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.

利什曼尼亚属。原生动物引起一组在许多地方性的疾病 全球国家。其中包括阿富汗和伊拉克，最近爆发的国家 利什曼病在美国军事人员中发起。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L. intantum或L. Donovani引起的Leishmania Major和内脏利什曼病（VL）。 利什曼原虫是哺乳动物中的务实细胞内寄生虫。大多数寄生虫居住在 巨噬细胞，它们复制并长期生存。最近的数据表明，中性粒细胞是 在被感染的沙蝇咬伤后，首先宿主细胞在皮肤中浸润并内化寄生虫。这 利什曼尼亚通过中性粒细胞通过其他吞噬细胞内化之前 被认为是瘫痪的一种手段 巨噬细胞和树突状细胞早期感染。在对人类利什曼病的研究中，我们是 惊讶地发现表达II类MHC抗原和其他标记的中性粒细胞的子集 慢性感染中的抗原呈递细胞（APC）。 MHCII+ PMN也表达了PD-L1，T细胞 疲惫的受体配体，导致我们质疑在适应性免疫中的潜在作用。进一步的角色 对缺乏NLRP10的小鼠的研究暗示了中性粒细胞的嗜中性粒细胞，而NLRP10延长，严重 皮肤病变，但没有改变其寄生虫负荷，这表明NLRP10对于 有助于疾病表现的中性粒细胞浸润的分辨率。这些 观察结果使我们假设中性粒细胞有助于加剧或延长 有症状的利什曼病，以独立于利什曼尼的活性的方式。我们建议 通过检查以下三个目标来追求这些假设。 目标1：中性粒细胞募集的程度和中性粒细胞表型 鼠类病中的炎症。假设：中性粒细胞的异常子集是 招募到利什曼尼亚属地点。急性感染，并通过感染的慢性阶段。 AIM 2：Leishmania spp中嗜中性粒细胞子集的发展和功能。感染。 假设：在利什曼病中观察到的功能失调的免疫反应，带领宿主1型 免疫反应误入了根除寄生虫和治愈疾病，部分放大了 表达APC和/或T细胞耗尽伴侣的标志物的中性粒细胞的子集。 AIM 3。NLRP10在嗜中性粒细胞炎症病变的分辨率中的作用。 假设：将嗜中性粒细胞浸润到感染部位，由组织表达介导 NLRP10是需要解决疾病的。