The Leishmania spp. protozoa cause a group of diseases that are common in the many endemic countries worldwide. These include Afghanistan and Iraq, countries where recent outbreaks of leishmaniasis have initiated among US military personnel. The most common clinical forms of leishmaniasis, and the most common causes of these outbreaks, are cutaneous leishmaniasis (CL) due to Leishmania major, and visceral leishmaniasis (VL) caused by L. infantum or L. donovani. Leishmania are obligate intracellular parasites in mammals. Most parasites reside in macrophages, where they replicate and survive long-term. Recent data show that neutrophils are the first host cells to infiltrate and internalize parasites in the skin after the bite of an infected sand fly. The passage of Leishmania through neutrophils before they are internalized by other phagocytes has been cited as a means of paralyzing the microbicidal and antigen presenting functions of macrophages and dendritic cells early in infection. During studies of human leishmaniasis we were surprised to find a subset of neutrophils expressing class II MHC antigens and other markers of antigen presenting cells (APCs) in chronic infection. MHCII+ PMNs also expressed PD-L1, a T cell exhaustion receptor ligand, leading us to question a potential role in adaptive immunity. A further role of neutrophils was implied by studies of mice lacking NLRP10, which developed prolonged, severe cutaneous lesions but no change in their parasite load, suggesting that NLRP10 is critical for resolution of a neutrophilic infiltrate that contributes to the manifestations of disease. These observations led us to hypothesize that neutrophils contribute toward exacerbating or prolonging symptomatic leishmaniasis, in a manner independent of leishmanicidal activity. We propose to pursue these hypotheses by examining the following three aims.
Aim 1 : The extent of neutrophil recruitment, and neutrophil phenotypes at the sites of inflammation during murine leishmaniasis. Hypothesis: Unusual subsets of neutrophils are recruited to the site of Leishmania spp. infection acutely, and through chronic phases of infection.
Aim 2 : The development and functions of neutrophil subsets in Leishmania spp. infection. Hypothesis: The dysfunctional immune responses observed in leishmaniasis, leading the host type 1 immune response astray from eradicating the parasite and curing disease, is amplified in part by subsets of neutrophils expressing markers of APCs and/or T cell exhaustion partners.
Aim 3. The role of NLRP10 in resolution of neutrophil-dominated inflammatory lesions. Hypothesis: Resolution of neutrophilic infiltration into the infection site, mediated by tissue-expressed NLRP10, is needed for resolution of disease.
The Leishmania species protozoa cause a divergent group of diseases, the most common of which are cutaneous and visceral leishmaniasis. These diseases are characterized by dysfunctional host immune responses, which fail to eradicate the parasite but can result in destructive disease symptoms in the infected individual. 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 operations in Iraq and Afghanistan. Despite the increasing incidence of leishmaniasis, we have limited knowledge of disease pathogenesis and a limited repertoire of drugs to treat the infections. We propose in this application to carefully examine pathologic immune responses that lead to symptomatic leishmaniasis. The ultimate goal of this research is discover immune pathways that could become targets of novel forms of treatment for leishmaniasis.
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