Mycobacterium tuberculosis (Mtb) grows in human macrophages, the principal host cell, where it occupies a niche allowing it to replicate without being recognized by the host. Attenuated Mtb induce apoptosis of the host macrophages resulting in containment of the bacilli and their elimination by phagocytes. An essential property of virulent Mtb and a virulence factor is the induction of necrosis characterized by plasma membrane lysis and release of the bacilli into the intercellular space that leads to spread of the infection. In contrast, attenuated Mtb induce predominantly apoptosis in the host macrophage. A hallmark of apoptosis is the presence of a 15 nm thick cell surface envelope scaffold consisting of cross-linked proteins including (annexin-1 and the protease inhibitor serpin plasminogen activator type 2 (PAI-2) as first described from the lkornified envelope of keratinocytes. Annexin-1, a 37 kDa protein with a phosphatidyl serine (PS) binding domain and a poly-gln region required for cross-linking is transported to the macrophage surface during apoptosis and binds to the PS lattice on the surface of the apoptotic Mcp. We found that annexin-1 is not only a common constituent of the apoptotic envelope of the macrophage infected with attenuated Mtb, but also an lorganizing principle required for cross-linking of the envelope by transglutaminases. In the presence of [protease inhibitors such as PAI-2 proteolytic degradation of annexin-1 resulting in an inactive product lacking lthe poly-gln region is blocked and formation of the apoptotic envelope is enabled. In this application we lpropose to investigate the capacity of virulent Mtb to interfere with the formation of the apoptotic envelope on host macrophages by modulating proteolytic degradation of annexin-1 and its transport to the cell surface. We will further study the role of membrane repair mechanisms in Mtb infection of the macrophage in the formation of the apoptotic envelope. These studies will enhance our knowledge about critical host-pathogen interactions in tuberculosis that could foster development of novel approaches to treatment and prevention.
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