| Summary: | Cumulative data link cytokine storms with coronavirus disease 2019 (COVID-19) severity. The precise identification of immune cell subsets in bronchoalveolar lavage (BAL) and their correlation with COVID-19 disease severity are currently being unraveled. Herein, we employed iterative clustering and guide-gene selection 2 (ICGS2) as well as uniform manifold approximation and projection (UMAP) dimensionality reduction computational algorithms to decipher the complex immune and cellular composition of BAL, using publicly available datasets from a total of 68,873 single cells derived from two healthy subjects, three patients with mild COVID-19, and five patients with severe COVID-19. Our analysis revealed the presence of neutrophils and macrophage cluster-1 as a hallmark of severe COVID-19. Among the identified gene signatures, <i>IFITM2</i>, <i>IFITM1</i>, <i>H3F3B</i>, <i>SAT1</i>, and <i>S100A8</i> gene signatures were highly associated with neutrophils, while <i>CCL8</i>, <i>CCL3</i>, <i>CCL2</i>, <i>KLF6</i>, and <i>SPP1</i> were associated with macrophage cluster-1 in severe-COVID-19 patients. Interestingly, although macrophages were also present in healthy subjects and patients with mild COVID-19, they had different gene signatures, indicative of interstitial and cluster-0 macrophage (i.e., <i>FABP4</i>, <i>APOC1</i>, <i>APOE</i>, <i>C1QB</i>, and <i>NURP1</i>). Additionally, <i>MALAT1</i>, <i>NEAT1</i>, and <i>SNGH25</i> were downregulated in patients with mild and severe COVID-19. Interferon signaling, FCγ receptor-mediated phagocytosis, IL17, and Tec kinase canonical pathways were enriched in patients with severe COVID-19, while PD-1 and PDL-1 pathways were suppressed. A number of upstream regulators (IFNG, PRL, TLR7, PRL, TGM2, TLR9, IL1B, TNF, NFkB, IL1A, STAT3, CCL5, and others) were also enriched in BAL cells from severe COVID-19-affected patients compared to those from patients with mild COVID-19. Further analyses revealed genes associated with the inflammatory response and chemotaxis of myeloid cells, phagocytes, and granulocytes, among the top activated functional categories in BAL from severe COVID-19-affected patients. Transcriptome data from another cohort of COVID-19-derived peripheral blood mononuclear cells (PBMCs) revealed the presence of several genes common to those found in BAL from patients with severe and mild COVID-19 (<i>IFI27</i>, <i>IFITM3</i>, <i>IFI6</i>, <i>IFIT3</i>, <i>MX1</i>, <i>IFIT1</i>, <i>OASL</i>, <i>IFI30</i>, <i>OAS1</i>) or to those seen only in BAL from severe-COVID-19 patients (<i>S100A8</i>, <i>IFI44</i>, <i>IFI44L</i>, <i>CXCL8</i>, <i>CCR1</i>, <i>PLSCR1</i>, <i>EPSTI1</i>, <i>FPR1</i>, <i>OAS2</i>, <i>OAS3</i>, <i>IL1RN</i>, <i>TYMP</i>, <i>BCL2A1</i>). Taken together, our data reveal the presence of neutrophils and macrophage cluster-1 as the main immune cell subsets associated with severe COVID-19 and identify their inflammatory and chemotactic gene signatures, also partially reflected systemically in the circulation, for possible diagnostic and therapeutic interventions.
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