Microbiology & Immunology - Research Publications

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    Robust and prototypical immune responses toward influenza vaccines in the high-risk group of Indigenous Australians
    Hensen, L ; Nguyen, THO ; Rowntree, LC ; Damelang, T ; Koutsakos, M ; Aban, M ; Hurt, A ; Harland, KL ; Auladell, M ; van de Sandt, CE ; Everitt, A ; Blacker, C ; Oyong, DA ; Loughland, JR ; Webb, JR ; Wines, BD ; Hogarth, PM ; Flanagan, KL ; Plebanski, M ; Wheatley, A ; Chung, AW ; Kent, SJ ; Miller, A ; Clemens, EB ; Doherty, PC ; Nelson, J ; Davies, J ; Tong, SYC ; Kedzierska, K (NATL ACAD SCIENCES, 2021-10-12)
    Morbidity and mortality rates from seasonal and pandemic influenza occur disproportionately in high-risk groups, including Indigenous people globally. Although vaccination against influenza is recommended for those most at risk, studies on immune responses elicited by seasonal vaccines in Indigenous populations are largely missing, with no data available for Indigenous Australians and only one report published on antibody responses in Indigenous Canadians. We recruited 78 Indigenous and 84 non-Indigenous Australians vaccinated with the quadrivalent influenza vaccine into the Looking into InFluenza T cell immunity - Vaccination cohort study and collected blood to define baseline, early (day 7), and memory (day 28) immune responses. We performed in-depth analyses of T and B cell activation, formation of memory B cells, and antibody profiles and investigated host factors that could contribute to vaccine responses. We found activation profiles of circulating T follicular helper type-1 cells at the early stage correlated strongly with the total change in antibody titers induced by vaccination. Formation of influenza-specific hemagglutinin-binding memory B cells was significantly higher in seroconverters compared with nonseroconverters. In-depth antibody characterization revealed a reduction in immunoglobulin G3 before and after vaccination in the Indigenous Australian population, potentially linked to the increased frequency of the G3m21* allotype. Overall, our data provide evidence that Indigenous populations elicit robust, broad, and prototypical immune responses following immunization with seasonal inactivated influenza vaccines. Our work strongly supports the recommendation of influenza vaccination to protect Indigenous populations from severe seasonal influenza virus infections and their subsequent complications.
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    The origins of SARS-CoV-2: A critical review
    Holmes, EC ; Goldstein, SA ; Rasmussen, AL ; Robertson, DL ; Crits-Christoph, A ; Wertheim, JO ; Anthony, SJ ; Barclay, WS ; Boni, MF ; Doherty, PC ; Farrar, J ; Geoghegan, JL ; Jiang, X ; Leibowitz, JL ; Neil, SJD ; Skern, T ; Weiss, SR ; Worobey, M ; Andersen, KG ; Garry, RF ; Rambaut, A (CELL PRESS, 2021-09-16)
    Since the first reports of a novel severe acute respiratory syndrome (SARS)-like coronavirus in December 2019 in Wuhan, China, there has been intense interest in understanding how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in the human population. Recent debate has coalesced around two competing ideas: a "laboratory escape" scenario and zoonotic emergence. Here, we critically review the current scientific evidence that may help clarify the origin of SARS-CoV-2.
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    Immune cellular networks underlying recovery from influenza virus infection in acute hospitalized patients
    Nguyen, THO ; Koutsakos, M ; van de Sandt, CE ; Crawford, JC ; Loh, L ; Sant, S ; Grzelak, L ; Allen, EK ; Brahm, T ; Clemens, EB ; Auladell, M ; Hensen, L ; Wang, Z ; Nussing, S ; Jia, X ; Gunther, P ; Wheatley, AK ; Kent, SJ ; Aban, M ; Deng, Y-M ; Laurie, KL ; Hurt, AC ; Gras, S ; Rossjohn, J ; Crowe, J ; Xu, J ; Jackson, D ; Brown, LE ; La Gruta, N ; Chen, W ; Doherty, PC ; Turner, SJ ; Kotsimbos, TC ; Thomas, PG ; Cheng, AC ; Kedzierska, K (NATURE PORTFOLIO, 2021-05-11)
    How innate and adaptive immune responses work in concert to resolve influenza disease is yet to be fully investigated in one single study. Here, we utilize longitudinal samples from patients hospitalized with acute influenza to understand these immune responses. We report the dynamics of 18 important immune parameters, related to clinical, genetic and virological factors, in influenza patients across different severity levels. Influenza disease correlates with increases in IL-6/IL-8/MIP-1α/β cytokines and lower antibody responses. Robust activation of circulating T follicular helper cells correlates with peak antibody-secreting cells and influenza heamaglutinin-specific memory B-cell numbers, which phenotypically differs from vaccination-induced B-cell responses. Numbers of influenza-specific CD8+ or CD4+ T cells increase early in disease and retain an activated phenotype during patient recovery. We report the characterisation of immune cellular networks underlying recovery from influenza infection which are highly relevant to other infectious diseases.
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    What have we learnt so far from COVID-19?
    Doherty, PC (NATURE RESEARCH, 2021-02)
    While COVID-19 shows us the enormous power of modern molecular medicine, it also reminds us of the basic contradictions and limitations of the human condition. As it is highly likely we will experience further such events through the twenty-first century, we should regard COVID-19 as a training run for something that could be much worse, and organize our governance, global interactions, institutions and practices accordingly.
