Impact of zinc and zinc transporters in Mycobacterium avium ssp. paratuberculosis pathogenicity

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Mycobacterium avium subspecies paratuberculosis (MAP) is the causative agent of Johne's disease (JD, paratuberculosis), a chronic, granulomatous enteritis in ruminants. JD is one of the most widespread bacterial diseases of animal husbandry with significant economic impact. However, pathobiology of MAP is largely unresolved. In our studies, we aimed to clarify differences in MAP pathobiology to other mycobacteria by comparison of MAP with the closely related Mycobacterium avium ssp. or nonpathogenic mycobacteria. Our recent deep sequencing analysis of RNA from MAP cultures after zinc starvation revealed that 70 genes responded to zinc limitation. Remarkably, 45 of these genes were located on a large genomic island (ZnGI) of approximately 90 kb which included the two MAP specific long sequence polymorphisms LSP14 and LSP15. Thirty-five of these genes were predicted to be controlled by the major transcriptional regulator for zinc, FurB. This clustering of zinc responsive genes was exclusively found in MAP and not in other mycobacteria. Furthermore, in contrast to other mycobacteria, MAP possesses three putative zinc transporters, of which two are unique to MAP and possibly acquired via horizontal gene transfer. For one of the transporters, MptABC, a FurB dependent regulation was demonstrated. Thus, zinc seems to play an important role in the metabolism of MAP. This particular aspect might be of main importance for disease progression of JD in ruminants as MAP induced inflammation is most frequently found in the distal ileum, the major site of zinc absorption of the host. The project aims to identify the relevance of zinc and zinc transporters for MAP metabolism and pathobiology.