Induction and persistence of Mycobacterium avium in myeloid derived suppressor cells

分枝杆菌(M.)禽类是兽医中仅次于牛分枝杆菌的第二大分枝杆菌物种。在分类学上，该菌可分为四个亚种：鸟分支杆菌亚种。Avium(MAA)、M.avium亚种。Silvaticum(MAS)、鸟霉亚种(M.avium subsp.副结核分枝杆菌(MAP)和禽类分支杆菌亚种。人(MAH)。MAA、MAS和MAP是动物专性病原体。MAA和MAS分别引起野鸽的禽结核病和禽类肺结核。MAP是反刍动物副结核的病原学病原体。相比之下，MAH是一种环境病原体，会优先在猪和人类中引起机会性感染。MAH也很少从其他几个动物物种中分离出来。尽管在遗传上有密切的亲缘关系，但鸟分支杆菌亚种表现出亚种特有的基因和大的基因组序列多态。这些序列编码的特征被认为是导致禽类支原体亚种不同致病性和寄主偏好的原因。长期以来，人们知道MAA株比MAH株在小鼠身上引起更严重的疾病。最近，我们发现MAA的高毒力是基于产生一氧化氮的单核细胞髓系衍生抑制细胞(MMDSC)中MAA的诱导和持续。MMDSC在MAH感染小鼠中不存在，在MAA感染小鼠的免疫抑制和疾病加重中起重要作用。提出的建议旨在确定使MAA在mMDSC中诱导和持续存在的因素和特征。这将通过系统生物学方法来完成，包括体内转录组和蛋白质组的测定以及小鼠体内MAA转座子文库的特征。这些数据将有助于更好地了解MAA的致病性和毒力，并可能有助于更好地预防、诊断和治疗MAA感染以及动物和人类的其他分枝杆菌感染。

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.