Role of C-type Lectin Receptors in Myeloid Plasticity in Neurocysticercosis

描述（由申请人提供）：脑囊虫病（NCC）是发展中国家和美国的一种常见神经系统疾病，由寄生虫猪带绦虫幼虫阶段引起。其发病机制和临床表现因寄生虫在脑内的位置和伴随的宿主免疫反应而异。我们的长期目标是表征和理解与NCC相关的宿主免疫应答和病理学，以建立更好的治疗干预措施。除了对NCC患者的脑标本进行分析外，我们还通过颅内感染相关绦虫（Mesocestoides corti）建立了NCC小鼠模型。我们已经表明，寄生虫释放具有不同糖特异性的聚糖，这些聚糖被人类和小鼠NCC中CNS环境中的宿主细胞摄取。特别相关的是，两种C型凝集素受体（CLR）在寄生虫感染后高度上调：甘露糖受体（MRC 1）和巨噬细胞半乳糖C型凝集素（MGL 1），其分别识别来自寄生虫和宿主来源的糖。我们假设通过MRC 1识别寄生虫释放的聚糖导致保护性CNS反应。这是基于观察到Mrc 1-/-小鼠存活时间显著延长，并表现出与具有抑制表型的髓样细胞新群体浸润增加相关的CNS病理学减少。相比之下，Mgl 1-/-小鼠显示存活率降低和炎性细胞因子上调。我们进一步假设，在小鼠NCC中，CLRs差异性地调节骨髓可塑性，从而调节炎症与抑制的程度。为了验证这一点，我们将确定MRC 1和MGL 1在小鼠NCC早期和晚期骨髓细胞功能中的作用（目的1），并确定MRC 1调节效应抗原特异性T细胞免疫应答的机制（目的2）。我们提出的研究将提供第一个详细的评估CNS寄生虫感染中的cardiac表达和功能，并提出新的治疗策略。

DESCRIPTION (provided by applicant): Neurocysticercosis (NCC) is a common neurological disease in developing countries and the United States caused by the larva stages of the parasite Taenia solium. The pathogenesis and clinical manifestations vary with the location of the parasite within the brain and accompanying host immune response. Our long term goal has been to characterize and understand the host immune response and the pathology associated with NCC to establish better therapeutic interventions. Apart from analyses of brain specimens from NCC patients, we have developed a mouse model of NCC by intra-cranial infection with the related cestode, Mesocestoides corti. We have shown that the parasite releases glycans with distinct sugar specificities that are taken up by host cells in the CNS environment in both human and murine NCC. Of particular relevance, two C-type lectin receptors (CLRs) are highly up-regulated after parasite infection: mannose receptor (MRC1) and macrophage galactose C-type lectin (MGL1) which recognize sugars from parasite and host origin respectively. We hypothesize that recognition of parasite- released glycans via MRC1 leads to protective CNS responses. This is based on the observation that Mrc1-/- mice survive significantly longer and exhibit reduced CNS pathology that correlates with increased infiltration a novel population of myeloid cells with a suppressor phenotype. In contrast, Mgl1-/- mice show decreased survival and up-regulation of inflammatory cytokines. We further hypothesize that CLRs differentially modulate myeloid plasticity thus regulating the degree of inflammation vs. suppression in murine NCC. To test this, we will identify the effects of MRC1 and MGL1 in myeloid cell function during the early and late stages of murine NCC (Aim 1), and determine the mechanisms by which MRC1 modulate effector antigen specific T cell immune responses (Aim 2). Our proposed studies will provide the first detailed assessment of CLR expression and function in CNS parasite infections and present novel therapeutic strategies.