Single-cell RNA sequencing reveals dysregulation of innate immune signaling in early-life respiratory syncytial virus infection with subsequent low-level cadmium exposure

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Early-life respiratory syncytial virus infection (eRSV) causes severe respiratory illness in vulnerable populations and has a significant global health burden. eRSV-associated pathologies are exacerbated by low levels of cadmium (Cd) in the diet, leading to increased cytokine and chemokine levels, inhibited autophagy by mechanistic target of rapamycin complex 1 (mTORC1) signaling and enhanced fibrosis. In this study, we used single-cell RNA sequencing of lung samples from mice subjected to eRSV at 2 weeks of age, followed by low-dose Cd (3.3 mg CdCl 2 /L in drinking water from 5 weeks old to 21 weeks old; eRSV+Cd) to determine responsive cell populations and identify new mechanistic targets. Alveolar macrophages exhibited the strongest response to eRSV+Cd treatment, with evidence of activated mTORC1 signaling and changes to macrophage phenotypes. Extensive differential expression also occurred in other cell types involved in alveolar repair, and analysis of cell-cell signaling revealed a significant strengthening of galectin-9 signaling between endothelial and innate immune cells only with eRSV+Cd. These results support mTORC1 signaling in macrophages, macrophage polarization, and galectin-9 signaling as promising areas of study to mitigate lung damage in individuals affected by eRSV with subsequent dietary Cd exposures.