Study on the Immunopathological Changes in the Brains of Blimp1 Transgenic and Conditional Knockout Mice Infected with Angiostrongylus Cantonensis by Using Nuclear Medicine Imaging Evaluation Model

Angiostrongylus cantonensis infects the hearts and pulmonary arteries of rats and also causes human eosinophilic meningitis and meningoencephalitis. Although many inflammatory mediators involved in A. cantonensis infection have been studied, the immune mechanisms by which these factors affect the pathogenesis and pathophysiology of eosinophilic meningitis and meningoencephalitis remain poorly defined. Results of our previous study showed that the microglia and Ym1 are critical in detecting A. cantonensis induced-inflammation in different hosts in our 18F-fluorodeoxyglucose (FDG)/position emission tomography (PET) imaging model. In this proposal, we would apply this radiological medical imaging model to not only investigate immune responses in specific brain regions during A. cantonensis infection but also to analyze the immunomodulatory relationship between various differentiated immune cell subset and inflammation -associated pathology in mice. On the other hand, our co-principal investigator (Co-PI) has generated T cell-specific B lymphocyte-induced maturation protein 1 (Blimp-1) transgenic (Tg) and conditional knockout (CKO) non-obese (NOD) mice, in which overproducing or ablating Th1 and Th17 cells, respectively. Therefore, we will apply these specific Tg or CKO mice with a Th1/Th17 imbalance to explore treatment strategies to rebalance Th cell subsets and to elucidate the mechanisms of pathogenesis in CNS inflammatory disorders such as eosinophilic meningitis and meningoencephalitis caused by angiostrongyliasis. We hypothesize that the inflammatory and pathological responses in respective regions of the brain in A. cantonensis-infected mice with eosinophilic meningitis or meningoencephalitis can be located and effectively evaluated by in vivo 18F-FDG PET/CT imaging. Pathological changes in the CNS induced by A. cantonensis infection will be enhanced in Blimp-1 Tg mice with reduced Th1/Th17 cells, whereas pathogenesis will be attenuated in Blimp-1 CKO mice by rebalanced Th2 and Th1/Th17 subsets. The long-term goal of our project is to investigate the roles of immune cells in the CNS associated with the pathogenesis of eosinophilic meningitis and meningoencephalitis that is caused by angiostrongyliasis and to develop an immunotherapeutic. Success of the proposed project will aid in the development of immune therapeutic interventions for eosinophilic meningitis or meningoencephalitis caused by angiostrongyliasis and provide the scientific and theoretical basis to integrate translational medicine into studies of CNS inflammatory pathologies in the future.