The recruitment of circulating mononuclear cells is crucial to the immune response to Mycobacterium tuberculosis (MTB) infection in vivo. It has been shown that both alpha and beta chemokines (CK) are induced by the infection of alveolar macrophages (AM). The predominant beta-CK induced by MTB infection of AM are MIP-1alpha, MIP-1alpha beta and RANTES. Virulent MTB induces significantly less MIP-1alpha than does avirulent MTB, while induction of MIP-1beta and RANTES are comparable for both virulent and avirulent MTB. The hypothesis is therefore that beta CK's produced by AM in response to infection play a significant role in the host response by activating macrophages and recruiting T cells. The mechanism of induction and regulation of beta-CK by MTB will be examined specifically by identifying the receptors involved, the importance of phagocytosis and the presence of preformed CK. Preliminary data suggests that MTB membrane induces the release of preformed beta-CK and that secretion is dependent on TNF. The functional impact of the released beta-CK on macrophages and T cells will be assessed, in particular the effect on MTB binding and uptake of MTB, and the effect on the nature of the T cell response. Further preliminary data show that MTB infection does not alter CK receptor expression on AM but reduces expression on monocytes. In addition beta-CK enhance phagocytosis of MTB and inhibit growth of MTB in macrophages. Mechanisms for these phenomenons will be determined. The role of these multi-functional molecules in protective immunity to TB will be identified.
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