Heminth Modulation of Mtb

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DESCRIPTION (provided by applicant): Mortality and morbidity caused by the pulmonary pathogen Mycobacterium tuberculosis (Mtb) remains alarmingly high. It is well established that the protective immune response to Mtb is dependent on the host's ability to initiate Th1 cellular responses. In addition, we are also gaining an appreciation for the mechanics of Th1 development and the dynamics of the microenvironment where the Mtb-reactive Thl response is initiated. Clearly these studies are providing some insights into host protective mechanisms in tuberculosis; nevertheless they do not take into account the affect that chronic co-endemic infectious agents may have on the development of Mtb-specific Th1 immunity in humans. Regions of the world with high incidence of Tuberculosis (TB) are also endemic for helminthic diseases. Helminth infections generate a strong Th2 response in the host. Together with the fact that Th2 cytokines have suppressive effects on Th1 responses, it is highly likely that co-infections with helminths may impact on the pathogenesis of TB. There is indeed an enhanced awareness that attempts to control the Big three killers-HIV, Malaria and Tuberculosis- need to take into consideration that chronic helminth infections make their victims more vulnerable to the big three. In this application, we bring together the expertise of the Salgame and Gause laboratories with respective interests in mycobacterial and helminth infections, to test the hypothesis that parasitic infections alter host immunity to Mtb and modulate the course of tuberculosis disease, and to determine the immune mechanisms responsible for these effects. Aim 1 will examine the development of Th1 responses in lymph nodes that have an ongoing N. brasielinsis (Nb)-induced Th2 response. Aim 2 will examine in an in vivo murine model of TB whether co-infection with helminths modulates tuberculosis disease.Relevance to Public health: There is increasing evidence that suggests that populations infected with parasites are more susceptible to tuberculosis. In this application we will test the hypothesis that infection with parasites compromises the host's ability to resist tuberculosis disease. The information obtained from these studies will be important for vaccine design and treatment against tuberculosis/