Hypoxia and therapeutic treatment of EV-A71 with an immune modulator TLR7 agonist in a new immunocompetent mouse model

Abstract

BACKGROUND: Enterovirus 71 (EV71 or EV-A71) was first identified in California about half a century ago. In recent years, outbreaks of EV-A71 were prevalent worldwide, including Taiwan, Malaysia, Singapore, Japan, and China. Between 2008 and 2011, China alone reported 1894 deaths associated with EV-A71 infection. In mild cases, EV-A71 can cause herpangina and hand-foot-and-mouth disease (HFMD). However, in severe cases, it could cause neurological disorders, including meningitis and encephalitis. Cardiopulmonary failure is common among hospitalized children with EV-A71 infection. No effective FDA-approved therapeutics against EV-A71 are clinically available. METHODS: We report the establishment of an immunocompetent wild type strain 129 (wt-129) mouse model, which can be cross-species infected with human EV-A71 clinical isolates via an intraperitoneal route. RESULTS: One intriguing disease phenotype of this new model is the development of characteristic "White-Jade" patches in the muscle, which lost sporadically the normal pink color of uninfected muscle. Viral VP1 protein and massive leukocyte infiltration were detected in muscles with or without white-jades. We demonstrated further that hypoxia is a general phenomenon associated with white-jades in both immunocompetent and immunodeficient mouse models. Therefore, hypoxia appears to be a feature intrinsic to EV-A71 infection, irrespective of its host's immunogenetic background. To date, no effective treatment for EV-A71 is available. Here, using this new wt-129 mouse model, we showed that timely treatment with compound R837 (a TLR7 immune modulator) via oral or intraperitoneal routes, rescued the hypoxia, limb paralysis, and death at a high therapeutic efficacy. CONCLUSIONS: In this new immunocompetent mouse 129 model, we observed an unexpected white-jade phenotype and its associated hypoxia. The successful treatment with TLR7 immune modulators via an oral route, provide us a new research direction for EV-A71 basic science and translational research. It remains an open issue whether R837 or its related compounds, will be a promising drug candidate in clinical trials in EV-A71 endemic or epidemic areas in the future.