Human nasal wash RNA-seq reveals distinct cell-specific innate immune responses between influenza and SARS-CoV-2

Gao, Kevin M; Derr, Alan G; Guo, Zhiru; Nundel, Kerstin; Marshak-Rothstein, Ann; Finberg, Robert W; Wang, Jennifer P

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 cells responses are also distinct, we performed single-cell RNA-sequencing (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.