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Article

Single-Cell Transcriptome Analysis Highlights a Role for Neutrophils and Inflammatory Macrophages in the Pathogenesis of Severe COVID-19

1
College of Health & Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
2
Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
*
Author to whom correspondence should be addressed.
Cells 2020, 9(11), 2374; https://doi.org/10.3390/cells9112374
Received: 17 September 2020 / Revised: 14 October 2020 / Accepted: 20 October 2020 / Published: 29 October 2020
(This article belongs to the Special Issue The Cell Biology of Coronavirus Infection)
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, IFITM2, IFITM1, H3F3B, SAT1, and S100A8 gene signatures were highly associated with neutrophils, while CCL8, CCL3, CCL2, KLF6, and SPP1 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., FABP4, APOC1, APOE, C1QB, and NURP1). Additionally, MALAT1, NEAT1, and SNGH25 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 (IFI27, IFITM3, IFI6, IFIT3, MX1, IFIT1, OASL, IFI30, OAS1) or to those seen only in BAL from severe-COVID-19 patients (S100A8, IFI44, IFI44L, CXCL8, CCR1, PLSCR1, EPSTI1, FPR1, OAS2, OAS3, IL1RN, TYMP, BCL2A1). 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. View Full-Text
Keywords: SARS-Cov-2; COVID-19; neutrophils; inflammatory macrophages; bronchoalveolar lavage (BAL); ICGS2; UMAP SARS-Cov-2; COVID-19; neutrophils; inflammatory macrophages; bronchoalveolar lavage (BAL); ICGS2; UMAP
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MDPI and ACS Style

Shaath, H.; Vishnubalaji, R.; Elkord, E.; Alajez, N.M. Single-Cell Transcriptome Analysis Highlights a Role for Neutrophils and Inflammatory Macrophages in the Pathogenesis of Severe COVID-19. Cells 2020, 9, 2374. https://doi.org/10.3390/cells9112374

AMA Style

Shaath H, Vishnubalaji R, Elkord E, Alajez NM. Single-Cell Transcriptome Analysis Highlights a Role for Neutrophils and Inflammatory Macrophages in the Pathogenesis of Severe COVID-19. Cells. 2020; 9(11):2374. https://doi.org/10.3390/cells9112374

Chicago/Turabian Style

Shaath, Hibah, Radhakrishnan Vishnubalaji, Eyad Elkord, and Nehad M. Alajez 2020. "Single-Cell Transcriptome Analysis Highlights a Role for Neutrophils and Inflammatory Macrophages in the Pathogenesis of Severe COVID-19" Cells 9, no. 11: 2374. https://doi.org/10.3390/cells9112374

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