Inflammation and NLR Proteins in Leishmaniasis

描述（由申请人提供）： 利什曼原虫属原生动物引起一系列人类疾病，其中最严重的是内脏利什曼病（VL）。VL是一种潜在的致命性疾病，其中寄生虫在宿主的网状内皮器官中传播，引起慢性消耗综合征，并严重抑制宿主免疫反应。在由白蛉载体沉积在人真皮中之后，寄生虫的前鞭毛体形式通过骨髓来源的宿主细胞的吞噬作用被吸收，在那里它转化为专性细胞内无鞭毛体形式。在整个慢性感染过程中，寄生虫作为专性细胞内寄生虫主要在组织巨噬细胞中存活。 长期以来，人们认为利什曼原虫在感染哺乳动物宿主的整个过程中只存在于单核细胞来源的细胞中。现在很明显，寄生虫感染其他骨髓细胞类型。中性粒细胞和炎性单核细胞是最先到达感染部位并内化利什曼原虫的细胞。本申请中的初步研究表明，Lic在整个慢性进行性感染过程中继续将骨髓细胞募集到感染部位。具有抑制功能的不成熟骨髓细胞的异质群体（称为骨髓源性抑制细胞或MDSC）已显示在癌症或移植模型中抑制适应性免疫应答并调节巨噬细胞表型。我们在此提出检查浸润播散性Lic感染部位的髓样细胞具有抑制性表型的假设。 NLR蛋白是响应病原体相关或危险相关分子模式的胞质蛋白。一些NLR蛋白激活多蛋白炎性体复合物，导致caspase-1的激活，IL-1 β和IL-18的释放，以及强烈的炎症反应。非炎性体形成NLR蛋白也通过不同的机制影响宿主防御，其中许多机制尚未明确。我们假设，骨髓细胞浸润的寄生虫传播的网站是负责慢性VL的免疫抑制的一部分，和NLR是LIC感染期间骨髓细胞功能的关键决定因素。我们建议研究以下目标。目标1。在整个感染过程中识别Lic定位部位的髓样细胞浸润。假设：在急性感染期间，成熟的中性粒细胞和炎性单核细胞浸润寄生虫接种部位，而一旦建立慢性感染，粒细胞和单核细胞髓源性抑制细胞（MDSC）定位于寄生虫传播部位。目标#2。确定NLR蛋白是否加重或改善小鼠模型中内脏利什曼病的病程。假设：Nlrp 10对于骨髓细胞的募集是必需的，而Nlrp 12对于保护性1型免疫应答的发展是必需的。

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.