A Time-Resolved Single-Cell Atlas Reveals Infection-Status, Age-, and Sex-Dependent Immune Responses Drive Viral Disease Severity
Year: 2026
Type: preprint
Abstract: The majority of mortality during viral infections occurs in older males; however, underlying mechanisms by which age and sex shape antiviral immunity and pathological inflammatory responses remain incompletely understood. Here, we performed time-resolved single-cell RNA sequencing across 16 conditions spanning age, sex, and four stages of influenza infection in mice, generating a high-resolution atlas. Aged mice demonstrate delayed antiviral and inflammatory responses in multiple myeloid cells, impairing viral clearance, which delays recovery. Similarly, endothelial cells from aging mice show prolonged inflammatory and antiviral gene signatures. Altered gene signatures in immune and endothelial cells result in a shift in endothelial-immune interactions in the aged lung. Further, the infection status of the cell is a major driver of transcriptional state, with infected myeloid cells exhibiting broad upregulation of genes, including interferon-stimulated, inflammatory, complement, and oxidative stress-related genes. To assess whether these age-associated transcriptional patterns are conserved in humans, we examined BAL cells obtained from healthy individuals and COVID-19 patients, and found that immune cells from aged COVID-19 patients had elevated antiviral and pro-inflammatory gene expression compared to cells from young patients. Our analyses of sex differences identified that multiple myeloid cell types in aged male mice, but not in young male mice, show persistent inflammatory responses at later stages of infection, a likely mechanism contributing to elevated mortality in older males. These data reveal how infection status of the cell, age, and sex interact to drive persistent inflammation and impaired resolution, providing a foundational resource for designing age- and sex-specific therapeutic strategies.
Authors: Lujia Chen, Aodong Qiu, Jooyoung Kim, Nebal AbuHusein, Mengyao Lu, Karen Agaronyan, Kexin Sun, Yifan Yuan, Amy Zhao, Gagan Heda, Xinghua Lu, Georgios Kitsios, Alicia N Rizzo, William Bain, Toru Nyunoya, Tomeka Suber, John Evankovich, Faraaz Shah, Charels Dela Cruz, Edward Manning, Lokesh Sharma
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7202282045