Clinical Pathology - Research Publications

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Type: Preprint × Start date: 2020 × End date: 2020 ×

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    Rapid and lasting generation of B-cell memory to SARS-CoV-2 spike and nucleocapsid proteins in COVID-19 disease and convalescence
    Hartley, G ; Edwards, ESJ ; Aui, P ; Varese, N ; Stojanovic, S ; McMahon, J ; Peleg, A ; Boo, I ; Drummer, H ; Hogarth, M ; O’Hehir, R ; van Zelm, M ( 2020)

    ABSTRACT

    Background

    Lasting immunity to SARS-CoV-2 following infection is questioned because serum antibodies decline in convalescence. However, functional immunity is mediated by long-lived memory T and B (Bmem) cells.

    Objective

    To determine the longevity and immunophenotype of SARS-CoV-2-specific Bmem cells in COVID-19 patients.

    Methods

    Recombinant spike receptor binding domain (RBD) and nucleocapsid protein (NCP) were produced for ELISA-based serology, and biotinylated for fluorescent tetramer generation to identify SARS-CoV-2-specific Bmem cells by flow cytometry with a panel of 13 mAbs. 36 blood samples were obtained from 25 COVID-19 patients (11 paired) between 4-242 days post-symptom onset for detection of neutralizing antibodies, IgG serology and flow cytometry.

    Results

    The recombinant RBD and NCP were specifically recognized by serum IgG in all patients and reactivity declined >20 days post-symptom onset. All patients had detectable RBD- and NCP-specific Bmem cells at 8.23-267.6 cells/ml of blood (0.004-0.13% of B cells) regardless of sampling time. RBD- and NCP-specific Bmem cells predominantly expressed IgM or IgG1, with the latter formed slightly later than the former. RBD-specific IgG + Bmem were predominantly CD27 + , and numbers significantly correlated with circulating follicular helper T cell numbers.

    Conclusion

    RBD- and NCP-specific Bmem cells persisted for 8 months, indicating that the decline in serum antibodies after 1 month does not indicate waning of immunity but a contraction of the immune response. Flowcytometric detection of SARS-CoV-2-specific Bmem cells enables detection of long-term functional immunity following infection or vaccination for COVID-19.
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    Epigenetic reprogramming of plasmacytoid dendritic cells drives type I interferon-dependent differentiation of acute myeloid leukemias for therapeutic benefit
    Salmon, J ; Todorovski, I ; Vervoort, S ; Stanley, K ; Kearney, C ; Martelotto, L ; Rossello, F ; Semple, T ; Mir-Arnau, G ; Zethoven, M ; Bots, M ; Vidacs, E ; McArthur, K ; Gressier, E ; de Weerd, N ; Lichte, J ; Kelly, M ; Cluse, L ; Hogg, S ; Hertzog, P ; Kats, L ; de Carvalho, D ; Scheu, S ; Bedoui, S ; Kile, B ; Wei, A ; Dominguez, P ; Johnstone, R ( 2020-08-24)
    Pharmacological inhibition of epigenetic enzymes can have therapeutic benefit, particularly against hematological malignancies. While these agents can affect tumor cell growth and proliferation, recent studies have demonstrated that pharmacological de-regulation of epigenetic modifiers may additionally mediate anti-tumor immune responses. Here we discovered a novel mechanism of immune regulation through the inhibition of histone deacetylases (HDACs). In a genetically engineered model of t(8;21) AML, leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor panobinostat required activation of the type I interferon (IFN) signaling pathway. Plasmacytoid dendritic cells (pDCs) were identified as the cells producing type I IFN in response to panobinostat, through transcriptional activation of IFN genes concomitant with increased H3K27 acetylation at these loci. Depletion of pDCs abrogated panobinostat-mediated activation of type I IFN signaling in leukemia cells and impaired therapeutic efficacy, while combined treatment of panobinostat and recombinant IFNα improved therapeutic outcomes. These discoveries offer a new therapeutic approach for t(8;21) AML and demonstrate that epigenetic rewiring of pDCs enhances anti-tumor immunity, opening the possibility of exploiting this cell type as a new target for immunotherapy.
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    A dual antigen ELISA allows the assessment of SARS-CoV-2 antibody seroprevalence in a low transmission setting
    Hicks, S ; Pohl, K ; Neeman, T ; McNamara, H ; Parsons, K ; He, J-S ; Ali, S ; Nazir, S ; Rowntree, L ; Nguyen, T ; Kedzierska, K ; Doolan, D ; Vinueas, C ; Cook, M ; Coatsworth, N ; Myles, P ; Kurth, F ; Sander, L ; Mann, G ; Gruen, R ; George, A ; Gardiner, E ; Cockburn, I ; the SARS-CoV-2 Testing in Elective Surgery Collaborators, (Cold Spring Harbor Laboratory, 2020)
    Estimates of seroprevalence of SARS-CoV-2 antibodies have been hampered by inadequate assay sensitivity and specificity. Using an ELISA-based approach to that combines data about IgG responses to both the Nucleocapsid and Spike-receptor binding domain antigens, we show that near-optimal sensitivity and specificity can be achieved. We used this assay to assess the frequency of virus-specific antibodies in a cohort of elective surgery patients in Australia and estimated seroprevalence in Australia to be 0.28% (0 to 0.72%). These data confirm the low level of transmission of SARS-CoV-2 in Australia before July 2020 and validate the specificity of our assay.