Investigating Immunopathologic Effects of Blimp-1 in the Brain of Mice Infected with Angiostrongylus Cantonensis by Evaluated Model of Nuclear Medical Imaging

Angiostrongylus cantonensis is an important local parasite in Taiwan and the infected patients show central nervous system symptoms. However, the detailed mechanisms that are triggered by A. cantonensis infection to induce cerebral immunopathological impairs of hosts with eosinophilic meningitis are still poorly understood. Our previous study showed that the microglia and Ym1 are critical in detecting A. cantonensis induced-inflammation by using a novel 18F-fluorodeoxyglucose (FDG) / position emission tomography (PET) imaging model. We also explored the relationship between the radioactivity uptakes in specific brain regions during A. cantonensis infection and the lethal inflammation-associated pathology in mice.The transcription factor B lymphocyte induced maturation protein 1 (Blimp-1) is important for T effector cells differentiation. Type 1 interferon receptor (IFNr)-mediated induction of Blimp-1 and subsequent expansion of Tr1 cells, which produced cytokines IL-10 and IFN-γ collaborate to limit the generation of protective humoral immunity and led to elevated parasite burdens. Whether A. cantonensis infection also regulates the immunopathological changes in the host brain through similar mechanisms of Blimp-1 pathway is the subject we want to explore in this project. We hypothesize that the inflammatory and pathological responses in respective regions of the brain in A. cantonensis-infected mice may be regulated by Blimp-1 pathway. A. cantonensis-induced pathological changes in CNS may affect by Blimp-1 expression of increased Tr1 cells. We also speculate the pathogenesis will be different in Blimp-1 Tg and CKO mice by the distribution regions of Tfh and Tr1 subsets. And we hope to develop a possible immunotherapeutic to CNS inflammatory disorders by rebalance abnormal immunodeficiency.This project will be conducted over a three-year period. In the first year, we expect to infect Blimp-1 Tg NOD mice with A. cantonensis to directly investigate the immunomodulatory mechanism of Blimp-1 pathway to the brain pathology caused by infection. In the second year, we will validate the effects of Blimp-1 to the immunopathological changes in the brains during infection by infecting Blimp-1 CKO NOD mice with A. cantonensis. Assessing side-by-side the pathology in different brain regions of Tg and CKO mice by our specific 18F-FDG/PET imaging model, we could dissect and locate the effects of Blimp-1 to T-helper subset-mediated immunomodulation for angiostrongyliasis. In the third year, we expect to apply the specific Tg and CKO mice with 18F-FDG/PET imaging model, and try to develop the possible treatment for rebalance of brain pathology caused by immune dysregulation. Completion of this project will identify pathogenic mechanisms of specific T regulatory cell responses and highlights Blimp-1 pathways that warrant consideration as potential targets when designing an efficacious angiostrongylus vaccine or novel immune therapeutics to combat this parasitic disease. A thorough understanding of the molecular and cellular circuits that regulate T cell activity during infection will help identify opportunities for the treatment of infectious and inflammatory disease in CNS.