Dr Alexandra Brown

Post Doctorate Researcher

School of Biomedical Sciences and Pharmacy

Career Summary

Qualifications

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

Keywords

  • Immunology
  • Microbiology
  • Respiratory Disease

Languages

  • English (Mother)

Fields of Research

Code Description Percentage
320103 Respiratory diseases 40
320211 Infectious diseases 30
320499 Immunology not elsewhere classified 30

Professional Experience

UON Appointment

Title Organisation / Department
Post Doctorate Researcher University of Newcastle
School of Biomedical Sciences and Pharmacy
Australia

Awards

Award

Year Award
2016 ICI Travel Award
Australasian Society for Immunology

Recipient

Year Award
2019 Faculty of Health and Medicine Research Travel Grant Scheme
Faculty of Health and Medicine, The University of Newcastle
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Publications

For publications that are currently unpublished or in-press, details are shown in italics.


Journal article (16 outputs)

Year Citation Altmetrics Link
2021 Brown AC, Horvat JC, 'Casting Iron in the Pathogenesis of Fibrotic Lung Disease.', Am J Respir Cell Mol Biol, 65 130-131 (2021)
DOI 10.1165/rcmb.2021-0135ED
Co-authors Jay Horvat
2020 Vidaillac C, Yong VFL, Aschtgen MS, Qu J, Yang S, Xu G, et al., 'Sex steroids induce membrane stress responses and virulence properties in pseudomonas aeruginosa', mBio, 11 1-19 (2020) [C1]

Estrogen, a major female sex steroid hormone, has been shown to promote the selection of mucoid Pseudomonas aeruginosa in the airways of patients with chronic respiratory diseases... [more]

Estrogen, a major female sex steroid hormone, has been shown to promote the selection of mucoid Pseudomonas aeruginosa in the airways of patients with chronic respiratory diseases, including cystic fibrosis. This results in long-term persistence, poorer clinical outcomes, and limited therapeutic options. In this study, we demonstrate that at physiological concentrations, sex steroids, including testosterone and estriol, induce membrane stress responses in P. aeruginosa. This is characterized by increased virulence and consequent inflammation and release of proinflammatory outer membrane vesicles promoting in vivo persistence of the bacteria. The steroid-induced P. aeruginosa response correlates with the molecular polarity of the hormones and membrane fluidic properties of the bacteria. This novel mechanism of interaction between sex steroids and P. aeruginosa explicates the reported increased disease severity observed in females with cystic fibrosis and provides evidence for the therapeutic potential of the modulation of sex steroids to achieve better clinical outcomes in patients with hormone-responsive strains. IMPORTANCE Molecular mechanisms by which sex steroids interact with P. aeruginosa to modulate its virulence have yet to be reported. Our work provides the first characterization of a steroid-induced membrane stress mechanism promoting P. aeruginosa virulence, which includes the release of proinflammatory outer membrane vesicles, resulting in inflammation, host tissue damage, and reduced bacterial clearance. We further demonstrate that at nanomolar (physiological) concentrations, male and female sex steroids promote virulence in clinical strains of P. aeruginosa based on their dynamic membrane fluidic properties. This work provides, for the first-time, mechanistic insight to better understand and predict the P. aeruginosa related response to sex steroids and explain the interindividual patient variability observed in respiratory diseases such as cystic fibrosis that are complicated by gender differences and chronic P. aeruginosa infection.

