Defining the Stressome ofMycobacterium aviumsubsp.paratuberculosisIn Vitro and in Naturally Infected Cows

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Abstract
Mycobacterium aviumsubsp.paratuberculosiscauses an enteric infection in cattle, with a great impact on the dairy industry in the United States and worldwide. Characterizing the gene expression profile ofM. aviumsubsp.paratuberculosisexposed to different stress conditions, or shed in cow feces, could improve our understanding of the pathogenesis ofM. aviumsubsp.paratuberculosis. In this report, the stress response ofM. aviumsubsp.paratuberculosison a genome-wide level (stressome) was defined for the first time using DNA microarrays. Expression data analysis revealed unique gene groups ofM. aviumsubsp.paratuberculosisthat were regulated under in vitro stressors while additional groups were regulated in the cow samples. Interestingly, acidic pH induced the regulation of a large number of genes (n= 597), suggesting the high sensitivity ofM. aviumsubsp.paratuberculosisto acidic environments. Generally, responses to heat shock, acidity, and oxidative stress were similar inM. aviumsubsp.paratuberculosisandMycobacterium tuberculosis, suggesting common pathways for mycobacterial defense against stressors. Several sigma factors (e.g.,sigHandsigE) were differentially coregulated with a large number of genes depending on the type of each stressor. Subsequently, we analyzed the virulence of sixM. aviumsubsp.paratuberculosismutants with inactivation of differentially regulated genes using a murine model of paratuberculosis. Both bacterial and histopathological examinations indicated the attenuation of all gene mutants, especially those selected based on their expression in the cow samples (e.g.,lipN). Overall, the employed approach profiled mycobacterial genetic networks triggered by variable stressors and identified a novel set of putative virulence genes. A similar approach could be applied to analyze other intracellular pathogens.

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