Inflammation and NLR Proteins in Leishmaniasis

利什曼病中的炎症和 NLR 蛋白

• 批准号: 8541341
• 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 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8541341
• 关键词: Acute; Affect; Afghanistan; Animal Model; Antigens; Bite; CD4 Positive T Lymphocytes; Cancer Model; Caspase-1; Cell physiology; Cells; Cessation of life; Chronic; Chronic Disease; Complex; Deposition; Dermal; Dermis; Development; Disease; Disease Outbreaks; Elements; Gene Expression; Goals; Grant; Host Defense; Human; Immune; Immune response; Immunosuppression; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-10; Interleukin-18; Investigation; Iraq; Knowledge; Latin America; Lead; Leishmania; Leishmania donovani; Leishmania major; Leishmaniasis; Literature; Malignant Neoplasms; Middle East; Military Personnel; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Organ; Parasites; Pathogenesis; Pathologic; Pathway interactions; Pattern; Phagocytosis; Pharmaceutical Preparations; Phenotype; Population Heterogeneity; Proteins; Protozoa; Recruitment Activity; Research; Resistance; Sand Flies; Site; Spleen; Suppressor-Effector T-Lymphocytes; Tissues; Transplantation; Visceral Leishmaniasis; Wasting Syndrome; base; cell type; high risk; human disease; macrophage; monocyte; mouse model; mycobacterial; neutrophil; obligate intracellular parasite; operation; pathogen; public health relevance; response; superinfection; vector

DESCRIPTION (provided by applicant): The Leishmania species protozoa cause a spectrum of human diseases, the most severe of which is visceral leishmaniasis (VL). VL is a potentially fatal disease in which parasites disseminate throughout reticuloendothelial organs of the host, causing a chronic wasting syndrome with profound suppression of host immune responses. After being deposited in human dermis by the sand fly vector, the promastigote form of the parasite is taken up through phagocytosis by host cells of myeloid origin, where it transforms to the obligate intracellular amastigote form. Throughout chronic infection, parasites survive as obligate intracellular parasites primarily in tissue macrophages. It was long believed that Leishmania reside exclusively in cells of monocytic origin throughout infection of the mammalian host. It is now apparent that parasites infect other myeloid cell types. Neutrophils and inflammatory monocytes are the first cells to arrive at the infection site and internalize Leishmania. Preliminary studiesin this application demonstrate that Lic continue to recruit myeloid cells to the infection site throughout chronic progressive infection. Heterogeneous populations of immature myeloid cells with suppressive functions, called Myeloid Derived Suppressor Cells or MDSCs, have been shown to suppress adaptive immune responses and modulate macrophage phenotype in models of cancer or transplantation. We propose herein to examine that hypothesis that myeloid cells infiltrating the sites of disseminated Lic infection have a suppressive phenotype. The NLR proteins are cytosolic proteins that respond to either pathogen-associated or danger- associated molecular patterns. Some of the NLR proteins activate the multi-protein inflammasome complex, resulting in activation of caspase-1, release of IL-1¿ and IL-18, and a potent inflammatory response. The non-inflammasome forming NLR proteins also affect host defenses through varied mechanisms, many of which are yet ill-defined. We hypothesize that myeloid cells infiltrating the sites of parasite dissemination are responsible in part for the immunosuppression of chronic VL, and that NLRs are critical determinants of myeloid cell function during Lic infection. We propose to investigate the following aims. AIM #1. Identify myeloid cells infiltratin the sites of Lic localization throughout infection. Hypothesis: Mature neutrophils and inflammatory monocytes infiltrate the site of parasite inoculation during acute infection, whereas granulocytic and monocytic myeloid derived suppressor cells (MDSCs) localize to the sites of parasite dissemination once chronic infection is established. AIM #2. Determine whether NLR proteins exacerbate or ameliorate the course of visceral leishmaniasis in murine models. Hypothesis: Nlrp10 is essential for recruitment of myeloid cells, whereas Nlrp12 is required for the development of a protective type 1 immune response.

描述（由申请人提供）： 利什曼原虫物种原生动物引起了一系列人类疾病，其中最严重的是内脏利什曼病（VL）。 VL是一种潜在的致命疾病，其中寄生虫在宿主的网状内脏器官中传播，导致慢性浪费综合征，并深深地抑制了宿主免疫反应。在被沙子蝇载体沉积在人真皮中后，寄生虫的前差形式被髓样生物的宿主细胞通过吞噬作用吸收，在那里它转化为强制性细胞内膜片形式。在整个慢性感染过程中，寄生虫在组织巨噬细胞中的主要细胞内寄生虫作为强制性生存。长期以来，人们一直认为利什曼尼亚仅居住在整个哺乳动物宿主感染的单核细胞来源细胞中。现在很明显，寄生虫感染其他髓样细胞类型。中性粒细胞和炎症单核细胞是第一个到达感染部位并内化Leishmania的细胞。该应用程序中的初步研究表明，LIC在整个慢性进行性感染过程中继续将髓样细胞募集到感染部位。已证明具有抑制功能的未成熟髓样细胞的异源群，称为髓样衍生的抑制细胞或MDSC，已被证明可抑制适应性免疫调查并在癌症或移植模型中调节巨噬细胞表型。我们在这里提出了这一假设，即渗透了传播LIC感染部位的髓样细胞具有抑制性表型。 NLR蛋白是胞质蛋白，可对病原体相关或与危险相关的分子模式反应。一些NLR蛋白激活了多蛋白炎症体复合物，从而激活caspase-1，IL-1？和IL-18的释放以及潜在的炎症反应。形成NLR蛋白的非炎症体组也通过各种机制影响宿主防御，其中许多机制尚未定义。我们假设渗透寄生虫传播部位的髓样细胞部分负责慢性VL的免疫抑制，而NLR是LIC感染期间髓样细胞功能的关键决定剂。我们建议调查以下目标。目标＃1。鉴定髓样细胞浸润整个感染的LIC定位部位。假设：急性感染期间寄生虫接种的部位的成熟中性粒细胞和炎性单核细胞浸润，而肉芽细胞和单核细胞髓样抑制细胞（MDSC）（MDSC）局部属于寄生虫一旦建立了寄生虫的部位。目标＃2。确定NLR蛋白在鼠模型中是否加剧或改善内脏利什曼病的过程。假设：NLRP10对于募集髓样细胞至关重要，而NLRP12对于开发受保护的1型免疫响应所必需。