Virulence and Immunity Orchestrated by the Global Gene RegulatorsigLin Mycobacterium avium subsp. paratuberculosis

Abstract

ABSTRACTMycobacterium aviumsubsp.paratuberculosiscauses Johne's disease in ruminants, a chronic enteric disease responsible for severe economic losses in the dairy industry. Global gene regulators, including sigma factors are important in regulating mycobacterial virulence. However, the biological significance of such regulators inM. aviumsubsp.paratuberculosisrremains elusive. To better decipher the role of sigma factors inM. aviumsubsp.paratuberculosispathogenesis, we targeted a key sigma factor gene,sigL, activated in mycobacterium-infected macrophages. We interrogated anM. aviumsubsp.paratuberculosisΔsigLmutant against a selected list of stressors that mimic the host microenvironments. Our data showed thatsigLwas important in maintaining bacterial survival under such stress conditions. Survival levels further reflected the inability of the ΔsigLmutant to persist inside the macrophage microenvironments. Additionally, mouse infection studies suggested a substantial role forsigLinM. aviumsubsp.paratuberculosisvirulence, as indicated by the significant attenuation of the ΔsigL-deficient mutant compared to the parental strain. More importantly, when thesigLmutant was tested for its vaccine potential, protective immunity was generated in a vaccine/challenge model of murine paratuberculosis. Overall, our study highlights critical role ofsigLin the pathogenesis and immunity ofM. aviumsubsp.paratuberculosisinfection, a potential role that could be shared by similar proteins in other intracellular pathogens.