Anti-tuberculosis vaccination: The role of macrophages

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DESCRIPTION (provided by applicant): Tuberculosis is a major world disease. The increasing incidence of TB cases caused by multidrug-resistant strains of Mycobacterium tuberculosis (Mtb) underscores the need for an efficacious anti-TB vaccine. Although much effort has recently been devoted to this cause, the majority of recently designed vaccines have proved no more protective against an Mtb challenge infection in mice and guinea pigs than BCG, the vaccine that they were designed to replace. In almost all cases vaccination provides mice the capacity to hold an Mtb challenge infection at about a 1 log lower level. It is established that immunity to Mtb infection is mediated by Th1 cell, and most anti-Mtb vaccines are designed with view to providing the host a capacity to generate larger numbers of Mtb-specific CD4 and CD8 Th1 cells. It needs to be kept in mind, however, that although mediated by Th1 cells, immunity is expressed by macrophages in which Mtb resides throughout the course of infection. Therefore, there is a need to know whether failure of susceptible hosts (5-10% of humans, and all mice and guinea pigs) to resolve Mtb infection is due to the generation of an inadequate number of Th1 cells, or to an intrinsic deficiency in macrophage function. As a way to begin investigating the macrophage component of the anti-Mtb Th1 response, the proposed research will use vaccinated and naive mice infected with Mtb via the airborne route to test the hypothesis that the 1 log protection afforded by vaccination is not the result of (a) more Th1 cells per lesion and per macrophage, (b) a higher level of macrophages activation, or (c) a lower Mtb load per macrophage. Instead, it is due entirely to earlier activation of macrophages because of earlier generation of Th1 cells. Relevance to human disease: The proposed study deals with the role of macrophages in the expression of immunity, to tuberculosis, a major world disease that kills over 2 million people annually.