IFA
UON Y

Understanding how lung infections in childhood promote the development of chronic lung diseases in later life$15,000

Funding body: Hunter Medical Research Institute

Funding body Hunter Medical Research Institute
Project Team Doctor Malcolm Starkey
Scheme Project Grant
Role Lead
Funding Start 2015
Funding Finish 2015
GNo G1501367
Type Of Funding Grant - Aust Non Government
Category 3AFG
UON Y

European Congress Immunology, Austria 6-9 September 2015$2,000

Funding body: University of Newcastle - Faculty of Health and Medicine

Funding body University of Newcastle - Faculty of Health and Medicine
Project Team Doctor Malcolm Starkey
Scheme Travel Grant
Role Lead
Funding Start 2015
Funding Finish 2015
GNo G1500847
Type Of Funding Internal
Category INTE
UON Y

20144 grants / $364,016

Understanding how early-life respiratory infections promote chronic lung diseases$316,450

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

Funding body NHMRC (National Health & Medical Research Council)
Project Team Doctor Malcolm Starkey
Scheme Early Career Fellowships
Role Lead
Funding Start 2014
Funding Finish 2017
GNo G1300678
Type Of Funding Aust Competitive - Commonwealth
Category 1CS
UON Y

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

Identification of novel therapeutic targets for Chronic Obstructive Pulmonary Disease$22,000

Funding body: Rebecca L Cooper Medical Research Foundation Ltd

Funding body Rebecca L Cooper Medical Research Foundation Ltd
Project Team Doctor Malcolm Starkey
Scheme Research Grant
Role Lead
Funding Start 2014
Funding Finish 2014
GNo G1301214
Type Of Funding Grant - Aust Non Government
Category 3AFG
UON Y

American Thoracic Society Annual Meeting, San Diego USA, 16-21 May 2014$2,000

Funding body: University of Newcastle - Faculty of Health and Medicine

Funding body University of Newcastle - Faculty of Health and Medicine
Project Team Doctor Malcolm Starkey
Scheme Travel Grant
Role Lead
Funding Start 2014
Funding Finish 2014
GNo G1400304
Type Of Funding Internal
Category INTE
UON Y

20132 grants / $20,000

HMRI Exchange Visit Travel Award 2012$10,000

Funding body: Hunter Medical Research Institute

Funding body Hunter Medical Research Institute
Project Team Doctor Malcolm Starkey
Scheme Project Grant
Role Lead
Funding Start 2013
Funding Finish 2013
GNo G1300228
Type Of Funding Contract - Aust Non Government
Category 3AFC
UON Y

Role of the transcriptional co-activator p300 in resetting epithelial differentiation: A potential pathway involved in asthma prevention and therapy$10,000

Funding body: University of Newcastle

Funding body University of Newcastle
Project Team Doctor Fatemeh Moheimani, Professor Darryl Knight, Ms Kirsty Wark, Doctor Alan Hsu, Doctor Malcolm Starkey
Scheme Early Career Researcher Grant
Role Investigator
Funding Start 2013
Funding Finish 2013
GNo G1301174
Type Of Funding Internal
Category INTE
UON Y

20121 grants / $4,000

PULSE Education Prize$4,000

Funding body: Hunter Medical Research Institute

Funding body Hunter Medical Research Institute
Project Team Doctor Malcolm Starkey
Scheme PULSE Education Prize
Role Lead
Funding Start 2012
Funding Finish 2012
GNo G1200107
Type Of Funding Scheme excluded from IGS
Category EXCL
UON Y
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Research Supervision

Number of supervisions

Completed3
Current4

Total current UON EFTSL

PhD0.65

Current Supervision

Commenced Level of Study Research Title Program Supervisor Type
2016 PhD Dietary Intervention to Reduce Exacerbations in Children with Asthma PhD (Nutritional Biochemistry), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor
2015 PhD Generational Effects of Smoking in Pregnancy PhD (Immunology & Microbiol), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor
2013 PhD Role of TLR/IL-13/STAT6/PI3K Response in Early-life Respiratory Infection and Infection-Induced Chronic Lung Disease PhD (Immunology & Microbiol), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor
2013 PhD Investigation of the pathogenesis and potential therapeutic interventions of influenza in Asthma and COPD PhD (Immunology & Microbiol), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor

