Innate inflammatory cells in leishmaniasis

利什曼病的先天炎症细胞

• 批准号: 10047691
• 负责人: Mary E Wilson
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10047691
• 关键词: Affect; Afghanistan; Antigen-Presenting Cells; Antigens; Belief; Bite; Cell physiology; Cells; Chronic; Chronic Disease; Chronic Phase; Clinical; Communicable Diseases; Country; Cutaneous; Cutaneous Leishmaniasis; Data; Dendritic Cells; Development; Differentiation Antigens; Disease; Disease Outbreaks; Environment; Goals; Growth; Histocompatibility Antigens Class II; Human; Immune; Immune response; Incidence; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Iraq; Knockout Mice; Knowledge; Latin America; Lead; Leishmania; Leishmania donovani; Leishmania major; Leishmaniasis; Lesion; Life; Ligands; Longevity; Mammals; Mediating; Middle East; Military Personnel; Modeling; Mucous Membrane; Mus; Myeloid Cells; Nature; Neutrophil Infiltration; Neutrophilic Infiltrate; Paralysed; Parasites; Pathogenesis; Pathologic; Pathway interactions; Persons; Phagocytes; Pharmaceutical Preparations; Phenotype; Physiological; Play; Population; Process; Proteins; Protozoa; Research; Research Personnel; Resolution; Role; Sand Flies; Severity of illness; Shapes; Site; Skin; Symptoms; T-Lymphocyte; Tissues; Visceral Leishmaniasis; acute infection; adaptive immune response; adaptive immunity; base; chronic infection; disorder control; exhaustion; high risk; human disease; human model; immunoregulation; macrophage; microbicide; mouse model; neutrophil; novel; novel strategies; obligate intracellular parasite; operation; programmed cell death ligand 1; receptor; senescence; trafficking

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.

利什曼原虫属。原虫引起一组在许多地方病中常见的疾病 世界各国。其中包括最近爆发新冠肺炎疫情的阿富汗和伊拉克等国家。 利什曼病已在美国军事人员中流行。最常见的临床形式 利什曼病以及这些暴发的最常见原因是皮肤利什曼病 (CL) 由大型利什曼原虫引起，以及由婴儿利什曼原虫或杜诺瓦尼利什曼原虫引起的内脏利什曼病（VL）。 利什曼原虫是哺乳动物体内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 被感染的沙蝇叮咬后，宿主细胞首先渗透并内化皮肤中的寄生虫。这 利什曼原虫在被其他吞噬细胞内化之前通过中性粒细胞 被认为是麻痹杀微生物和抗原呈递功能的一种手段 感染早期的巨噬细胞和树突状细胞。在人类利什曼病的研究过程中，我们 惊讶地发现中性粒细胞亚群表达 II 类 MHC 抗原和其他标记物 慢性感染中的抗原呈递细胞（APC）。 MHCII+ PMN 也表达 PD-L1（一种 T 细胞） 耗尽受体配体，使我们质疑适应性免疫中的潜在作用。进一步的作用 对缺乏 NLRP10 的小鼠的研究表明，中性粒细胞会出现长期、严重的 皮肤损伤但寄生虫载量没有变化，这表明 NLRP10 对于 消除导致疾病表现的中性粒细胞浸润。这些 观察结果使我们推测中性粒细胞会加剧或延长病情 有症状的利什曼病，其方式与杀利什曼病活动无关。我们建议 通过检查以下三个目标来追求这些假设。 目标 1：中性粒细胞募集的程度以及中性粒细胞表型 小鼠利什曼病期间的炎症。假设：中性粒细胞的异常亚群是 被招募到利什曼原虫属的网站。急性感染和慢性感染阶段。 目标 2：利什曼原虫属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宿主 1 型 偏离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 表达 APC 和/或 T 细胞耗竭伙伴标记的中性粒细胞亚群。 目标 3.NLRP10 在解决中性粒细胞为主的炎症病变中的作用。 假设：由组织表达介导的中性粒细胞浸润消退到感染部位 NLRP10 是解决疾病所必需的。