Innate inflammatory cells in leishmaniasis

利什曼原虫。原生动物引起一组在许多地方性疾病中常见的疾病 世界各国。这些国家包括阿富汗和伊拉克，这些国家最近爆发了埃博拉病毒 利什曼病在美国军事人员中开始流行。最常见的临床形式 利什曼病和这些暴发的最常见原因是皮肤利什曼病(CL)。 由于主要利什曼原虫和内脏利什曼原虫病(VL)，由L.infantum或L.donovani引起。 利什曼原虫是哺乳动物的专性细胞内寄生虫。大多数寄生虫居住在 巨噬细胞，它们在那里复制并长期存活。最近的数据显示，中性粒细胞是 在被感染的沙蝇叮咬后，第一个宿主细胞渗透并内化皮肤中的寄生虫。这个 利什曼原虫在被其他吞噬细胞内化之前通过中性粒细胞 被引用为一种瘫痪杀菌和抗原呈递功能的方法 感染早期的巨噬细胞和树突状细胞。在对人类利什曼病的研究中，我们 惊讶地发现中性粒细胞亚群表达II类MHC抗原和其他标志 慢性感染中的抗原提呈细胞(APC)MHCII中性粒细胞也表达PD-L1，一种T细胞 耗竭受体配体，使我们质疑在适应性免疫中的潜在作用。进一步发挥作用 对缺乏NLRP10的小鼠的研究表明，中性粒细胞的增加是可能的，NLRP10会发展为长期、严重的 皮肤损伤，但其寄生虫负荷没有变化，表明NLRP10在 导致疾病表现的中性粒细胞渗出物的分解。这些 观察结果使我们假设，中性粒细胞有助于加重或延长 有症状的利什曼病，以一种独立于利什曼杀伤性活动的方式。我们建议 通过检查以下三个目标来追求这些假设。 目的1：中性粒细胞募集的程度和中性粒细胞表型 小鼠利什曼病期间的炎症。假设：不寻常的中性粒细胞亚群是 被招募到利什曼原虫的现场。急性感染，并通过慢性感染阶段。 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：利什曼病中观察到的功能失调的免疫反应，导致1型宿主 根除寄生虫和治愈疾病的免疫反应在一定程度上被放大了 中性粒细胞亚群，表达APC和/或T细胞衰竭伙伴的标记。 目的3.NLRP10在中性粒细胞为主的炎性病变消退中的作用。 假设：中性粒细胞通过组织表达的方式进入感染部位 NLRP10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.