Without vaccine to prevent visceral leishmaniasis (VL) (kala-azar), current management of this disseminated intracellular protozoa! disease necessarily requires successful drug therapy. In 2006, pentavalent antimony (Sb) remains conventional but suboptimal treatment, and resistance has ended its usefulness in India. Development of new drug regimens and identification of immunologic mechanisms to translate into treatment represent primary therapeutic strategies in VL. This project's long-term goal is to bring these two approaches together as immunochemotherapy to optimize macrophage activation and host responses to antileishmanial treatment. The project's overall objective is to identify, learn how to manipulate and apply immunoregulatory mechanisms in the experimental host receiving chemotherapy. The unifying hypothesis behind the research is that targeting discrete activating or suppressive mechanisms can be joined with chemotherapy to produce enhanced killing of Leishmania donovani and more durable prevention of posttreatment relapse. To accomplish the objective and test this translational strategy, this work will (a) be carried out in a clinically relevant sequential fashion, (b) test novel immunologic hypotheses in established visceral infection and (c) will be directed at enhancing specific in vivo therapeutic responses. Three related Specific Aims support the objective and advance the analysis of immunochemotherpy. Aim 1: Determine how interferon-gamma regulates host responses to Sb and induces Sb's killing action in the tissues. Aim 2: Test the superiority of synergistically amplifying macrophage intracellular signaling and activation to enhance chemotherapy's efficacy. And Aim 3: Determine how the host and the cytokineactivated macrophage prevent posttreatment relapse of persistent intracellular infection. This research is relevant to NIH's mission because of the (a) recognized clinical significance of the health problem of kalaazar, (b) clear-cut need for new treatment approaches, and (c) likelihood that identifiable host immune mechanisms can be harnessed to meaningfully enhance initial and long-lasting responses to antileishmanial drug therapy and help prevent relapse of visceral infection. This project's experimental treatment strategy also hold promise for improving the chemotherapeutic management of other allied intracellular infections in which host defense depends on immune mechanisms and activated macrophages.