Immunologic perturbations in severe COVID-19/SARS-CoV-2 infection

Abstract

Although critical illness has been associated with SARS-CoV-2-induced hyperinflammation, the immune correlates of severe COVID-19 remain unclear. Here, we comprehensively analyzed peripheral blood immune perturbations in 42 SARS-CoV-2 infected and recovered individuals.We identified broad changes in neutrophils, NK cells, and monocytes during severe COVID-19, suggesting excessive mobilization of innate lineages. We found marked activation within T and B cells, highly oligoclonal B cell populations, profound plasmablast expansion, and SARS-CoV-2specific antibodies in many, but not all, severe COVID-19 cases. Despite this heterogeneity, we found selective clustering of severe COVID-19 cases through unbiased analysis of the aggregated immunological phenotypes. Our findings demonstrate broad immune perturbations spanning both innate and adaptive leukocytes that distinguish dysregulated host responses in severe SARS-CoV-2 infection and warrant therapeutic investigation.One Sentence Summary: Broad immune perturbations in severe COVID-19 surrogates, as well as the medical personnel in charge of patient care.

Dissecting the common and compartment-specific features of COVID-19 severity in the lung and periphery with single-cell resolution

“…Compositional changes were not as readily apparent in PBMCs, although we observed an expansion of multiple plasma cell types in severe donors compared to healthy control subjects, consistent with previous reports [23,33,34,44].…”

“…Our investigation revealed that the only overlapping surface markers of interest between BALF and PBMC samples are HLADQA1 and HLADQA2 on MPs/CD16+ monocytes and HLADRA on MPs/CD14+ monocytes; these HLA class II transcripts are downregulated in severe compared to mild disease. Similar observations of severity-specific loss of HLA-DR on CD14+ monocytes and T cells have been previously observed in recent scRNA-seq and flow cytometry studies [29,30,31,32,34,36]. Only a minimal set of cell surface markers appears to be shared between BALF and PBMCs, likely stemming from a general trend in our dataset that BALF and PBMC samples do not exhibit substantial overlap in differentially expressed genes, an observation previously reported in bulk RNA-seq data [21].…”

“…Treg cells), and pDCs in mild patients compared to both severe and control patients. Although severityspecific compositional changes in BALF samples remain largely unaddressed in the literature [27], the severity-specific lymphopenia of NK cells and CD4+ naive T cells that we report in BALF agrees with findings from compositional studies of PBMCs [30,31,34]. We additionally report severity-specific compositional shifts in lung mononuclear phagocyte populations and identify clusters expressing MRC1, C1QA, and FABP4 suggesting an M2 macrophage-like phenotype expanded in control subjects.…”

“…Despite recent advances, the immunological signatures of severe COVID-19 remain largely uncharacterized in both the lung [27,28] and systemic circulation [34,36]. In particular, a need exists to define markers of severity that can be used to assess patient disease trajectory in a clinical setting for the purposes of triage or to inform the use of immunomodulatory treatment strategies [34]. Here, we leveraged BALF and PBMC transcriptional data to nominate cell surface proteins that could be incorporated into a flow cytometry panel for COVID-19 patient immunophenotyping.…”

“…Previous analyses of BALF samples have shown neutrophil and proliferating T cell enrichment in severe over mild patients accompanied by CD8+ T cell lymphopenia, a shift towards inflammatory macrophage polarization, and increased transcriptional expression of a variety of cytokines [27,28]. Previous investigations of peripheral blood responses have shown various compositional shifts between severe and mild disease including cytopenias of monocytes, natural killer (NK) cells, dendritic cells (DCs), and T cells, [28,29,30,31,32] accompanied by increases in plasmablasts, B cells, and neutrophils [33,34,35,36]. Serum cytokine levels are reportedly altered between severe and mild patients, including increased IL-6, IL-8, and TNF-ɑ [11,35] and deficient IFN-α and IFN-γ [33], while blood single-cell transcriptional analyses have shown alteration of the TNF-α/NF-κB pathway, interferon signatures, and HLA class II expression [33,34,36,32].…”