Dr Prabuddha Pathinayake
Postdoctoral Research Associate
School of Medicine and Public Health
- Phone:(02) 40420407
Dr. Prabuddha Pathinayake is a Post-doctoral researcher at the Department of Respiratory Medicine, School of Medicine and Public Health, University of Newcastle, Australia. His current research focus is to understand the cellular and molecular mechanisms underpinning chronic airway inflammatory diseases, particularly in asthma, and investigate new therapeutic avenues.
Dr. Pathinayake graduated with a Bachelor of Science (B.Sc.) degree from the University of Peradeniya, Sri Lanka in 2009, and he completed his master’s degree (M.Sc.) from Chungnam National University, the Republic of Korea in 2014. In 2015, he was awarded the University Postgraduate Research Fellowship from the University of Newcastle, Australia to pursue his Ph.D. in Medicine under the supervision of Professor Peter Wark.
Research background and expertise:
During my master’s degree, I did various research projects related to viral immunology. My work mostly focused on understanding the host-pathogen interactions in mammalian cells during different virus infections and investigate cellular mechanisms of how viruses impair type I interferon (IFN) responses in cells. In addition, I was involved in human vaccine development projects particularly for influenza virus and enterovirus 71. We developed a mucosal administered Lactobacillus surface-displayed system to boost up humoral and cellular immune response and provides protective immunity against diverse influenza virus infections.
In my Ph.D., I combine my skills and knowledge in microbiology, molecular biology, and cell biology to understand the pathobiology of airway inflammation in asthma. My Ph.D. research project was to investigate the functional role of Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in airway epithelium in asthma. The UPR is an adaptive response to perturbations in ER homeostasis. It is a collection of phylogenetically conserved signalling pathways that monitor the conditions of the ER and when triggered, upregulates compensatory responses to restore homeostasis. We found that ERS and UPR is a critical metabolic signalling pathway involved in asthma pathogenesis. This research led to many important findings and we have presented in various research forums and has been recognized with research awards including the ATS trainee award by the American Thoracic Society in 2018, Priority Research Center for Healthy Lungs basic science award 2018, and several travel awards. In 2020, we were able successful in the NHMRC ideas grant application and received funding to further continue this work.
My current research work is focusing on understanding the molecular mechanisms behind airway remodelling in asthma particularly, to investigate the role of ERS and UPR on airway remodelling. I am using advanced 3D cell culture models and molecular biology techniques to investigate this in a PC2 laboratory at Hunter Medical Research Institute, Newcastle, Australia. This work collaborates with various respiratory research groups at Hunter Medical Research Institute, University of Technology Sydney, and Centenary Institute, Sydney.
- Doctor of Philosophy in Medicine, University of Newcastle
- Airway cell biology
- Airway inflammation
- Airway remodelling
- ER stress and Unfolded protein response
- Respiratory virus infections
- English (Fluent)
- Sinhalese (Mother)
Fields of Research
PRC travel award
PRC For Healthy Lungs, University of Newcastle
American Thoracic Society (ATS) International Trainee Scholarship Award
American Thoracic Society
TSANZSRS travel award
The Australian and New Zealand Society of Respiratory Science (TSANZSRS)
PRC award for the best student in translational research
PRC For Healthy Lungs, University of Newcastle
Grant-In-Aid top-up scholarship 2018
Faculty of Health and Medicine, The University of Newcastle
UNIPRS (International Postgraduate Research Scholarship)
The University of Newcastle
UNRSC 50:50 (University of Newcastle Research Scholarship)
The University of Newcastle, NSW
For publications that are currently unpublished or in-press, details are shown in italics.
