Improved humanized mouse model of Staphylococcus aureus infection.

Staphylococcus aureus is a significant cause of pulmonary infections, but existing mouse models fail to recapitulate human-specific responses. In this study, we developed a novel mouse model of S. aureus infection using humanized mice implanted with autologous fetal lung tissue. We show that these human lung implants support S. aureus survival and dissemination. Immunological profiling revealed extensive immune cell death after infection and an absence of chemokine induction. Transcriptomic profiling of the human lung implants revealed significant changes in gene expression, including NF-κB and JAK/STAT signaling. We identified upregulation of Cyp24a1, suggesting a role for vitamin D metabolism in host defense, but it had a mild effect on dissemination. Examination of the bacterial response to the host environment, found downregulation of virulence factors and metabolic genes, and upregulation of stress response pathways. The importance of the heat shock response in bacterial survival was shown as hrcA-deficient S. aureus exhibited reduced tissue colonization. These findings underscore the utility of this humanized lung model for studying S. aureus pathogenesis and bacterial adaptation to the human pulmonary environment.