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Single-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19.

ABSTRACT: Dysregulated immune responses against the SARS-CoV-2 virus are instrumental in severe COVID-19. However, the immune signatures associated with immunopathology are poorly understood. Here we use multi-omics single-cell analysis to probe the dynamic immune responses in hospitalized patients with stable or progressive course of COVID-19, explore V(D)J repertoires, and assess the cellular effects of tocilizumab. Coordinated profiling of gene expression and cell lineage protein markers shows that S100A^hi/HLA-DR^lo classical monocytes and activated LAG-3^hi T cells are hallmarks of progressive disease and highlights the abnormal MHC-II/LAG-3 interaction on myeloid and T cells, respectively. We also find skewed T cell receptor repertories in expanded effector CD8⁺ clones, unmutated IGHG⁺ B cell clones, and mutated B cell clones with stable somatic hypermutation frequency over time. In conclusion, our in-depth immune profiling reveals dyssynchrony of the innate and adaptive immune interaction in progressive COVID-19.

SUBMITTER: Unterman A

PROVIDER: S-EPMC8782894 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Single-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19.

Unterman Avraham A Sumida Tomokazu S TS Nouri Nima N Yan Xiting X Zhao Amy Y AY Gasque Victor V Schupp Jonas C JC Asashima Hiromitsu H Liu Yunqing Y Cosme Carlos C Deng Wenxuan W Chen Ming M Raredon Micha Sam Brickman MSB Hoehn Kenneth B KB Wang Guilin G Wang Zuoheng Z DeIuliis Giuseppe G Ravindra Neal G NG Li Ningshan N Castaldi Christopher C Wong Patrick P Fournier John J Bermejo Santos S Sharma Lokesh L Casanovas-Massana Arnau A Vogels Chantal B F CBF Wyllie Anne L AL Grubaugh Nathan D ND Melillo Anthony A Meng Hailong H Stein Yan Y Minasyan Maksym M Mohanty Subhasis S Ruff William E WE Cohen Inessa I Raddassi Khadir K Niklason Laura E LE Ko Albert I AI Montgomery Ruth R RR Farhadian Shelli F SF Iwasaki Akiko A Shaw Albert C AC van Dijk David D Zhao Hongyu H Kleinstein Steven H SH Hafler David A DA Kaminski Naftali N Dela Cruz Charles S CS

Nature communications 20220121 1

Dysregulated immune responses against the SARS-CoV-2 virus are instrumental in severe COVID-19. However, the immune signatures associated with immunopathology are poorly understood. Here we use multi-omics single-cell analysis to probe the dynamic immune responses in hospitalized patients with stable or progressive course of COVID-19, explore V(D)J repertoires, and assess the cellular effects of tocilizumab. Coordinated profiling of gene expression and cell lineage protein markers shows that S10 ...[more]

PMID: 35064122

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Project description:CONTEXT Slowly progressive chronic tubulo-interstitial damage jeopardizes long-term renal allograft survival. Both immune and non-immune mechanisms are thought to contribute, but the most promising targets for timely intervention have not been identified. OBJECTIVE In the current study we seek to determine the driving force behind progressive histological damage of renal allografts, without the interference of donor pathology, delayed graft function and acute graft rejection. DESIGN We used microarrays to examine whole genome expression profiles in renal allograft protocol biopsies, and analyzed the correlation between gene expression and the histological appearance over time. The gene expression profiles in these protocol biopsies were then compared with gene expression of biopsies with acute T-cell mediated rejection. PATIENTS Human renal allograft biopsies (N=120) were included: 96 rejection-free protocol biopsies and 24 biopsies with T-cell mediated acute rejection. RESULTS In this highly cross-validated study, we demonstrate the significant association of established, ongoing and future chronic histological damage with regulation of adaptive immune gene expression (T-cell and B-cell transcript sets) and innate immune response gene expression (dendritic cell, NK-cell, mast cell and granulocyte transcripts). We demonstrate the ability of gene expression analysis to perform as a quantitative marker for ongoing inflammation with a wide dynamic range: from subtle subhistological inflammation prior to development of chronic damage, over moderate subclinical inflammation associated with chronic histological damage, to marked inflammation of Banff-grade acute T-cell mediated rejection. CONCLUSION Progressive chronic histological damage after kidney transplantation is associated with significant regulation of both innate and adaptive immune responses, months before the histological lesions appear. This study therefore corroborates the hypothesis that quantitative inflammation below the diagnostic threshold of classic T-cell or antibody-mediated rejection is associated with early subclinical stages of progressive renal allograft damage. We used microarrays to examine whole genome expression profiles in renal allograft protocol biopsies, and analyzed the correlation between gene expression and the histological appearance over time. The gene expression profiles in these protocol biopsies were then compared with gene expression of biopsies with acute T-cell mediated rejection. Human renal allograft biopsies (N=120) were included: 96 rejection-free protocol biopsies and 24 biopsies with T-cell mediated acute rejection.

Dataset Information

Single-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19.

Publications

Single-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19.

Similar Datasets

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