Chapter (1 outputs)
Wark P, Williams T, Pathinayake P, 'The interplay of the host, virus, and the environment', Rhinovirus Infections: Rethinking the Impact on Human Health and Disease, Elsevier, London 169-194 (2019) [B1]
Journal article (21 outputs)
Waters DW, Schuliga M, Pathinayake PS, Wei L, Tan HY, Blokland KEC, et al., 'A senescence bystander effect in human lung fibroblasts', Biomedicines, 9 (2021)
Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterised by a dense fibrosing of the lung parenchyma. An association between IPF and cellular senescence is well esta... [more]
Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterised by a dense fibrosing of the lung parenchyma. An association between IPF and cellular senescence is well established and several studies now describe a higher abundance of senescent fibroblasts and epithelial cells in the lungs of IPF patients compared with age-matched controls. The cause of this abnormal accumulation of senescent cells is unknown but evidence suggests that, once established, senescence can be transferred from senescent to non-senescent cells. In this study, we investigated whether senescent human lung fibroblasts (LFs) and alveolar epithelial cells (AECs) could induce a senescent-like phenotype in ¿naïve¿ non-senescent LFs in vitro. Primary cultures of LFs from adult control donors (Ctrl-LFs) with a low baseline of senescence were exposed to conditioned medium (CM) from: (i) Ctrl-LFs induced to become senescent using H2 O2 or etoposide; (ii) LFs derived from IPF patients (IPF-LFs) with a high baseline of senescence; or (iii) senescence-induced A549 cells, an AEC line. Additionally, ratios of non-senescent Ctrl-LFs and senescence-induced Ctrl-LFs (100:0, 0:100, 50:50, 90:10, 99:1) were co-cultured and their effect on induction of senescence measured. We demonstrated that exposure of naïve non-senescent Ctrl-LFs to CM from senescence-induced Ctrl-LFs and AECs and IPF-LFs increased the markers of senescence including nuclear localisation of phosphorylated-H2A histone family member X (H2AX¿) and expression of p21, IL-6 and IL-8 in Ctrl-LFs. Additionally, co-cultures of non-senescent and senescence-induced Ctrl-LFs induced a senescent-like phenotype in the non-senescent cells. These data suggest that the phenomenon of ¿senescence-induced senescence¿ can occur in vitro in primary cultures of human LFs, and provides a possible explanation for the abnormal abundance of senescent cells in the lungs of IPF patients.
Pathinayake PS, Waters DW, Nichol KS, Brown AC, Reid AT, Hsu AC-Y, et al., 'Endoplasmic reticulum-unfolded protein response signalling is altered in severe eosinophilic and neutrophilic asthma.', Thorax, (2021)
Chong WC, Shastri MD, Peterson GM, Patel RP, Pathinayake PS, Dua K, et al., 'The complex interplay between endoplasmic reticulum stress and the NLRP3 inflammasome: a potential therapeutic target for inflammatory disorders', Clinical and Translational Immunology, 10 (2021) [C1]
Inflammation is the result of a complex network of cellular and molecular interactions and mechanisms that facilitate immune protection against intrinsic and extrinsic stimuli, pa... [more]
Inflammation is the result of a complex network of cellular and molecular interactions and mechanisms that facilitate immune protection against intrinsic and extrinsic stimuli, particularly pathogens, to maintain homeostasis and promote tissue healing. However, dysregulation in the immune system elicits excess/abnormal inflammation resulting in unintended tissue damage and causes major inflammatory diseases including asthma, chronic obstructive pulmonary disease, atherosclerosis, inflammatory bowel diseases, sarcoidosis and rheumatoid arthritis. It is now widely accepted that both endoplasmic reticulum (ER) stress and inflammasomes play critical roles in activating inflammatory signalling cascades. Notably, evidence is mounting for the involvement of ER stress in exacerbating inflammasome-induced inflammatory cascades, which may provide a new axis for therapeutic targeting in a range of inflammatory disorders. Here, we comprehensively review the roles, mechanisms and interactions of both ER stress and inflammasomes, as well as their interconnected relationships in inflammatory signalling cascades. We also discuss novel therapeutic strategies that are being developed to treat ER stress- and inflammasome-related inflammatory disorders.
