(100IDP005-2) Establish an Enterovirus 71 Infected Mouse Model for Evaluation of Immunotherapy (I)

The first epidemic outbreak of Enterovirus 71 (EV 71) was reported in 1998 in Taiwan and the outbreak of EV 71 infection happens every year. Recently, Taiwan has to face the trend of declining birth rate. Thus, development of diagnosis methods, therapeutic drugs and preventive vaccines is a national policy for protecting our children threats by EV 71. EV 71 belongs to piconaviridae family and is a major causative agent to induce hand, foot and mouth disease (HFMD). However, EV 71 infection can cause the severe symptoms in a minority of children, including fatal brainstem encephalitis, polio-like paralysis, and pulmonary edema etc. Thus, understanding the interaction between host and EV 71 may facilitate the discovery of anti-EV 71 drugs and preventive vaccine. The main theme of this project is to develop the immunotherapy by enhancement of anti-EV 71 immune response and/or decrease the EV 71 mediated immunopathologic effect, using the approach of adult and newborn infectious mice. EV 71 mainly transmits by respiratory and fecal-oral transmission. Study from the Chang Gung memorial hospital has shown that EV 71 can be detected in stool samples within 11 weeks after HFMD recovery. This result suggests that there is a defect in mucosal immunity of neonatal gastrointestinal tract for EV71 virus clearance so that virus can shed in gastrointestinal tract. So, we propose three specific aims as follow: (1) to establish an EV 71 infected mouse model and compare the anti-EV 71 responses between adult and newborn mice (2) to identify and characterize what and how CD4 T subsets are involved in EV71 infection (3) to set platforms for detection the EV 71 specific CD8 T cell quality and anti-EV 71 IgA production. In general, antiviral immunity can be divided to two types, innate and adaptive immune responses. Most importantly, the adaptive immune response (CD4, CD8 and Ig-producing B cells) plays as a terminator in virus clearance. Functionally, viral specific CD8 T cells and Ig producing B cells need the help from CD4 T cells, which provide co-stimulatory signals and cytokines. So far, several subsets of CD4 T cells have been characterized, including Th1, Th17, Treg and Tfh subsets. In this grant, we will try to identify and characterize what and how CD4 T subsets are involved in the anti-EV 71 immunity or EV 71-mediated immunopathogenesis. Then, the adoptive CD4 T-cell therapy of distinct CD4 T subset may apply to modulate the anti-EV 71 immunity or to decrease the EV 71-mediated immunopathogenesis. Activated CD8 T cells are heterogeneous populations; even they recognize the same peptide. Heterogeneous CD8 T cells against the same peptide express different patterns of cytokines, chemokines, cytotoxic enzymes, survival molecules and transcriptional factors. According to the results of our preliminary study, functional CD8 T cells can express almost all above indicators and clean the viruses efficiently; in contrast, exhausted CD8 T cells lost the production of cytokines and have an impaired function to clear virus-infected cells. This platform can be applied to determine the efficacy of therapeutic drugs and preventive vaccines.

Project ID:PC10006-0137
External Project ID:NSC100-2325-B182-003