Neurocysticercosis (NCC) is the most common parasitic disease of the central nervous system and is caused by encystment of the brain with the larval form of the cestode parasite Taenia solium. Clinical manifestations include seizures, hydrocephalus, and other symptoms associated with increased intra-cranial pressure. As the severity of the symptoms is associated with the intensity and chronicity of the local immune response, the long term goal of this project has been to characterize the immune response to NCC and the associated pathology. Apart from our previous analyses of brain specimens from NCC patients, a mouse model of NCC was developed by intra-cranial infection with larvae of the related cestode Mesocestoides corti. Preliminary findings indicate that T. solium and M. corti have teguments rich in glycoproteins and glycolipids that are released during invasion. Based upon the findings, the central hypothesis is that the uptake and storage of glycoconjugates play an important role in effecting a prolonged innate immune response, breach of the blood brain barrier (BBB), and granulomatous hypersensitivity responses. To test this, the first aims are to isolate parasitic glycoconjugates to determine if they act as persistent antigens and effect immune modulation. The approaches include use of in situ immunofluorescence to follow the amount and distribution of parasitic antigens as well as to determine their potential negative effects on antigen presentation. Another aim is to analyze in detail the innate immune response examining Toll like receptors (TLRs) and their regulation of chemokine expression. The approach is to use gene profiling to determine which genes for these molecules are regulated by infection followed by triple label immunofluorescence microscopy (IF) in situ to determine colocalisation of these molecules and the cell types producing them. In vitro cell culture assays stimulating with known TLR ligands and parasitic glycoconjugates will aid in the study of regulatory mechanisms. The last aim is to study mechanism by which matrix metalloproteinases (MMPs) influence the integrity of the BBB. The approaches will combine gene profiling, in situ IF, and in situ zymography as above. In vitro studies and inhibitors of MMPs will elucidate mechanisms. The studies outlined will provide a deeper understanding of the immunopathology of NCC and should provide important insights for developing therapeutic interventions. ? ? ?
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