Wark PAB, Pathinayake PS, Kaiko G, Nichol K, Ali A, Chen L, et al., 'ACE2 expression is elevated in airway epithelial cells from older and male healthy individuals but reduced in asthma', Respirology, 26 442-451 (2021) [C1]
Background and objective: COVID-19 is complicated by acute lung injury, and death in some individuals. It is caused by SARS-CoV-2 that requires the ACE2 receptor and serine protea... [more]
Background and objective: COVID-19 is complicated by acute lung injury, and death in some individuals. It is caused by SARS-CoV-2 that requires the ACE2 receptor and serine proteases to enter AEC. We determined what factors are associated with ACE2 expression particularly in patients with asthma and COPD. Methods: We obtained lower AEC from 145 people from two independent cohorts, aged 2¿89 years, Newcastle (n = 115) and Perth (n = 30), Australia. The Newcastle cohort was enriched with people with asthma (n = 37) and COPD (n = 38). Gene expression for ACE2 and other genes potentially associated with SARS-CoV-2 cell entry was assessed by qPCR, and protein expression was confirmed with immunohistochemistry on endobronchial biopsies and cultured AEC. Results: Increased gene expression of ACE2 was associated with older age (P = 0.03) and male sex (P = 0.03), but not with pack-years smoked. When we compared gene expression between adults with asthma, COPD and healthy controls, mean ACE2 expression was lower in asthma patients (P = 0.01). Gene expression of furin, a protease that facilitates viral endocytosis, was also lower in patients with asthma (P = 0.02), while ADAM-17, a disintegrin that cleaves ACE2 from the surface, was increased (P = 0.02). ACE2 protein expression was also reduced in endobronchial biopsies from asthma patients. Conclusion: Increased ACE2 expression occurs in older people and males. Asthma patients have reduced expression. Altered ACE2 expression in the lower airway may be an important factor in virus tropism and may in part explain susceptibility factors and why asthma patients are not over-represented in those with COVID-19 complications.
Wark PAB, Pathinayake PS, Eapen MS, Sohal SS, 'Asthma, COPD and SARS-CoV-2 infection (COVID-19): potential mechanistic insights.', Eur Respir J, 58 (2021)
Davis JS, Chu G, Pathinayake P, Jones D, Giffard P, Macera L, et al., 'Seroprevalence of Torque Teno Virus in hemodialysis and renal transplant patients in Australia: A cross-sectional study', TRANSPLANT INFECTIOUS DISEASE, 22 (2020) [C1]
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]
Waters DW, Blokland KEC, Pathinayake PS, Wei L, Schuliga M, Jaffar J, et al., 'STAT3 Regulates the Onset of Oxidant-induced Senescence in Lung Fibroblasts.', Am J Respir Cell Mol Biol, 61 61-73 (2019) [C1]
Singanayagam A, Loo SL, Calderazzo M, Finney LJ, Torralbo MBT, Bakhsoliani E, et al., 'Antiviral immunity is impaired in COPD patients with frequent exacerbations', American Journal of Physiology - Lung Cellular and Molecular Physiology, 317 L893-L903 (2019) [C1]
Patients with frequent exacerbations represent a chronic obstructive pulmonary disease (COPD) subgroup requiring better treatment options. The aim of this study was to determine t... [more]
Patients with frequent exacerbations represent a chronic obstructive pulmonary disease (COPD) subgroup requiring better treatment options. The aim of this study was to determine the innate immune mechanisms that underlie susceptibility to frequent exacerbations in COPD. We measured sputum expression of immune mediators and bacterial loads in samples from patients with COPD at stable state and during virusassociated exacerbations. In vitro immune responses to rhinovirus infection in differentiated primary bronchial epithelial cells (BECs) sampled from patients with COPD were additionally evaluated. Patients were stratified as frequent exacerbators (=2 exacerbations in the preceding year) or infrequent exacerbators (<2 exacerbations in the preceding year) with comparisons made between these groups. Frequent exacerbators had reduced sputum cell mRNA expression of the antiviral immune mediators type I and III interferons and reduced interferon-stimulated gene (ISG) expression when clinically stable and during virus-associated exacerbation. A role for epithelial cellintrinsic innate immune dysregulation was identified: induction of interferons and ISGs during in vitro rhinovirus (RV) infection was also impaired in differentiated BECs from frequent exacerbators. Frequent exacerbators additionally had increased sputum bacterial loads at 2 wk following virus-associated exacerbation onset. These data implicate deficient airway innate immunity involving epithelial cells in the increased propensity to exacerbations observed in some patients with COPD. Therapeutic approaches to boost innate antimicrobial immunity in the lung could be a viable strategy for prevention and treatment of frequent exacerbations.
