Hand, foot and mouth disease (HFMD) is a global health concern. Family Picornaviridae members, particularly enterovirus 71 (EVA71) and Coxsackievirus A16 (CVA16), are the primary etiological agents of HFMD, however, a third enterovirus A species, Coxsackievirus A6 (CVA6), has been recently associated with epidemic outbreaks. Study of the pathogenesis of CVA6 infection and development of antivirals and vaccines are hindered due to the lack of appropriate animal models. We have developed and characterized a murine model of CVA6 infection which was employed to evaluate the antiviral activities of different drugs and the protective efficacies of CVA6-inactivated vaccines. Neonatal mice were susceptible to CVA6 infection via intramuscular inoculation and the susceptibility of mice to CVA6 infection was age- and dose-dependent. Five day-old mice infected with 105.5 TCID50 of the CVA6 WF057R strain consistently exhibited clinical signs, including reduced mobility, lower weight gain and quadriplegia with significant pathology in the brain, hindlimb skeletal muscles and lungs of the infected mice in the moribund state. Immunohistochemistry and qRT-PCR analyses showed high viral loads (12 log10) in skeletal muscle and elevated levels of IL-6 (>2000 pg/ml) was associated with severe viral pneumonia and encephalitis. Ribavirin and IFN-γ administered prophylactically diminished CVA6-associated pathology in vivo and treatment with IL-6 accelerated the death of neonatal mice. Both specific anti-CVA6 serum and maternal antibody play an important role in controlling CVA6 infection and viral replication. Collectively, these findings indicate that this neonatal murine model will be invaluable in future studies to develop CVA6-specific antivirals and vaccines.

01 / ESTABLISHMENT OF NEONATAL MURINE MODELS OF COXSACKIEVIRUS INFECTION FOR EVALUATION OF ANTIVIRAL AND VACCINE EFFICACY