Enterovirus 71 (EV71), a single-positive-stranded RNA virus that belongs to the Enterovirus genus of the Picornaviridae family, is a highly neurotropic virus and has been regarded as the most important neurotropic EV after the eradication of the poliovirus (11). The brain stem is most likely the major target of EV71 infection (2, 8). However, neither the host cell receptor nor the neurotransmission route of EV71 is fully defined.As for poliovirus (PV), two possible routes by which the virus reaches the central nervous system (CNS) have been suggested: the virus either enters the CNS from the blood across the blood-brain barrier (BBB) or is transmitted to the CNS through peripheral nerves via retrograde axonal transport (1,3,14,23). Expression of certain gene segments would be responsible for determining the capacity of PV to spread to the CNS through bloodstream or neuronal pathways (18).In a cynomologus monkey model (12, 13), EV71 showed a wider-spread distribution pattern in the CNS than PV following both intracranial (i.c.) and intravenous inoculations, and monkeys exhibited extrapyramidal signs, including tremor and ataxia. However, after intraspinal inoculation, monkeys developed flaccid paralysis, a pyramidal sign suggesting direct virus invasion in the inoculation site. EV infection and persistence have been implicated in the pathogenesis of certain chronic muscle diseases (17). Furthermore, PV replicated in muscle cells that maintained constant viremia and spread to CNS from peripheral nerves (23). We previously showed that EV71 propagated more effectively in RD (human rhabdomyosarcoma) cells than in SK-N-SH (neuroblastoma) cells and Caco-2 (colorectal adenocarcinoma) cells. Furthermore, after oral (p.o.) inoculation of a mouse-adapted EV71 strain, EV71/MP4, 7-day-old ICR mice developed paralysis, with a mortality rate of 80%. Virus was first seen in the intestine. The virus then spread to muscle and CNS. A vast amount of virus was detected in the CNS and muscle, which led to neuronal loss and rhabdomyolysis of the mice with severe paralysis (21). In this study, we demonstrated that EV71 possesses strong neurotropism and that retrograde axonal transport in neuron cells might represent the major transmission route of EV71 in mice. MATERIALS AND METHODSCells and virus. RD cells (American Type Culture Collection, Manassas, VA) were maintained in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum plus 2 mM L-glutamine, 100 IU penicillin, and 100 g of streptomycin per ml. EV71/MP4 strain, a mouse-adapted strain derived from parental virus EV71/Tainan/4643/98 (GenBank accession number AF304458) (22), was grown in RD cells. Working stocks contained 2 ϫ 10 7 PFU/ml. Experimental infection. Specific-pathogen-free, 7-day-old ICR mice
In this study, we sought to determine whether intratypic and intertypic cross-reactivity protected against enterovirus 71 (EV71) infection in a murine infection model. We demonstrate that active immunization of 1-day-old mice with avirulent EV71 strain or coxsackie A16 virus (CA16) by the oral route developed anti-EV71 antibodies with neutralizing activity (1:16 and 1:2, respectively). Splenocytes from both EV71-and CA16-immunized mice proliferated upon EV71 or CA16, but not coxsackie B3 virus (CB3), antigen stimulation. Immunized mice became more resistant to virulent EV71 strain challenge than nonimmunized mice. There was an increase in the percentage of activated splenic T cells and B cells in the immunized mice 2 days after EV71 challenge. The CA16 immune serum reacted with EV71 antigens in an enzyme-linked immunosorbent assay and neutralized EV71 but not CB3 or poliovirus at a titer of 1:4. Passive immunization with the CA16 immune serum reduced the clinical score, diminished the organ viral load, and increased the survival rate of mice upon EV71 challenge. CB3 neither shared in vitro cross-reactivity with EV71 nor provided in vivo protection after both active and passive immunization. These results illustrated that live vaccine is feasible for EV71 and that intertypic cross-reactivity of enteroviruses may provide a way to determine the prevalence of EV71.
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