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The Intracellular Life of Mycobacterium avium subsp. paratuberculosis During Macrophage Stress: A Key Role for the Alternative Sigma Factor, SigH

ABSTRACT: Mycobacterium avium subspecies paratuberculosis (a.k.a. M. paratuberculosis) causes Johne’s disease, an enteric infection in cattle and other ruminants, greatly afflicting the dairy industry worldwide. Once inside the cell, M. paratuberculosis is known to survive harsh microenvironments, especially those inside activated macrophages. To improve our understanding of M. paratuberculosis pathogenesis, we examined the phagosome maturation associated with transcriptional responses of M. paratuberculosis during macrophage infection. Monitoring cellular markers, only live M. paratuberculosis bacilli were able to prevent phagosome maturation and reduce its acidification. On the transcriptional level, over 300 of M. paratuberculosis genes were significantly, differentially regulated in both naïve and IFN-γ-activated macrophages. These genes include the sigma factor H (sigH) that was shown to be important during persistent infection in M. tuberculosis. Interestingly, a sigH-knockout mutant showed increased sensitivity to a sustained level of thiol-specific oxidative stress. Large-scale RNA sequence analysis revealed that a large number of genes belong to the sigH regulon, especially following diamide stress. Genes involved in oxidative stress and virulence were among the induced genes in the sigH regulon with a putative consensus sequence for SigH binding was recognized in a subset of these genes (N=30), suggesting direct regulation with SigH. Finally, mice infections showed a significant attenuation of the ∆sigH mutant compared to its parental strain suggesting a role for sigH in M. paratuberculosis virulence. Such analysis could identify potential targets for further testing as vaccine candidates against Johne’s disease.

ORGANISM(S): Mycobacterium avium subsp. paratuberculosis K-10

PROVIDER: GSE43182 | GEO | 2012/12/29

SECONDARY ACCESSION(S): PRJNA184854

REPOSITORIES: GEO

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Project description:Background: Mycobacterium avium subsp. paratuberculosis (M. paratuberculosis) is the causative agent of Johne’s disease, a chronic enteric infection of ruminants. Infection occurs within the first few months of life but remains subclinical for an average of 2-5 years. Current diagnostics to detect early subclinical infections lack diagnostic sensitivity, which hinders disease control resulting in significant economic losses to the dairy industry worldwide. The pathophysiology of early infection with M. paratuberculosis is still not well understood and represents a key hurdle towards the development of better diagnostics. Methods: The present study employed a large-scale RNA-Sequencing technology to better understand early stages of M. paratuberculosis infection and immunization. Specifically, gene expression profiles of peripheral blood mononuclear cells (PBMCs) from infected and vaccinated goats were compared to controls. Results: The transcriptome of the control goats revealed a large number of genes (N = 226, 1018, 1714, 1133) that were differentially expressed compared to the M. paratuberculosis-infected goats, goats vaccinated with live attenuated or inactivated vaccines, and goats both vaccinated and infected. Bioinformatics evaluation of the differentially expressed genes indicated the regulation of a large number of genes with immunity and inflammatory functions including IL-18BP, IFN-γ, IL-17A, NOS2, LIPG and IL-22. Interestingly, a large number of goat genes (N=667) were regulated whether live or inactivated vaccine were used. Some of the regulated genes (e.g. IL-17A, IFN-g) continued its unique transcriptional profile up to 12 months post-challenge. Conclusions: Overall, transcriptome analysis of infected and/or immunized goats identified potential targets for developing early diagnostics for Johne’s disease and a potential approach to differentiate infected from vaccinated animals. A similar approach could be used to analyze later stages of Johne’s disease or other chronic infections.

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The Intracellular Life of Mycobacterium avium subsp. paratuberculosis During Macrophage Stress: A Key Role for the Alternative Sigma Factor, SigH

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