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Mycobacterium avium  subspecies  paratuberculosis  (MAP) causes Johne's disease, a chronic granulomatous enteritis in ruminants. Furthermore, infections of humans with MAP have been reported and a possible association with Crohn's disease and diabetes type I is currently discussed. MAP owns large sequence polymorphisms (LSPs) that were exclusively found in this mycobacteria species. The relevance of these LSPs in the pathobiology of MAP is still unclear. The  mpt D gene (MAP3733c) of MAP belongs to a small group of functionally uncharacterized genes, which are not present in any other sequenced mycobacteria species.  mpt D is part of a predicted operon ( mpt ABCDEF), encoding a putative ATP binding cassette-transporter, located on the MAP-specific LSP14. In the present study, we generated an  mpt D knockout strain (MAPΔ mpt D) by specialized transduction. In order to investigate the potential role of  mpt D in the host, we performed infection experiments with macrophages. By this, we observed a significantly reduced cell number of MAPΔ mpt D early after infection, indicating that the mutant was hampered with respect to adaptation to the early macrophage environment. This important role of  mpt D was supported in mouse infection experiments where MAPΔ mpt D was significantly attenuated after peritoneal challenge. Metabolic profiling was performed to determine the cause for the reduced virulence and identified profound metabolic disorders especially in the lipid metabolism of MAPΔ mpt D. Overall our data revealed the  mpt D gene to be an important factor for the metabolic adaptation of MAP required for persistence in the host.

frontiers in cellular and infection microbiology

The Mycobacterium avium ssp. paratuberculosis specific mptD gene is required for maintenance of the metabolic homeostasis necessary for full virulence in mouse infections