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

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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.