DOI 10.1128/mBio.01774-20.
Citations Scopus - 3Web of Science - 4
Co-authors Jay Horvat, Philip Hansbro
2020 Marshall RJ, Armart P, Hulme KD, Chew KY, Brown AC, Hansbro PM, et al., 'Glycemic Variability in Diabetes Increases the Severity of Influenza', MBIO, 11 (2020) [C1]
DOI 10.1128/mBio.02841-19
Citations Scopus - 16Web of Science - 16
Co-authors Philip Hansbro
2020 Ali MK, Kim RY, Brown AC, Donovan C, Vanka KS, Mayall JR, et al., 'Critical role for iron accumulation in the pathogenesis of fibrotic lung disease', JOURNAL OF PATHOLOGY, 251 49-62 (2020) [C1]
DOI 10.1002/path.5401
Citations Scopus - 19Web of Science - 18
Co-authors Chantal Donovan, Liz Milward, Jay Horvat, Jemma Mayall, Philip Hansbro
2020 Ali MK, Kim RY, Brown AC, Mayall JR, Karim R, Pinkerton JW, et al., 'Crucial role for lung iron level and regulation in the pathogenesis and severity of asthma', EUROPEAN RESPIRATORY JOURNAL, 55 (2020) [C1]
DOI 10.1183/13993003.01340-2019
Citations Scopus - 5Web of Science - 7
Co-authors Liz Holliday, Philip Hansbro, Jay Horvat, Jemma Mayall, Chantal Donovan, Prabuddha Pathinayake, Paul Foster, Liz Milward, Peter Wark, Malcolm Starkey, Hock Tay
2020 Vidaillac C, Yong VFL, Aschtgen M-S, Qu J, Yang S, Xu G, et al., 'Sex Steroids Induce Membrane Stress Responses and Virulence Properties in Pseudomonas aeruginosa (vol 11, e01774-20, 2020)', MBIO, 11 (2020)
DOI 10.1128/mBio.02809-20
Co-authors Jay Horvat, Philip Hansbro
2020 Pinkerton JW, Kim RY, Koeninger L, Armbruster NS, Hansbro NG, Brown AC, et al., 'Human beta-defensin-2 suppresses key features of asthma in murine models of allergic airways disease', CLINICAL AND EXPERIMENTAL ALLERGY, 51 120-131 (2020) [C1]
DOI 10.1111/cea.13766
Citations Scopus - 2Web of Science - 2
Co-authors Jay Horvat, Philip Hansbro
2019 Keenan CR, Iannarella N, Garnham AL, Brown AC, Kim RY, Horvat JC, et al., 'Polycomb repressive complex 2 is a critics mediator of allergic inflammation', JCI INSIGHT, 4 (2019) [C1]
DOI 10.1172/jci.insight.127745
Citations Scopus - 9Web of Science - 9
Co-authors Philip Hansbro, Jay Horvat
2017 Liu G, Cooley MA, Nair PM, Donovan C, Hsu AC, Jarnicki AG, et al., 'Airway remodelling and inflammation in asthma are dependent on the extracellular matrix protein fibulin-1c', JOURNAL OF PATHOLOGY, 243 510-523 (2017) [C1]
DOI 10.1002/path.4979
Citations Scopus - 49Web of Science - 50
Co-authors Paul Foster, Peter Wark, Alan Hsu, Christopher Grainge, Philip Hansbro, Jay Horvat, Hock Tay, Darryl Knight, Chantal Donovan
2017 Kim RY, Pinkerton JW, Essilfie AT, Robertson AAB, Baines KJ, Brown AC, et al., 'Role for NLRP3 inflammasome-mediated, IL-1ß-dependent responses in severe, steroid-resistant asthma', American Journal of Respiratory and Critical Care Medicine, 196 283-297 (2017) [C1]

Rationale: Severe, steroid-resistant asthma is the major unmet need in asthma therapy. Disease heterogeneity and poor understanding of pathogenic mechanisms hampers the identifica... [more]

Rationale: Severe, steroid-resistant asthma is the major unmet need in asthma therapy. Disease heterogeneity and poor understanding of pathogenic mechanisms hampers the identification of therapeutic targets. Excessive nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome and concomitant IL-1ß responses occur in chronic obstructive pulmonary disease, respiratory infections, and neutrophilic asthma. However, the direct contributions to pathogenesis, mechanisms involved, and potential for therapeutic targeting remain poorly understood, and are unknown in severe, steroid-resistant asthma. Objectives: To investigate the roles and therapeutic targeting of the NLRP3 inflammasome and IL-1ß in severe, steroid-resistant asthma. Methods: We developed mouse models of Chlamydia and Haemophilus respiratory infection-mediated, ovalbumin-induced severe, steroid-resistant allergic airway disease. These models share the hallmark features of human disease, including elevated airway neutrophils, and NLRP3 inflammasome and IL-1ß responses. The roles and potential for targeting of NLRP3 inflammasome, caspase-1, and IL-1ß responses in experimental severe, steroid-resistant asthma were examined using a highly selective NLRP3 inhibitor, MCC950; the specific caspase-1 inhibitor Ac-YVAD-cho; and neutralizing anti-IL-1ß antibody. Roles for IL-1ß-induced neutrophilic inflammation were examined using IL-1ß and anti-Ly6G. Measurements and Main Results: Chlamydia and Haemophilus infections increase NLRP3, caspase-1, IL-1ß responses that drive steroid-resistant neutrophilic inflammation and airway hyperresponsiveness. Neutrophilic airway inflammation, disease severity, and steroid resistance in human asthma correlate with NLRP3 and IL-1ß expression. Treatment with anti-IL-1ß, Ac- YVAD-cho, and MCC950 suppressed IL-1ß responses and the important steroid-resistant features of disease in mice, whereas IL-1ß administration recapitulated these features. Neutrophil depletion suppressed IL-1ß-induced steroid-resistant airway hyperresponsiveness. Conclusions: NLRP3 inflammasome responses drive experimental severe, steroid-resistant asthma and are potential therapeutic targets in this disease.