Past Supervision

Year Level of Study Research Title Program Supervisor Type
2016 PhD Investigation of Pathogenesis of Chronic Obstructive Pulmonary Disease PhD (Immunology & Microbiol), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor
2016 PhD Immunoregulatory Therapies for Inflammatory Diseases PhD (Immunology & Microbiol), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor
2015 PhD Mechanisms of Increased Susceptibility to Influenza Infection in Mouse Models of Chronic Lung Diseases PhD (Immunology & Microbiol), Faculty of Health and Medicine, The University of Newcastle Co-Supervisor
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Research Opportunities

Understanding how innate lymphoid cells regulate mammalian lung development

This project aims to identify new basic biological processes that are involved in mammalian lung development. For this we will elucidate the roles of a recently described subset of innate immune cells, known as innate lymphoid cells (ILCs), to promote normal lung development through the regulation of stem cells. The lung is constantly exposed to countless environmental challenges. Mammalian systems have evolved a local immune system that protects the lung against these challenges. This is particularly important in early-life when the lung is still developing. In ground-breaking studies, we have discovered new processes that regulate ILC homeostasis and that challenges in early-life impair ILC homeostasis and result in a loss of stem cells, and abnormal lung development. The logical and important next step is to understand the contribution of ILCs to these processes.

PHD

School of Biomedical Sciences and Pharmacy

30/06/2017 - 30/12/2020

Contact

Doctor Malcolm Starkey
University of Newcastle
School of Biomedical Sciences and Pharmacy
malcolm.starkey@newcastle.edu.au

Understanding how immune cells repair the kidney after acute kidney injury

Acute kidney injury is increasing in incidence globally and there is a strong association between acute kidney injury and the development of chronic kidney disease. In Australia more than 5,000 deaths are attributed to acute kidney injury annually and the health care burden of kidney disease exceeds $4 billion annually. The number of hospitalisations for acute kidney injury have more than doubled over the last decade and those who live in remote areas, are socioeconomically disadvantaged or are of aboriginal and Torress Strait Islander descent are at the greatest risk of hospitalisation and death. Ischemia reperfusion injury is a common cause of acute kidney injury and results from impaired oxygen and nutrient delivery to, and waste product removal from, the cells of the kidney. There are many causes of ischemia including multiple organ failure and sepsis. The immune system is known to be pivotal in regulating the repair of the kidney after injury. However, as our understanding of the immune system grows and becomes more complex, new cells are identified that may hold the key to understanding the switch that controls whether the kidney is appropriately repaired or not. We believe a new immune cell subset known as innate lymphoid cells may be the regulator of that switch as these cells promote repair and regeneration of structural cells in other organs such as the lung and intestine. However, their role in the kidney is poorly understood.

PHD

School of Biomedical Sciences and Pharmacy

30/06/2017 - 30/12/2020

Contact

Doctor Malcolm Starkey
University of Newcastle
School of Biomedical Sciences and Pharmacy
malcolm.starkey@newcastle.edu.au

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Research Collaborations

The map is a representation of a researchers co-authorship with collaborators across the globe. The map displays the number of publications against a country, where there is at least one co-author based in that country. Data is sourced from the University of Newcastle research publication management system (NURO) and may not fully represent the authors complete body of work.

Country Count of Publications
Australia 56
United Kingdom 9
Japan 5
Canada 4
United States 4
More...
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News

Australian Research Council Funding Success

November 1, 2016

The University of Newcastle (UON) has been successfully awarded over $5.7 million in 2016 Australian Research Council (ARC) funding for Discovery Projects, Future Fellowships and Discovery Early Career Researcher Awards.

UON researchers shine in a glittering field of finalists

September 7, 2016

The University of Newcastle (UON) Alumni Awards Finalists have been announced, and we are delighted to see a broad range of UON researchers represented in the outstanding field.

Dr Malcolm Starkey

Position

NHMRC Early Career Fellow
School of Biomedical Sciences and Pharmacy
Faculty of Health and Medicine

Focus area

Immunology and Microbiology

Contact Details

Email malcolm.starkey@newcastle.edu.au
Phone (02) 40420204

Office

Room W2-106 Level 2 East
Building HMRI Building
Location John Hunter Hospital New Lambton Heights

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