Waters DW, Blokland KEC, Pathinayake PS, Burgess JK, Mutsaers SE, Prele CM, et al., 'Fibroblast senescence in the pathology of idiopathic pulmonary fibrosis', American Journal of Physiology - Lung Cellular and Molecular Physiology, 315 L162-L172 (2018) [C1]
Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial pneu monia of unknown cause with a median survival of only three years. Little is known about the mechanism... [more]
Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial pneu monia of unknown cause with a median survival of only three years. Little is known about the mechanisms that precede the excessive collagen deposition seen in IPF, but cellular senescence has been strongly implicated in disease pathology. Senescence is a state of irreversible cell-cycle arrest accompanied by an abnormal secretory profile and is thought to play a critical role in both development and wound repair. Normally, once a senescent cell has contributed to wound repair, it is promptly removed from the environment via infiltrating immune cells. However, if immune clearance fails, the persistence of senescent cells is thought to drive disease pathology through their altered secretory profile. One of the major cell types involved in wound healing is fibroblasts, and senescent fibroblasts have been identified in the lungs of patients with IPF and in fibroblast cultures from IPF lungs. The question of what is driving abnormally high numbers of fibroblasts into senescence remains unanswered. The transcription factor signal transducer and activator of transcription 3 (STAT3) plays a role in a myriad of processes, including cell-cycle progression, gene transcription, as well as mitochondrial respiration, all of which are dysregulated during senescence. Activation of STAT3 has previously been shown to correlate with IPF progression and therefore is a potential molecular target to modify early-stage senescence and restore normal fibroblast function. This review summarizes what is presently known about fibroblast senescence in IPF and how STAT3 may contribute to this phenotype.
Singanayagam A, Glanville N, Girkin JL, Ching YM, Marcellini A, Porter JD, et al., 'Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations', NATURE COMMUNICATIONS, 9 (2018) [C1]
Pathinayake PS, Gayan Chathuranga WA, Lee HC, Chowdhury MYE, Sung MH, Lee JS, Kim CJ, 'Inactivated enterovirus 71 with poly- -glutamic acid/Chitosan nano particles (PC NPs) induces high cellular and humoral immune responses in BALB/c mice', Archives of Virology, 163 2073-2083 (2018) [C1]
Enterovirus 71 (EV71) is the major causative agent of hand-foot-and-mouth disease (HFMD) and many neurological manifestations. Recently, this virus has become a serious concern be... [more]
Enterovirus 71 (EV71) is the major causative agent of hand-foot-and-mouth disease (HFMD) and many neurological manifestations. Recently, this virus has become a serious concern because of consecutive epidemics in the Asia-Pacific region. However, no effective vaccine for EV71 has been discovered except two EV71 vaccines which are being used in local communities of China. To develop a safe and efficient EV71 vaccine candidate, we generated inactivated EV71 and evaluated its efficacy with ¿-PGA/Chitosan nanoparticles (PC NPs), which are safe, biodegradable and effective as an adjuvant. The subcutaneous administration of inactivated EV71 with PC NPs adjuvant induces higher levels of virus-specific humoral (IgG, IgG1, and IgG2a) and cell-mediated immune responses (IFN-¿ and IL-4). Additionally, inactivated EV71 with PC NPs adjuvant induces significantly higher virus neutralizing antibody responses compared to the virus only group, and resulted in a long lasting immunity without any noticeable side effects. Together, our findings demonstrate that PC NPs are safe and effective immunogenic adjuvants which may be promising candidates in the development of more efficacious EV71 vaccines.
