Chlamydia species provoke serious infections of humans and animals worldwide, despite extensive work to better characterize the biology of the infection and develop vaccines. The biphasic developmental cycle of chlamydia allows for multiple sites of communication between the pathogen and the host call; examples include the signals that block, and then later induce apoptosis. Apoptosis of chlamydia-infected calls triggered with external ligands is blocked through inhibition of cytochrome c release and caspase-3 activation, while apoptosis induced by the infection itself is independent of known caspases, and dependent on activation of the pro-apoptotic factor, BAX. Our data show that BAX translocates from the cytosol to mitochondria in infected calls, and inhibition or absence of BAX results in lower chlamydia-induced apoptosis and chlamydial propagation. This process has an intimate role in the host inflammatory response and tissue pathology as mica genetically deficient in BAX exhibit increased inflammation and tissue damage despite a lower level of infection. The overall hypothesis to be tested is that chlamydiae induce apoptosis as a quiet means of escape from the call, but that infection-related cellular necrosis inevitably occurs, leading to the release of 'danger' signals and subsequent inflammation. The primary goal of these studies is to examine the entwined pathways of apoptosis and inflammation in vitro and in vivo as they relate to chlamydial disease pathogenesis. Our first two goals are to 1) determine mechanisms for, and roles of chlamydia induced apoptosis and chlamydia-induced protection from apoptosis in infection and disease, and 2) evaluate whether danger signals released from necrotic cells, such as ATP and adenosine, modulate infection and inflammation. Cellular recognition of pathogens initiates signals related to inflammation, as well as to cell survival. Thus, our last goal will be to 3) determine the contribution of Toll-like receptors (TLRs), cytosolic TLR-related proteins such as Nod1, and downstream signaling proteins in recognition of chlamydia and initiation of cellular responses in vitro and in vivo. Studies of chlamydia infection in cell lines and primary cell cultures from knockout mice will determine signaling events and proteins important in the innate immune response to chlamydia in vitro. The relevance of these data to disease pathogenesis will be determined with the use of knockout mice and an established mouse model of chlamydial genital tract disease. ? ?
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