DOI 10.1164/rccm.201609-1830OC
Citations Scopus - 152Web of Science - 152
Co-authors Lisa Wood, Jay Horvat, Darryl Knight, Jemma Mayall, Philip Hansbro, Katherine Baines, Malcolm Starkey, Peter Wark, Peter Gibson, Jodie Simpson
2016 Simpson JL, Baines KJ, Horvat JC, Essilfie AT, Brown AC, Tooze M, et al., 'COPD is characterized by increased detection of Haemophilus influenzae, Streptococcus pneumoniae and a deficiency of Bacillus species', Respirology, 21 697-704 (2016) [C1]

Background and objective Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation and inflammation. Airway bacterial colonization is increas... [more]

Background and objective Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation and inflammation. Airway bacterial colonization is increased in COPD; however, the role of potentially pathogenic and non-pathogenic bacteria in the pathogenesis of disease is unclear. This study characterized the presence of bacteria in a well-characterized cohort of adults with COPD and healthy controls. Methods Adults with COPD (n = 70) and healthy controls (n = 51) underwent clinical assessment and sputum induction. Sputum was dispersed, and total and differential cell counts were performed. Bacteria were cultured, identified and enumerated. Supernatants were assessed for neutrophil elastase (NE) and IL-1ß. Common respiratory pathogens were also determined using real-time PCR. Results Participants with COPD had a typical neutrophilic inflammatory profile. The total load of bacteria was increased in COPD and was associated with poorer respiratory health status, as measured by the St George's Respiratory Questionnaire (Spearman's r = 0.336, P = 0.013). Significantly lower levels of culturable Bacillus species were identified compared with healthy controls. PCR analyses revealed increased rates of detection of potentially pathogenic bacteria with Haemophilus influenzae detection associated with higher sputum levels of NE and IL-1ß, while Streptococcus pneumoniae was more common in male ex-smokers with emphysema and a deficit in diffusion capacity. Conclusion Non-pathogenic and pathogenic bacteria were altered in the sputum of patients with COPD. These observations highlight the potential to identify treatment and management strategies that both target specific bacterial pathogens and restore the microbial balance, which may lead to reductions in inflammation and subsequent improvements in lung health.

DOI 10.1111/resp.12734
Citations Scopus - 38Web of Science - 35
Co-authors Jodie Simpson, Peter Gibson, Philip Hansbro, Vanessa Mcdonald, Katherine Baines, Jay Horvat
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 - 45Web of Science - 47
Co-authors Philip Hansbro, Malcolm Starkey, Darryl Knight, Jay Horvat
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 - 17Web of Science - 15
Co-authors Jay Horvat, Philip Hansbro, Malcolm Starkey
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 - 14Web of Science - 13
Co-authors Philip Hansbro, Malcolm Starkey, Jay Horvat
2013 Thorburn AN, Brown AC, Nair PM, Chevalier N, Foster PS, Gibson PG, Hansbro PM, 'Pneumococcal Components Induce Regulatory T Cells That Attenuate the Development of Allergic Airways Disease by Deviating and Suppressing the Immune Response to Allergen', JOURNAL OF IMMUNOLOGY, 191 4112-4120 (2013) [C1]
DOI 10.4049/jimmunol.1201232
Citations Scopus - 18Web of Science - 17
Co-authors Paul Foster, Peter Gibson, Philip Hansbro
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 - 53Web of Science - 54
Co-authors Philip Hansbro, Malcolm Starkey, Jay Horvat, Paul Foster
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Grants and Funding

