VapC12 ribonuclease toxin modulates host immune response duringMycobacterium tuberculosisinfection

Abstract

AbstractMechanistic understanding of antibiotic persistence is a prerequisite in controlling the emergence of MDR cases in Tuberculosis (TB). We have reported that the cholesterol-induced activation of VapC12 ribonuclease is critical for disease persistence in TB. In this study, we observed that relative to the wild type, mice infected with ΔvapC12induced a proinflammatory response, had a higher pathogen load, and responded better to the anti-TB treatment. In a high-dose infection model, all the mice infected with ΔvapC12succumbed early to the disease. Finally, we reported that the above phenotype of ΔvapC12was dependent on the presence of the TLR4 receptor. Overall, the data suggest that the inability of ΔvapC12to resolve neutrophil-mediated inflammation reduced bacterial killing by altering the T-cell response. In conclusion, our findings suggest the role of the VapC12 toxin in modulating the host’s innate immune response in ways that favor the long-term survival of the pathogen inside the host.