Single-Cell Transcriptome Analysis Highlights a Role for Neutrophils and Inflammatory Macrophages in the Pathogenesis of Severe COVID-19
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 g...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-10-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/9/11/2374 |
| _version_ | 1797549417928065024 |
|---|---|
| author | Hibah Shaath Radhakrishnan Vishnubalaji Eyad Elkord Nehad M. Alajez |
| author_facet | Hibah Shaath Radhakrishnan Vishnubalaji Eyad Elkord Nehad M. Alajez |
| author_sort | Hibah Shaath |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T15:14:26Z |
| format | Article |
| id | doaj.art-f7c009c40f1344d6a004f8de794fb6d8 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T15:14:26Z |
| publishDate | 2020-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-f7c009c40f1344d6a004f8de794fb6d82023-11-20T19:04:28ZengMDPI AGCells2073-44092020-10-01911237410.3390/cells9112374Single-Cell Transcriptome Analysis Highlights a Role for Neutrophils and Inflammatory Macrophages in the Pathogenesis of Severe COVID-19Hibah Shaath0Radhakrishnan Vishnubalaji1Eyad Elkord2Nehad M. Alajez3College of Health & Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, QatarCollege of Health & Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, QatarCollege of Health & Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, QatarCollege of Health & Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, QatarCumulative 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.https://www.mdpi.com/2073-4409/9/11/2374SARS-Cov-2COVID-19neutrophilsinflammatory macrophagesbronchoalveolar lavage (BAL)ICGS2 |
| spellingShingle | Hibah Shaath Radhakrishnan Vishnubalaji Eyad Elkord Nehad M. Alajez Single-Cell Transcriptome Analysis Highlights a Role for Neutrophils and Inflammatory Macrophages in the Pathogenesis of Severe COVID-19 Cells SARS-Cov-2 COVID-19 neutrophils inflammatory macrophages bronchoalveolar lavage (BAL) ICGS2 |
| title | Single-Cell Transcriptome Analysis Highlights a Role for Neutrophils and Inflammatory Macrophages in the Pathogenesis of Severe COVID-19 |
| title_full | Single-Cell Transcriptome Analysis Highlights a Role for Neutrophils and Inflammatory Macrophages in the Pathogenesis of Severe COVID-19 |
| title_fullStr | Single-Cell Transcriptome Analysis Highlights a Role for Neutrophils and Inflammatory Macrophages in the Pathogenesis of Severe COVID-19 |
| title_full_unstemmed | Single-Cell Transcriptome Analysis Highlights a Role for Neutrophils and Inflammatory Macrophages in the Pathogenesis of Severe COVID-19 |
| title_short | Single-Cell Transcriptome Analysis Highlights a Role for Neutrophils and Inflammatory Macrophages in the Pathogenesis of Severe COVID-19 |
| title_sort | single cell transcriptome analysis highlights a role for neutrophils and inflammatory macrophages in the pathogenesis of severe covid 19 |
| topic | SARS-Cov-2 COVID-19 neutrophils inflammatory macrophages bronchoalveolar lavage (BAL) ICGS2 |
| url | https://www.mdpi.com/2073-4409/9/11/2374 |
| work_keys_str_mv | AT hibahshaath singlecelltranscriptomeanalysishighlightsaroleforneutrophilsandinflammatorymacrophagesinthepathogenesisofseverecovid19 AT radhakrishnanvishnubalaji singlecelltranscriptomeanalysishighlightsaroleforneutrophilsandinflammatorymacrophagesinthepathogenesisofseverecovid19 AT eyadelkord singlecelltranscriptomeanalysishighlightsaroleforneutrophilsandinflammatorymacrophagesinthepathogenesisofseverecovid19 AT nehadmalajez singlecelltranscriptomeanalysishighlightsaroleforneutrophilsandinflammatorymacrophagesinthepathogenesisofseverecovid19 |