Wark PAB, Ramsahai JM, Pathinayake P, Malik B, Bartlett NW, 'Respiratory Viruses and Asthma', Seminars in Respiratory and Critical Care Medicine, 39 45-55 (2018) [C1]
Asthma remains the most prevalent chronic respiratory disorder, affecting people of all ages. The relationship between respiratory virus infection and asthma has long been recogni... [more]
Asthma remains the most prevalent chronic respiratory disorder, affecting people of all ages. The relationship between respiratory virus infection and asthma has long been recognized, though remains incompletely understood. In this article, we will address key issues around this relationship. These will include the crucial role virus infection plays in early life, as a potential risk factor for the development of asthma and lung disease. We will assess the impact that virus infection has on those with established asthma as a trigger for acute disease and how this may influence asthma throughout life. Finally, we will explore the complex interaction that occurs between the airway and the immune responses that make those with asthma so susceptible to the effects of virus infection.
Pathinayake PS, Hsu AC-Y, Waters DW, Hansbro PM, Wood LG, Wark PAB, 'Understanding the Unfolded Protein Response in the Pathogenesis of Asthma', FRONTIERS IN IMMUNOLOGY, 9 (2018) [C1]
Pathinayake PS, Hsu A, wark PA, 'Innate Immunity and Immune Evasion by Enterovirus 71', Viruses, 7 (2015) [C1]
Chowdhury MYE, Li R, Kim JH, Park ME, Kim TH, Pathinayake P, et al., 'Mucosal vaccination with recombinant Lactobacillus casei-displayed CTA1-conjugated consensus matrix protein-2 (sM2) induces broad protection against divergent influenza subtypes in BALB/c mice', PLoS ONE, 9 (2014)
To develop a safe and effective mucosal vaccine against pathogenic influenza viruses, we constructed recombinant Lactobacillus casei strains that express conserved matrix protein ... [more]
To develop a safe and effective mucosal vaccine against pathogenic influenza viruses, we constructed recombinant Lactobacillus casei strains that express conserved matrix protein 2 with (pgsA-CTA1-sM2/ L. casei) or without (pgsA-sM2/ L. casei) cholera toxin subunit A1 (CTA1) on the surface. The surface localization of the fusion protein was verified by cellular fractionation analyses, flow cytometry and immunofluorescence microscopy. Oral and nasal inoculations of recombinant L. casei into mice resulted in high levels of serum immunoglobulin G (IgG) and mucosal IgA. However, the conjugation of cholera toxin subunit A1 induced more potent mucosal, humoral and cell-mediated immune responses. In a challenge test with 10 MLD50 of A/EM/Korea/W149/ 06(H5N1), A/Puerto Rico/8/34(H1N1), A/Aquatic bird /Korea/W81/2005(H5N2), A/Aquatic bird/Korea/W44/2005(H7N3), and A/Chicken/Korea/116/2004(H9N2) viruses, the recombinant pgsA-CTA1-sM2/ L. casei provided better protection against lethal challenges than pgsA-sM2/ L. casei, pgsA/ L. casei and PBS in mice. These results indicate that mucosal immunization with recombinant L. casei expressing CTA1-conjugated sM2 protein on its surface is an effective means of eliciting protective immune responses against diverse influenza subtypes. © 2014 Chowdhury et al.