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    Suboptimal SARS-CoV-2-specific CD8+ T cell response associated with the prominent HLA-A*02:01 phenotype
    Habel, JR ; Nguyen, THO ; van de Sandt, CE ; Juno, JA ; Chaurasia, P ; Wragg, K ; Koutsakos, M ; Hensen, L ; Jia, X ; Chua, B ; Zhang, W ; Tan, H-X ; Flanagan, KL ; Doolan, DL ; Torresi, J ; Chen, W ; Wakim, LM ; Cheng, AC ; Doherty, PC ; Petersen, J ; Rossjohn, J ; Wheatley, AK ; Kent, SJ ; Rowntree, LC ; Kedzierska, K (NATL ACAD SCIENCES, 2020-09-29)
    An improved understanding of human T cell-mediated immunity in COVID-19 is important for optimizing therapeutic and vaccine strategies. Experience with influenza shows that infection primes CD8+ T cell memory to peptides presented by common HLA types like HLA-A2, which enhances recovery and diminishes clinical severity upon reinfection. Stimulating peripheral blood mononuclear cells from COVID-19 convalescent patients with overlapping peptides from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the clonal expansion of SARS-CoV-2-specific CD8+ and CD4+ T cells in vitro, with CD4+ T cells being robust. We identified two HLA-A*02:01-restricted SARS-CoV-2-specfic CD8+ T cell epitopes, A2/S269-277 and A2/Orf1ab3183-3191 Using peptide-HLA tetramer enrichment, direct ex vivo assessment of A2/S269+CD8+ and A2/Orf1ab3183+CD8+ populations indicated that A2/S269+CD8+ T cells were detected at comparable frequencies (∼1.3 × 10-5) in acute and convalescent HLA-A*02:01+ patients. These frequencies were higher than those found in uninfected HLA-A*02:01+ donors (∼2.5 × 10-6), but low when compared to frequencies for influenza-specific (A2/M158) and Epstein-Barr virus (EBV)-specific (A2/BMLF1280) (∼1.38 × 10-4) populations. Phenotyping A2/S269+CD8+ T cells from COVID-19 convalescents ex vivo showed that A2/S269+CD8+ T cells were predominantly negative for CD38, HLA-DR, PD-1, and CD71 activation markers, although the majority of total CD8+ T cells expressed granzymes and/or perforin. Furthermore, the bias toward naïve, stem cell memory and central memory A2/S269+CD8+ T cells rather than effector memory populations suggests that SARS-CoV-2 infection may be compromising CD8+ T cell activation. Priming with appropriate vaccines may thus be beneficial for optimizing CD8+ T cell immunity in COVID-19.
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    This Scientific Life.
    Doherty, PC (Mary Ann Liebert Inc, 2020-04)
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    The Origin of COVID-19 and Why It Matters.
    Morens, DM ; Breman, JG ; Calisher, CH ; Doherty, PC ; Hahn, BH ; Keusch, GT ; Kramer, LD ; LeDuc, JW ; Monath, TP ; Taubenberger, JK (American Society of Tropical Medicine and Hygiene, 2020-09)
    The COVID-19 pandemic is among the deadliest infectious diseases to have emerged in recent history. As with all past pandemics, the specific mechanism of its emergence in humans remains unknown. Nevertheless, a large body of virologic, epidemiologic, veterinary, and ecologic data establishes that the new virus, SARS-CoV-2, evolved directly or indirectly from a β-coronavirus in the sarbecovirus (SARS-like virus) group that naturally infect bats and pangolins in Asia and Southeast Asia. Scientists have warned for decades that such sarbecoviruses are poised to emerge again and again, identified risk factors, and argued for enhanced pandemic prevention and control efforts. Unfortunately, few such preventive actions were taken resulting in the latest coronavirus emergence detected in late 2019 which quickly spread pandemically. The risk of similar coronavirus outbreaks in the future remains high. In addition to controlling the COVID-19 pandemic, we must undertake vigorous scientific, public health, and societal actions, including significantly increased funding for basic and applied research addressing disease emergence, to prevent this tragic history from repeating itself.
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    Make science evolve into a One Health approach to improve health and security: a white paper
    Osterhaus, ADME ; Vanlangendonck, C ; Barbeschi, M ; Bruschke, CJM ; Christensen, R ; Daszak, P ; de Groot, F ; Doherty, P ; Drury, P ; Gmacz, S ; Hamilton, K ; Hart, J ; Katz, R ; Longuet, C ; McLeay, J ; Morelli, G ; Schlundt, J ; Smith, T ; Suri, S ; Umali, K ; van Aken, J ; Wagenaar, JA (BMC, 2020-04-17)
    The World One Health Congresses are biennial gatherings of approximately 1500 professionals from relevant international organisations, OIE, FAO, WHO, World Bank, leading scientific experts and researchers in the field of One Health, animal production and trade, food safety, animal health, human health and environmentology/ecology, government representatives in public health, human health, food safety, environmental health and global health security. The Congress is organized by the One Health Platform. This white paper summarizes highlights of the 5th International One Health Congress in Saskatoon, Canada, June 2018 and serves as a roadmap for the future, detailing several concrete action points to be carried out in the run-up to the 6th World One Health Congress in Edinburgh, Scotland, June 2020.