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Single-cell multi-omics analysis of the immune response in COVID-19
Funder: Lister Institute of Preventive Medicine; doi: https://doi.org/10.13039/501100001255Funder: University College London, Birkbeck MRC Doctoral Training ProgrammeFunder: The Jikei University School of MedicineFunder: Action Medical Research (GN2779)Funder: NIHR Clinical Lectureship (CL-2017-01-004)Funder: NIHR (ACF-2018-01-004) and the BMA FoundationFunder: Chan Zuckerberg Initiative (grant 2017-174169) and from Wellcome (WT211276/Z/18/Z and Sanger core grant WT206194)Funder: UKRI Innovation/Rutherford Fund Fellowship allocated by the MRC and the UK Regenerative Medicine Platform (MR/5005579/1 to M.Z.N.). M.Z.N. and K.B.M. have been funded by the Rosetrees Trust (M944)Funder: Barbour FoundationFunder: ERC Consolidator and EU MRG-Grammar awardsFunder: Versus Arthritis Cure Challenge Research Grant (21777), and an NIHR Research Professorship (RP-2017-08-ST2-002)Funder: European Molecular Biology Laboratory (EMBL)Abstract: Analysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19. We identified expansion of nonclassical monocytes expressing complement transcripts (CD16+C1QA/B/C+) that sequester platelets and were predicted to replenish the alveolar macrophage pool in COVID-19. Early, uncommitted CD34+ hematopoietic stem/progenitor cells were primed toward megakaryopoiesis, accompanied by expanded megakaryocyte-committed progenitors and increased platelet activation. Clonally expanded CD8+ T cells and an increased ratio of CD8+ effector T cells to effector memory T cells characterized severe disease, while circulating follicular helper T cells accompanied mild disease. We observed a relative loss of IgA2 in symptomatic disease despite an overall expansion of plasmablasts and plasma cells. Our study highlights the coordinated immune response that contributes to COVID-19 pathogenesis and reveals discrete cellular components that can be targeted for therapy
Systemic Cytokine Levels Do Not Predict CD4(+) T-Cell Recovery After Suppressive Combination Antiretroviral Therapy in Chronic Human Immunodeficiency Virus Infection.
Background.  Subjects on suppressive combination antiretroviral therapy (cART) who do not achieve robust reconstitution of CD4(+) T cells face higher risk of complications and death. We studied participants in the Women's Interagency HIV Study with good (immunological responder [IR]) or poor (immunological nonresponder [INR]) CD4(+) T-cell recovery after suppressive cART (n = 50 per group) to determine whether cytokine levels or low-level viral load correlated with INR status. Methods.  A baseline sample prior to viral control and 2 subsequent samples 1 and 2 years after viral control were tested. Serum levels of 30 cytokines were measured at each time point, and low-level human immunodeficiency virus (HIV) viral load and anti-HIV antibody levels were measured 2 years after viral suppression. Results.  There were minimal differences in cytokine levels between IR and INR subjects. At baseline, macrophage inflammatory protein-3β levels were higher in IR subjects; after 1 year of suppressive cART, soluble vascular endothelial growth factor-R3 levels were higher in IR subjects; and after 2 years of suppressive cART, interferon gamma-induced protein 10 levels were higher in INR subjects. Very low-level HIV viral load and anti-HIV antibody levels did not differ between IR and INR subjects. Conclusions.  These results imply that targeting residual viral replication might not be the optimum therapeutic approach for INR subjects