Woo HM, Kim KS, Lee JM, Shim HS, Cho SJ, Lee WK, et al., 'Single-stranded DNA aptamer that specifically binds to the influenza virus NS1 protein suppresses interferon antagonism', Antiviral Research, 100 337-345 (2013)
Non-structural protein 1 (NS1) of the influenza A virus (IAV) inhibits the host's innate immune response by suppressing the induction of interferons (IFNs). Therefore, blocki... [more]
Non-structural protein 1 (NS1) of the influenza A virus (IAV) inhibits the host's innate immune response by suppressing the induction of interferons (IFNs). Therefore, blocking NS1 activity can be a potential strategy in the development of antiviral agents against IAV infection. In the present study, we selected a single-stranded DNA aptamer specific to the IAV NS1 protein after 15 cycles of systematic evolution of ligands by exponential enrichment (SELEX) procedure and examined the ability of the selected aptamer to inhibit the function of NS1. The selected aptamer binds to NS1 with a Kd of 18.91 ± 3.95 nM and RNA binding domain of NS1 is determined to be critical for the aptamer binding. The aptamer has a G-rich sequence in the random sequence region and forms a G-quadruplex structure. The localization of the aptamer bound to NS1 in cells was determined by confocal images, and flow cytometry analysis further demonstrated that the selected aptamer binds specifically to NS1. In addition, luciferase reporter gene assay, quantitative RT-PCR, and enzyme-linked immunosorbent assay (ELISA) experiments demonstrated that the selected aptamer had the ability to induce IFN-ß by suppressing the function of NS1. Importantly, we also found that the selected aptamer was able to inhibit the viral replication without affecting cell viability. These results indicate that the selected ssDNA aptamer has strong potential to be further developed as a therapeutic agent against IAV. © 2013 Elsevier B.V. All rights reserved.
|Show 18 more journal articles|
Conference (2 outputs)
Pathinayake PS, Nichol KS, Baines KJ, Wood LG, Hsu AC, Wark PAB, 'The Unfolded Protein Response Is Heightened in Eosinophilic Asthma', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, San Diego, CA (2018)
Pathinayake PS, Hsu AC-Y, Parsons K, Loo S-L, Fricker M, Wood LG, et al., 'Effect of oxidative stress and rhinovirus infection on mitochondrial/endoplasmic reticular function in human primary bronchial epithelial cells', EUROPEAN JOURNAL OF IMMUNOLOGY, Melbourne, AUSTRALIA (2016)
Grants and Funding
|Number of grants||4|
Click on a grant title below to expand the full details for that specific grant.
20211 grants / $789,475
ER stress-Unfolded Protein Response a critical metabolic pathway for airway remodelling in asthma$789,475
Funding body: NHMRC (National Health & Medical Research Council)
|Funding body||NHMRC (National Health & Medical Research Council)|
|Project Team||Conjoint Professor Peter Wark, Associate Professor Jay Horvat, Doctor Prabuddha Pathinayake, Professor Philip Hansbro, A/Prof Brian Oliver, Doctor Alan Hsu, Doctor Alexandra Brown, Doctor Gerard Kaiko, Doctor Katie Baines|
|Type Of Funding||C1100 - Aust Competitive - NHMRC|
20202 grants / $22,162
Investigation of the molecular mechanisms of how ER stress drives epithelial mucus hypersecretion and goblet cell metaplasia in severe asthma$12,162
Funding body: John Hunter Hospital Charitable Trust
Investigating airway epithelial cell death signalling pathways induced by SARS-CoV-2 leading to acute lung injuries$10,000
Funding body: 2020 Faculty Strategic Pilot Grant
|Funding body||2020 Faculty Strategic Pilot Grant|
Prof. Peter Wark, Dr. Alan Hsu, Ms. Kristy Nichol
|Scheme||2020 Faculty of Health and Medicine Strategic Pilot Grant|
|Type Of Funding||Internal|
20171 grants / $20,000
Mechanisms of heightened airway inflammation in asthma and chronic obstructive pulmonary disease$20,000
Funding body: John Hunter Hospital Charitable Trust
Dr Prabuddha Pathinayake
Postdoctoral Research Associate
School of Medicine and Public Health
College of Health, Medicine and Wellbeing