Induction and persistence of Mycobacterium avium in myeloid derived suppressor cells

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Mycobacterium (M.) avium is the second most important mycobacteria species in veterinary medicine next to M. bovis. Taxonomically M. avium is classified in four subspecies: M. avium subsp. avium (MAA), M. avium subsp. silvaticum (MAS), M. avium subsp. paratuberculosis (MAP), and M. avium subsp. hominissuis (MAH). MAA, MAS, and MAP are obligate animal pathogens. MAA and MAS cause avian tuberculosis and avian tuberculosis like disease in wild pigeons, respectively. MAP is the etiological agent of paratuberculosis in ruminants. In contrast, MAH is an environmental pathogen causing opportunistic infections preferentially in pigs and humans. MAH is also isolated infrequently from several other animal species. Despite of being genetically closely related, M. avium subspecies exhibit subspecies-specific genes and large genome sequence polymorphisms. Feature encoded by these sequences are suspected to be responsible for the different pathogenicity and host preferences of the M. avium subspecies.Since long it is known that MAA strains cause more severe disease in mice than MAH strains. Recently we could show that higher virulence of MAA is based on the induction and persistence of MAA in nitric oxide producing monocytic myeloid derived suppressor cells (mMDSC). mMDSC were not present in MAH infected mice and contributed significantly to immune suppression and disease exacerbation of MAA infected mice. The presented proposal aims to identify the factors and features which enable MAA to induce and persist in mMDSC. This will be accomplished by a systems biological approach including the determination of the in vivo transcriptome and proteome and the characterisation of an in vivo transposon library of MAA in mice. These data will help to better understand MAA pathogenicity and virulence and may contribute to better prevention, diagnosis and treatment of MAA infections and other mycobacterial infections of animals and humans.