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Comparative Single-Cell Analyses in Infants Revealed RSV-Specific Declines in NK Cell Responses and COVID-19-Specific Increases in Inflammatory Responses [COVID_RSV_snATAC]

ABSTRACT: The clinical phenotype of infants infected with respiratory syncytial virus (RSV) differs from that of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. RSV is the leading cause of hospitalization for lower respiratory tract infection and carries a significant higher risk of respiratory failure compared to SARS-CoV-2, which has been generally linked to fever and croup in young infants. The underlying mechanisms these differences remain unclear. We analyzed peripheral blood mononuclear cells (PBMCs) and serum from infants infected with SARS-CoV-2 (n=30), RSV (n=19), and healthy controls (n=17) using single-cell RNA sequencing, single-nucleus ATAC sequencing and cytokine profiling. Both viruses triggered type I interferon responses across PBMC subsets but differed in their NK cell and inflammatory responses. Severe RSV cases were characterized by lower NK cell percentages, lower IFNG expression and diminished chromatin accessibility at T-BET and EOMES binding sites in NK cells. Furthermore, RSV infections were associated with increased frequencies of CD4+ TEMRA and memory Treg cells. In contrast, SARS-CoV-2 infections were marked by more pronounced pro-inflammatory signatures, including increased transcriptional and epigenetic activity at NFKB factors and higher serum TNF concentrations. These findings highlight distinct immune response pathways in RSV and SARS-CoV-2 infections that may inform future therapeutic strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE283744 | GEO | 2026/01/15

REPOSITORIES: GEO

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Project description:COVID-19 is a pandemic that shares only certain clinical characteristics with other acute viral infections. Here, we studied the whole-blood transcriptomic host response to SARS-CoV-2 and compared it with other viral infections to understand similarities and differences in host response. We profiled peripheral blood from 24 healthy controls and 62 prospectively enrolled patients with community-acquired lower respiratory tract infection by SARS-Cov-2 within the first 24 hours of hospital admission using RNA-seq. We also collected 23 independent studies that profiled 1,855 blood samples from patients with one of six viruses (influenza, RSV, HRV, Ebola, Dengue, and SARS). We identified differentially expressed genes that change in patients with COVID-19 or other viral infections. We show changes in gene expression in peripheral blood from patients with COVID-19 are highly correlated with changes in response to other viral infections (r=0.74, p<0.001). However, two genes, ACO1 and ATL3, show significantly different changes in expression. Pathway analysis of differentially expressed genes in patients with COVID-19 or other viral infections versus healthy controls also identified similar pathways including neutrophil activation, innate immune response, immune response to viral infection, and cytokine production for over-expressed genes, as well as lymphocyte differentiation and T cell activation for under-expressed genes. When comparing transcriptome profiles of patients with COVID-19 directly with those with other viral infections, we found 114 and 302 genes were over- and under-expressed, respectively during COVID-19. Pathways analysis did not identify any significant pathways in these genes. Statistical deconvolution using immunoStates found that M1 macrophages, plasmacytoid dendritic cells, CD14+ monocytes, CD4+ T cells, and total B cells showed changes consistently in the same direction across all viral infections including COVID-19. Those that increased in COVID-19 but decreased in non-COVID were CD56bright NK cells, M2 macrophages, and total NK cells. The concordant and discordant responses mapped out via such a comparison provides a window to explore the underlying biology of why COVID-19 is so different from other viral infections encountered so far. Together, results from pathway and immunoStates analyses help dissect major shifts in cellularity and activation of signaling pathways as part of host response to SARS-CoV-2

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Comparative Single-Cell Analyses in Infants Revealed RSV-Specific Declines in NK Cell Responses and COVID-19-Specific Increases in Inflammatory Responses [COVID_RSV_snATAC]

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