The Dual Role of RsiP in Regulating Virulence and Host Adaptation in Bacillus anthracis

TL;DR

This study reveals that RsiP in Bacillus anthracis regulates antibiotic resistance, protease activity, and host adaptation, impacting virulence and survival in different models.

Contribution

The study identifies RsiP's dual role in regulating virulence and host adaptation beyond antibiotic resistance in Bacillus anthracis.

Findings

Deletion of rsiP increases nprR gene expression and protease secretion.

ΔrsiP mutant causes higher mortality in cellular and Galleria mellonella models and triggers elevated inflammatory cytokines in macrophages.

ΔrsiP is attenuated in DBA/2 mice, with increased host survival and reduced bacterial loads due to impaired macrophage internalization.

Abstract

Bacillus anthracis displays susceptibility to penicillin despite harboring a β-lactamase gene, a phenotype governed by the anti-sigma factor RsiP. While RsiP represses σP-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 of rsiP significantly upregulated the nprR gene, which is an important quorum-sensing (QS) system regulator and enhanced protease secretion. The ΔrsiP mutant caused higher mortality in cellular and Galleria mellonella models and triggered elevated inflammatory cytokines (IL-6, IL-1β, TNF-α, MIP-2) in macrophages models. Surprisingly, in DBA/2 mice models, ΔrsiP was 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 ΔrsiP spores, reducing early colonization. Our findings indicate that RsiP not only modulates β-lactam resistance but also influences extracellular protease activity and host adaptation.

Figures