Role of surface exposed proteins of M. paratuberculosis in the pathogenesis of Johne's disease in ruminants

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Mycobacterium avium subsp. paratuberculosis (Map) is the causative agent of Johne's disease (JD), a debilitating chronic gastroenteritis in ruminants. JD has a great economic impact in dairy cattle due to premature culling, reduced carcass value and decreased milk production. There is also a growing concern about the association of Map with Crohn's disease. With no available cure for JD and hampered control programs, there is an urgent need to improve diagnostic tools by the identification and characterization of the bacterial components involved in the pathogenesis and the host immune response. We have identified two protein families in Map, the PE and PPE proteins, which are promising candidates in this respect. Those families are unique to Mycobacteria and are highly expanded in the pathogenic members of this genus. In M. tuberculosis (Mtb), they are implicated as virulence factors and known to be immunostimulatory during infection. Some of the Mtb PE/PPE proteins are expressed on the cell surface and are suggested to provide the antigenic variation that could lead to immune evasion. There are 10 PE and 37 PPE genes in Map, comprising 1% of the genome, but their potential role in JD has never been studied. The hypothesis of the proposed studies is that some PPE proteins of Map are surface exposed by binding to the cell wall where they interact with host cells to promote infection. We have recently discovered four PPE proteins of Map to be surface exposed on the cell wall in vitro. We will further study the subcellular localization of the PPE proteins in Map since this is suggestive of their function. We will gain a better understanding of their role in infection by analyzing the expression of the PPE proteins after ingestion of Map cells by macrophages and invasion in epithelial cells. We will study the putative complex formation between PE and PPE proteins and identify other protein-protein interactions of the PPE proteins with host proteins, cells and tissues. Finally, we will investigate the specific interactions of the PPE proteins with the cell wall. We anticipate that the discovery of the function(s) and interactions of the PE and PPE proteins of Map will have a great impact on the understanding of the pathogenesis of JD.