Human nasal wash RNA-Seq reveals distinct cell-specific innate immune responses in influenza versus SARS-CoV-2

Abstract

Influenza A virus (IAV) and SARS-CoV-2 are pandemic viruses causing millions of deaths, yet their clinical manifestations are distinctly different. With the hypothesis that upper airway immune and epithelial cell responses are also distinct, we performed single-cell RNAsequencing (scRNA-Seq) on nasal wash cells freshly collected from adults with either acute COVID-19 or influenza or from healthy controls. We focused on major cell types and subtypes in a subset of donor samples. Nasal wash cells are enriched for macrophages and neutrophils for both influenza and COVID-19 compared to healthy controls. Hillock-like epithelial cells, M2-like macrophages, and age-dependent B cells are enriched in COVID-19 samples. A global decrease in interferon (IFN)-associated transcripts in neutrophils, macrophages, and epithelial cells is apparent in COVID-19 compared to influenza. The innate immune response to SARS-CoV-2 appears to be maintained in macrophages, despite evidence for limited epithelial immune sensing. Cell-to-cell interaction analyses reveal a decrease in epithelial interactions in COVID-19 and highlight differences in macrophage-macrophage interactions for COVID-19 and influenza. Our study demonstrates that scRNA-Seq can define host and viral transcriptional activity at the site of infection and reveal distinct local epithelial and immune cell responses for COVID-19 and influenza that may contribute to their divergent disease courses.

Immunosenescence and COVID-19

“…Admittedly, neither human T and B cells nor monocyte/macrophages express ACE2 or TMPRSS2( Shen et al, 2022 ). Direct SARS-CoV-2 infection of T cells is proposed to be the mechanism of lymphopenia seen in severe COVID-19 patients ( Gao et al, 2021 ). In our opinion this finding is extremely important for understanding the relations between changes occurring during aging of the immune system and the consequences of SARS-CoV-2 infection.…”

Differential upregulation of AU-rich element-containing mRNAs in COVID-19

“…In previous studies, we measured the "isolated" ARE-dependent post-transcriptional response to inflammation, using post-transcriptional reporter assays and it turned out to be in the range of only 1.5to twofold of control much less than upregulation due to transcription of the combination of transcription and post-transcription which can be in the hundreds of folds [29][30][31]. Accordingly, this may be the reason for a lack of global ARE-upregulation signature in some clinical data originating from three of the investigated studies [18][19][20]. Therefore, and also due to the fact that clinical samples are heterogeneous compared to cell lines, a higher number of samples and higher statistical power should be necessary to detect a weak transcriptional or a post-transcriptional effect.…”

“…The authors concluded that compared to the other viruses, SARS-CoV-2 infection drives a lower antiviral interferon response but a higher cytokine response [18]. Other similar studies were conducted on clinical samples, with comparable conclusions [19][20][21][22].…”

“…weak preferential enrichment and upregulation of ARE-mRNAs in neutrophils only. This, however, did not result in a global preferential upregulation of ARE-mRNAs [20]. In the same study, the authors investigated the effect of IVA infection in the same type of cells.…”

“…Bronchoalveolar lavage fluid (BLAF) and PBMCs of SARS-CoV2infected patients from Xiong et al [19]. Macrophages, Epithelial cells and neutrophils from Gao et al [20]. Tracheal aspirate from COVID-19 patients from Sarma et al [22].…”