The Leishmania species protozoa cause a spectrum of human diseases, the most severe of which is visceral leishmaniasis (VL). VL is a potentially fatal disease in which parasites disseminate throughout reticuloendothelial organs of the host, causing a chronic wasting syndrome with profound suppression of host immune responses. After being deposited in human dermis by the sand fly vector, the promastigote form of the parasite is taken up through phagocytosis by host cells of myeloid origin, where it transforms to the obligate intracellular amastigote form. Throughout chronic infection, parasites survive as obligate intracellular parasites primarily in tissue macrophages. It was long believed that Leishmania reside exclusively in cells of monocytic origin throughout infection of the mammalian host. It is now apparent that parasites infect other myeloid cell types. Neutrophils and inflammatory monocytes are the first cells to arrive at the infection site and internalize Leishmania. Preliminary studiesin this application demonstrate that Lic continue to recruit myeloid cells to the infection site throughout chronic progressive infection. Heterogeneous populations of immature myeloid cells with suppressive functions, called Myeloid Derived Suppressor Cells or MDSCs, have been shown to suppress adaptive immune responses and modulate macrophage phenotype in models of cancer or transplantation. We propose herein to examine that hypothesis that myeloid cells infiltrating the sites of disseminated Lic infection have a suppressive phenotype. The NLR proteins are cytosolic proteins that respond to either pathogen-associated or danger- associated molecular patterns. Some of the NLR proteins activate the multi-protein inflammasome complex, resulting in activation of caspase-1, release of IL-1 and IL-18, and a potent inflammatory response. The non-inflammasome forming NLR proteins also affect host defenses through varied mechanisms, many of which are yet ill-defined. We hypothesize that myeloid cells infiltrating the sites of parasite dissemination are responsible in part for the immunosuppression of chronic VL, and that NLRs are critical determinants of myeloid cell function during Lic infection. We propose to investigate the following aims.
AIM #1. Identify myeloid cells infiltratin the sites of Lic localization throughout infection. Hypothesis: Mature neutrophils and inflammatory monocytes infiltrate the site of parasite inoculation during acute infection, whereas granulocytic and monocytic myeloid derived suppressor cells (MDSCs) localize to the sites of parasite dissemination once chronic infection is established.
AIM #2. Determine whether NLR proteins exacerbate or ameliorate the course of visceral leishmaniasis in murine models. Hypothesis: Nlrp10 is essential for recruitment of myeloid cells, whereas Nlrp12 is required for the development of a protective type 1 immune response.
The Leishmania species protozoa cause a divergent group of diseases, the most severe of which is visceral leishmaniasis. Underlying all Leishmania infections is the ability of the parasites to suppress or evade effective host immune responses. Military personnel in the Middle East and Latin America are at high risk for leishmaniasis. Indeed, major outbreaks of leishmaniasis affected hundreds of military personnel during recent operations in Iraq and Afghanistan. New forms of leishmaniasis are emerging and the incidence of disease is increasing, but our limited knowledge of disease pathogenesis and limited repertoire of drugs leaves us ill-prepared for this disease. We propose in this application to carefully examine the pathologic immune responses that allow Leishmania to survive in a host. The ultimate goal of this research is discover immune pathways that could become the targets of new forms of treatment for all types of leishmaniasis.
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