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

描述(申请人提供)：神经囊虫病(NCC)是发展中国家和美国常见的神经系统疾病，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。我们的长期目标是确定和了解与NCC相关的宿主免疫反应和病理，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，我们还建立了一种NCC的小鼠模型，该模型是通过脑部感染相关的线虫--介形线虫Corti建立的。我们已经证明，在人类和小鼠的NCC中，寄生虫释放具有不同糖特异性的多糖，这些多糖被中枢神经系统环境中的宿主细胞摄取。尤其重要的是，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(MRC1)和巨噬细胞半乳糖C型凝集素(MGL1)，它们分别识别寄生虫和宿主来源的糖。我们假设，通过MRC1识别寄生虫释放的多糖会导致保护性的中枢神经系统反应。这是基于观察到，mrc1-/-小鼠存活时间显著延长，并表现出与渗透增加相关的中枢神经系统病理改变，这是一种具有抑制表型的新的髓系细胞群。相比之下，Mgl1-/-小鼠的存活率降低，炎性细胞因子表达上调。我们进一步假设，在小鼠NCC中，CLRs不同地调节髓系可塑性，从而调节炎症与抑制的程度。为了验证这一点，我们将确定MRC1和MGL1在小鼠NCC早期和晚期对髓系细胞功能的影响(AIM 1)，并确定MRC1调节效应抗原特异性T细胞免疫反应(AIM 2)的机制。我们提出的研究将首次详细评估CLR在中枢神经系统寄生虫感染中的表达和功能，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.