Early life respiratory syncytial virus infection enhances cadmium-induced lung toxicity through protein S-palmitoylation.

Cadmium (Cd) is a toxic metal found in food and water that accumulates with age and induces lung toxicity. Early life infection by respiratory syncytial virus (eRSV) increases risk of chronic lung diseases in humans, and we previously found that eRSV followed by low-level Cd (eRSV-Cd) exposure in male mice, increased lung Cd accumulation and toxicity through a mechanism involving protein S-palmitoylation (Pr-S-Pal). Whether such amplification of toxicity also occurs in female mice was not addressed, and specific protein targets and pathways for palmitoylation in eRSV-Cd toxicity remain unknown. The present study compared Cd toxicity in groups of female C57BL/6 J mice that were intranasally infected with RSV at two-weeks old, followed by three weeks for recovery, to paired groups of mice without infection. Consistent with findings in males, eRSV increased Cd accumulation in lungs and potentiated airway inflammation, and these responses were attenuated by bromopalmitate, an inhibitor of Pr-S-Pal. Palmitoylome profiling showed that eRSV-Cd stimulated palmitoylation of proteins functioning in calcium signaling, neutrophil degranulation, ion channel transport, and necroptosis. Lung metabolomics showed consistent effects of eRSV-Cd on metabolic pathways functioning in calcium signaling, immune regulation, and tissue repair. These findings support a role of protein S-palmitoylation as a mechanistic regulator of enhanced cadmium toxicity following early-life RSV infection.