The Dual Role of RsiP in Regulating Virulence and Host Adaptation in.

Abstract

displays susceptibility to penicillin despite harboring a β-lactamase gene, a phenotype governed by the anti-sigma factor RsiP. While RsiP represses σ-dependent β-lactamase expression, its broader roles in physiology and virulence remain unclear. This study aimed to define the global regulatory functions of RsiP beyond antibiotic resistance. Deletion ofsignificantly upregulated thegene, which is an important quorum-sensing (QS) system regulator and enhanced protease secretion. The Δmutant caused higher mortality in cellular andmodels and triggered elevated inflammatory cytokines (IL-6, IL-1β, TNF-α, MIP-2) in macrophages models. Surprisingly, in DBA/2 mice models, Δwas attenuated, with increased host survival and reduced bacterial loads. Competitive indices (CI) confirmed fitness defects in mice (spleen CI = 0.39; liver CI = 0.42). These defects were not due to altered oxidative stress tolerance but were attributed to impaired macrophage internalization of Δspores, reducing early colonization. Our findings indicate that RsiP not only modulates β-lactam resistance but also influences extracellular protease activity and host adaptation.