Human brucellosis, caused by Brucella spp., is one of the most widespread zoonotic diseases globally, with an estimated 500,000 new cases each year. Brucella infections result in significant morbidity in endemic areas. The molecular mechanisms employed by this pathogen to cause disease are largely unknown. An important aspect of Brucella infection is its ability to persist within phagocytic cells of the reticuloendothelial system. We have shown that the virB locus, encoding a Type IV secretion system (T4SS), is essential for survival in phagocytes and virulence in mice. However, the mechanisms by which the T4SS allows the human pathogenic Brucella species to establish their niche in the host are unknown. The objective of this application is to characterize the cellular interactions with innate immune signaling pathways elicited by the Brucella T4SS. The central hypothesis of this application is that the T4SS functions in establishing a niche for persistence in the host by eliciting proinflammatory responses leading to granuloma formation. This hypothesis will be tested by determining effects of the caspase-1 inflammasome in Th1 polarization of the immune response and granuloma formation. Further, cytosolic pattern recogntion receptor(s) will be identified that sense T4SSmediated protein translocation into cells. It is expected that the results of this work will establish new paradigms of how a virulence factor can elicit cellular responses that promote establishment of persistent infection.
for human health: Brucella is a bacterial pathogen that causes a febrile illness in people who have consumed unpasteurized goat, sheep or cow?s milk contaminated with the bacteria, or in workers occupationally exposed to infected animals. Worldwide, there are over 500,000 new cases of brucellosis each year. The fevers caused by Brucella are particularly debilitating and if not treated properly, can recur for years after the initial infection. This application proposes to determine how Brucella is able to persist in infected cells and tissues of the immune system, using a virulence factor known as the Type IV secretion system. Information gained from this work will help understand the basis for this debilitating disease, which will ultimately aid in the development of improved human vaccines and diagnostics for brucellosis.
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