Elucidating the molecular mechanisms of Mycobacterium avium subsp. paratuberculosis intracellular survival (618.7)

Abstract

Johne’s Disease (JD), a wasting disease of ruminants, is of major concern within the agricultural and food defense industries. The etiological agent of JD is Mycobacterium avium subsp. paratuberculosis (MAP). MAP evades host‐mediated immune responses, forming an environmental niche that supports bacterial growth, ‘containment’ of the infection, and metabolic dormancy. Latent bacilli can persist for long periods or through unclear mechanisms render disease. The MAP genome is closely related to other mycobacterial pathogens, particularly Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis disease, and has led to hypotheses on the contribution of various genes to MAP pathogenesis.Mechanisms underlying Mtb infection include the stringent response and iron acquisition. The stringent response is initiated by unfavorable environmental conditions and expression of the relA gene.Deleting relA in Mtb results in attenuation. During active growth, Mtb synthesizes carboxymycobactin, a secreted siderophore. The co‐transcribed gene cluster irtAB has been characterized to function in iron transport from Fe‐carboxymycobactin. Deletion of the irtA gene abrogates this transport mechanism.An analysis of MAP differential gene expression suggests relA and irtAB homologs as virulence factors. Further, a relA deficient MAP strain demonstrated survival attenuation in vivo and elicited an immune response that limited colonization by challenge with wild‐type MAP. We hypothesize that MAP relA and irtAB genes contribute to pathogenesis and compared in vitro growth characteristics and epithelial cell invasion of wild‐type MAP to strains harboring deletions in these genes. Our findings suggest a clear role for RelA in MAP growth. Currently, there is no effective vaccine against JD in cattle, which underscores the need to investigate the molecular mechanisms associated with MAP pathogenesis. Department of Homeland Security National Center for Food Protection and DefenseGrant Funding Source: Supported by Department of Homeland Security