Abstract
Enterovirus A71 (EV-A71) infection can induce encephalitis, which causes death or long-term neurological sequelae, especially in young children. Using a murine infection model, we searched for anti-EV-A71 agents, because effective therapies are not available to control fatal infection. In EV-A71-infected mice, treatment with the hematopoietic growth factor, Fms-like tyrosine-kinase 3 ligand (Flt3 ligand) before infection reduced the lethality and tissue viral loads. Flt3 ligand failed to enhance the production of type I interferons. Instead, Flt3 ligand boosted the numbers of dendritic cells and, particularly lymphocytes in infected organs with an expansion of spleen B cells, and resulted in an increased titer of virus-specific antibody with neutralizing activity in the serum. The protective effect of Flt3 ligand was abolished in B cell-deficient mice. Our findings revealed that Flt3 ligand administration promotes resistance to EV-A71 infection with enhanced B cell response in a mechanism rarely reported before.
Highlights
Enterovirus A71 (EV-A71), a member of the Picornaviridae family, infects humans by the fecal-oral route and induces mild symptoms, such as herpangina and hand-foot-and-mouth disease
With regard to EV-A71 infection, we reported that the responses of endogenous type I or type II IFNs, CD4 T cells, CD8 T cells, B cells, or antibody in mice provide resistance to infection by reducing tissue viral loads[11,12,13]
The serum IFN-β levels of infected mice pretreated with saline or Flt[3] ligand were comparable on days 1 and 3 p.i. (Fig. 5B). These results showed the failure of Flt[3] ligand pretreatment to enhance type I IFN expression
Summary
Enterovirus A71 (EV-A71), a member of the Picornaviridae family, infects humans by the fecal-oral route and induces mild symptoms, such as herpangina and hand-foot-and-mouth disease. Conventional DCs (cDCs) primarily activate adaptive immunity to reduce viral loads in mouse tissues[19,20]. Previous studies assessed Flt[3] ligand pretreatment in mice with respiratory syncytial virus (RSV) or lethal herpes simplex virus 1 (HSV-1) infection[7,8,25,26] and concluded that Flt[3] ligand exerts protection mainly through innate immune responses, type I IFNs and pDCs. Given that Flt[3] ligand is capable of boosting both type I IFN and B cell responses, which effectively decrease EV-A71 infection[11,13], we tested the efficacy of Flt[3] ligand treatment on neonatal mice infected with EV-A71 in this study. Flt[3] ligand pretreatment increased the number and antibody response of B cells, but failed to enhance the production of type I IFNs
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