Innate inflammatory cells in leishmaniasis

利什曼原虫属原生动物引起一组疾病，这些疾病在许多地方性疾病中很常见。 世界各国。这些国家包括阿富汗和伊拉克， 利什曼病在美国军人中开始流行。最常见的临床形式 皮肤利什曼病（CL）是利什曼病的最常见病因， 内脏利什曼病（VL）由利什曼原虫引起。infantum或L. donovani。 利什曼原虫是哺乳动物的专性细胞内寄生虫。大多数寄生虫寄生在 巨噬细胞，它们在那里复制并长期存活。最近的数据表明，中性粒细胞是 在被感染的白蛉叮咬后，第一个宿主细胞渗透并内化皮肤中的寄生虫。的 利什曼原虫在被其他吞噬细胞内化之前通过中性粒细胞， 被认为是一种麻痹微生物和抗原呈递功能的手段， 巨噬细胞和树突状细胞在感染早期。在人类利什曼病的研究中， 令人惊讶的是，发现了一个表达II类MHC抗原和其他标志物的嗜中性粒细胞亚群， 抗原提呈细胞（APC）在慢性感染中的作用。MHCII + PMNs也表达PD-L1，一种T细胞 耗尽受体配体，导致我们质疑在适应性免疫中的潜在作用。进一步的作用 对缺乏NLRP 10的小鼠的研究表明， 皮肤病变，但其寄生虫负荷没有变化，这表明NLRP 10对于 有助于疾病表现的嗜中性粒细胞浸润的消退。这些 观察结果使我们假设中性粒细胞有助于加重或延长 症状性利什曼病，以独立于杀利什曼活性的方式。我们建议 通过检查以下三个目标来实现这些假设。 目的1：中性粒细胞募集的程度，和中性粒细胞表型在网站的 小鼠利什曼病期间的炎症。假设：中性粒细胞的异常亚群 招募到利什曼原虫属（Leishmania spp.）急性感染和慢性感染阶段。 目的2：利什曼原虫中性粒细胞亚群的发育和功能。感染 假设：在利什曼病中观察到的免疫应答功能障碍，导致宿主1型 免疫反应偏离了消灭寄生虫和治愈疾病的方向，部分被放大， 表达APC和/或T细胞耗竭配偶体的标志物的嗜中性粒细胞亚群。 目标3。NLRP 10在嗜中性粒细胞为主的炎性病变消退中的作用。 假设：通过组织表达的 NLRP 10是解决疾病所必需的。

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.