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Integrated immune dynamics define correlates of COVID-19 severity and antibody responses.

ABSTRACT: SARS-CoV-2 causes a spectrum of COVID-19 disease, the immunological basis of which remains ill defined. We analyzed 85 SARS-CoV-2-infected individuals at acute and/or convalescent time points, up to 102 days after symptom onset, quantifying 184 immunological parameters. Acute COVID-19 presented with high levels of IL-6, IL-18, and IL-10 and broad activation marked by the upregulation of CD38 on innate and adaptive lymphocytes and myeloid cells. Importantly, activated CXCR3⁺cT_FH1 cells in acute COVID-19 significantly correlate with and predict antibody levels and their avidity at convalescence as well as acute neutralization activity. Strikingly, intensive care unit (ICU) patients with severe COVID-19 display higher levels of soluble IL-6, IL-6R, and IL-18, and hyperactivation of innate, adaptive, and myeloid compartments than patients with moderate disease. Our analyses provide a comprehensive map of longitudinal immunological responses in COVID-19 patients and integrate key cellular pathways of complex immune networks underpinning severe COVID-19, providing important insights into potential biomarkers and immunotherapies.

SUBMITTER: Koutsakos M

PROVIDER: S-EPMC7862905 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Integrated immune dynamics define correlates of COVID-19 severity and antibody responses.

Koutsakos Marios M Rowntree Louise C LC Hensen Luca L Chua Brendon Y BY van de Sandt Carolien E CE Habel Jennifer R JR Zhang Wuji W Jia Xiaoxiao X Kedzierski Lukasz L Ashhurst Thomas M TM Putri Givanna H GH Marsh-Wakefield Felix F Read Mark N MN Edwards Davis N DN Clemens E Bridie EB Wong Chinn Yi CY Mordant Francesca L FL Juno Jennifer A JA Amanat Fatima F Audsley Jennifer J Holmes Natasha E NE Gordon Claire L CL Smibert Olivia C OC Trubiano Jason A JA Hughes Carly M CM Catton Mike M Denholm Justin T JT Tong Steven Y C SYC Doolan Denise L DL Kotsimbos Tom C TC Jackson David C DC Krammer Florian F Godfrey Dale I DI Chung Amy W AW King Nicholas J C NJC Lewin Sharon R SR Wheatley Adam K AK Kent Stephen J SJ Subbarao Kanta K McMahon James J Thevarajan Irani I Nguyen Thi H O THO Cheng Allen C AC Kedzierska Katherine K

Cell reports. Medicine 20210205 3

SARS-CoV-2 causes a spectrum of COVID-19 disease, the immunological basis of which remains ill defined. We analyzed 85 SARS-CoV-2-infected individuals at acute and/or convalescent time points, up to 102 days after symptom onset, quantifying 184 immunological parameters. Acute COVID-19 presented with high levels of IL-6, IL-18, and IL-10 and broad activation marked by the upregulation of CD38 on innate and adaptive lymphocytes and myeloid cells. Importantly, activated CXCR3<sup>+</sup>cT<sub>FH</ ...[more]

PMID: 33564749

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Project description:It remains unclear why some patients infected with SARS-CoV-2 readily resolve infection while others develop severe disease. To address this question, we employed a novel assay to interrogate immune-metabolic programs of T cells and myeloid cells in severe and recovered COVID-19 patients. Using this approach, we identified a unique population of T cells expressing high H3K27me3 and the mitochondrial membrane protein voltage-dependent anion channel (VDAC), which were expanded in acutely ill COVID-19 patients and distinct from T cells found in patients infected with hepatitis c or influenza and in recovered COVID-19. Increased VDAC was associated with gene programs linked to mitochondrial dysfunction and apoptosis. High-resolution fluorescence and electron microscopy imaging of the cells revealed dysmorphic mitochondria and release of cytochrome c into the cytoplasm, indicative of apoptosis activation. The percentage of these cells was markedly increased in elderly patients and correlated with lymphopenia. Importantly, T cell apoptosis could be inhibited in vitro by targeting the oligomerization of VDAC or blocking caspase activity. In addition to these T cell findings, we also observed a robust population of Hexokinase II+ polymorphonuclear-myeloid derived suppressor cells (PMN-MDSC), exclusively found in the acutely ill COVID-19 patients and not the other viral diseases. Finally, we revealed a unique population of monocytic MDSC (M-MDSC) expressing high levels of carnitine palmitoyltransferase 1a (CPT1a) and VDAC. The metabolic phenotype of these cells was not only highly specific to COVID-19 patients but the presence of these cells was able to distinguish severe from mild disease. Overall, the identification of these novel metabolic phenotypes not only provides insight into the dysfunctional immune response in acutely ill COVID-19 patients but also provide a means to predict and track disease severity as well as an opportunity to design and evaluate novel metabolic therapeutic regimens.

Dataset Information

Integrated immune dynamics define correlates of COVID-19 severity and antibody responses.

Publications

Integrated immune dynamics define correlates of COVID-19 severity and antibody responses.

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