Summary

Number of grants 5
Total funding $86,717

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


20212 grants / $22,994

Investigating the role of sex hormones in obesity associated susceptibility to respiratory viral disease$18,182

Funding body: Hunter New England Local Health District

Funding body Hunter New England Local Health District
Project Team Doctor Evan Williams, Doctor Alexandra Brown, Associate Professor Jay Horvat, Doctor Bronwyn Berthon, Doctor David Arnold
Scheme John Hunter Hospital Charitable Trust Grant
Role Investigator
Funding Start 2021
Funding Finish 2021
GNo G2100212
Type Of Funding C2400 – Aust StateTerritoryLocal – Other
Category 2400
UON Y

Investigating the role of sex hormones in obesity associated susceptibility to respiratory viral disease$4,812

Funding body: Hunter Medical Research Institute

Funding body Hunter Medical Research Institute
Project Team Doctor Alexandra Brown
Scheme Research Grant
Role Lead
Funding Start 2021
Funding Finish 2021
GNo G2100151
Type Of Funding C3300 – Aust Philanthropy
Category 3300
UON Y

20201 grants / $12,162

Investigating the role of sex hormones in in obese and non-obese asthmatic females$12,162

Funding body: John Hunter Hospital Charitable Trust

Funding body John Hunter Hospital Charitable Trust
Project Team Doctor Evan Williams, Doctor Alexandra Brown, Professor Lisa Wood, Associate Professor Jay Horvat, Doctor David Arnold, Doctor Bronwyn Berthon
Scheme Research Grant
Role Investigator
Funding Start 2020
Funding Finish 2020
GNo G2000392
Type Of Funding C3200 – Aust Not-for Profit
Category 3200
UON Y

20191 grants / $25,000

The role and therapeutic manipulation of female sex hormones in asthma$25,000

Funding body: Priority Research Centre (PRC) for Healthy Lungs | The University of Newcastle

Funding body Priority Research Centre (PRC) for Healthy Lungs | The University of Newcastle
Project Team

Alexandra Brown, Jemma Mayall, Hayley Scott, Katie Wynne, Jay Horvat, Lisa Wood

Scheme Integration Grant
Role Lead
Funding Start 2019
Funding Finish 2019
GNo
Type Of Funding Internal
Category INTE
UON N

20121 grants / $26,561

Mechanisms of predisposition to secondary bacterial pneumonia$26,561

Funding body: Hunter Medical Research Institute

Funding body Hunter Medical Research Institute
Project Team Doctor Alexandra Brown
Scheme Research Higher Degree Support Grant
Role Lead
Funding Start 2012
Funding Finish 2012
GNo G1201160
Type Of Funding Contract - Aust Non Government
Category 3AFC
UON Y
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Research Supervision

Number of supervisions

Completed1
Current2

Current Supervision

Commenced Level of Study Research Title Program Supervisor Type
2021 PhD Investigation and Therapeutic Manipulation of Iron Uptake Responses in Respiratory Disease PhD (Immunology & Microbiol), College of Health, Medicine and Wellbeing, The University of Newcastle Co-Supervisor
2020 PhD The role & therapeutic manipulation of female sex hormones in asthma PhD (Immunology & Microbiol), College of Health, Medicine and Wellbeing, The University of Newcastle Co-Supervisor

Past Supervision

Year Level of Study Research Title Program Supervisor Type
2021 PhD Mechanisms and Therapeutic Targeting of Immunometabolism in Lung Disease PhD (Immunology & Microbiol), College of Health, Medicine and Wellbeing, The University of Newcastle Co-Supervisor
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Dr Alexandra Brown

Position

Post Doctorate Researcher
School of Biomedical Sciences and Pharmacy
College of Health, Medicine and Wellbeing

Contact Details

Email alexandra.brown@newcastle.edu.au
Phone (02) 4042 0201

Office

Room Level 2 East
Building HMRI
Location New Lambton Heights

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