Microbiology & Immunology - Research Publications

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Author: Crowe, Jane × Author: Kedzierska, Katherine × Author: Rowntree, Louise × Start date: 2019 ×

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    Systems serology detects functionally distinct coronavirus antibody features in children and elderly
    Selva, KJ ; van de Sandt, CE ; Lemke, MM ; Lee, CY ; Shoffner, SK ; Chua, BY ; Davis, SK ; Nguyen, THO ; Rowntree, LC ; Hensen, L ; Koutsakos, M ; Wong, CY ; Mordant, F ; Jackson, DC ; Flanagan, KL ; Crowe, J ; Tosif, S ; Neeland, MR ; Sutton, P ; Licciardi, P ; Crawford, NW ; Cheng, AC ; Doolan, DL ; Amanat, F ; Krammer, F ; Chappell, K ; Modhiran, N ; Watterson, D ; Young, P ; Lee, WS ; Wines, BD ; Hogarth, PM ; Esterbauer, R ; Kelly, HG ; Tan, H-X ; Juno, JA ; Wheatley, AK ; Kent, SJ ; Arnold, KB ; Kedzierska, K ; Chung, AW (NATURE PORTFOLIO, 2021-04-01)
    The hallmarks of COVID-19 are higher pathogenicity and mortality in the elderly compared to children. Examining baseline SARS-CoV-2 cross-reactive immunological responses, induced by circulating human coronaviruses (hCoVs), is needed to understand such divergent clinical outcomes. Here we show analysis of coronavirus antibody responses of pre-pandemic healthy children (n = 89), adults (n = 98), elderly (n = 57), and COVID-19 patients (n = 50) by systems serology. Moderate levels of cross-reactive, but non-neutralizing, SARS-CoV-2 antibodies are detected in pre-pandemic healthy individuals. SARS-CoV-2 antigen-specific Fcγ receptor binding accurately distinguishes COVID-19 patients from healthy individuals, suggesting that SARS-CoV-2 infection induces qualitative changes to antibody Fc, enhancing Fcγ receptor engagement. Higher cross-reactive SARS-CoV-2 IgA and IgG are observed in healthy elderly, while healthy children display elevated SARS-CoV-2 IgM, suggesting that children have fewer hCoV exposures, resulting in less-experienced but more polyreactive humoral immunity. Age-dependent analysis of COVID-19 patients, confirms elevated class-switched antibodies in elderly, while children have stronger Fc responses which we demonstrate are functionally different. These insights will inform COVID-19 vaccination strategies, improved serological diagnostics and therapeutics.
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    Challenging immunodominance of influenza-specific CD8+ T cell responses restricted by the risk-associated HLA-A*68:01 allomorph
    van de Sandt, CE ; Clemens, EB ; Grant, EJ ; Rowntree, LC ; Sant, S ; Halim, H ; Crowe, J ; Cheng, AC ; Kotsimbos, TC ; Richards, M ; Miller, A ; Tong, SYC ; Rossjohn, J ; Nguyen, THO ; Gras, S ; Chen, W ; Kedzierska, K (NATURE PORTFOLIO, 2019-12-06)
    Although influenza viruses lead to severe illness in high-risk populations, host genetic factors associated with severe disease are largely unknown. As the HLA-A*68:01 allele can be linked to severe pandemic 2009-H1N1 disease, we investigate a potential impairment of HLA-A*68:01-restricted CD8+ T cells to mount robust responses. We elucidate the HLA-A*68:01+CD8+ T cell response directed toward an extended influenza-derived nucleoprotein (NP) peptide and show that only ~35% individuals have immunodominant A68/NP145+CD8+ T cell responses. Dissecting A68/NP145+CD8+ T cells in low vs. medium/high responders reveals that high responding donors have A68/NP145+CD8+ memory T cells with clonally expanded TCRαβs, while low-responders display A68/NP145+CD8+ T cells with predominantly naïve phenotypes and non-expanded TCRαβs. Single-cell index sorting and TCRαβ analyses link expansion of A68/NP145+CD8+ T cells to their memory potential. Our study demonstrates the immunodominance potential of influenza-specific CD8+ T cells presented by a risk HLA-A*68:01 molecule and advocates for priming CD8+ T cell compartments in HLA-A*68:01-expressing individuals for establishment of pre-existing protective memory T cell pools.