Productive Enterovirus71Infection Relies On Cell Surface SCARB2Receptorexpression And Cytosolic RIG-Ⅰ Antiviral Pathway Signaling

Enterovirus71(EV71) is a single-stranded, positive-sense RNA virus belonging to the Picornaviridae family. EV71is most frequently associated with hand, foot and mouth disease (HFMD).It can progress to severe neurological disease, including fatal encephalitis, aseptic meningitis and acute flaccid paralysis. Recently, large epidemics of HFMD occurred in the mainland of China, including an outbreak that affected nearly half million children with120deaths in eastern China in2008.The initial event in viral infection involves the attachment of virus to the host cell surface-specific receptors, thus, to some extent; the distribution of the receptor determines the host range of the virus. However, the innate immune system is essential for the initial detection of invading viruses and subsequent activation of adaptive immunity. Three classes of receptors, designated retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), Toll-like receptors (TLRs), and nucleotide oligomerization domain (NOD)-like receptors (NLRs), sense viral components, such as double-stranded RNA (dsRNA), single-stranded RNA, and DNA. RLRs and TLRs play essential roles in the production of type I interferons (IFNs) and proinflammatory cytokines in cell type-specific manners. While the RLRs play essential roles in the recognition of RNA viruses in various cells, plasmacytoid dendritic cells utilize TLRs for detecting virus invasion. NLRs play a role in the production of mature interleukin-1beta to dsRNA stimulation. Two events required to trigger an effective anti-viral innate immune response are:a) detection of the invading virus by immune system receptors; and b) initiation of protein signaling cascades that regulate the synthesis of IFNs.The scavenger receptor B2has recently identified as a putative receptor for EV71infection of epithelial cells. We found that cells with low levels of SCARB2expression are refractory to EV71infection. Those with high levels of SCARB2expression showed markedly different susceptibility to EV71infection. Both the permissive rhabdomyosarcoma RD cells and more resistant HeLa cells express SCARB2at comparable levels, support EV71binding as well as EV71cell entry equally effectively. RD however produces at least2log more infectious EV71than that by HeLa cells. Of the major pattern recognition receptors of non-immunecells, RD cells lack the expression of RIG-I protein and are defective in induction of antiviral gene expression. We show that overexpression of RIG-I, but not MDA5, helicase resulted in RD cell resistant to EV71infection. Conversely, suppression of RIG-I expression in HeLa cells renders those cells more susceptible to EV71infection. In addition to SCARB2expression, the study demonstrates that intracellular antiviral signaling is also a determining factor of EV71tropism.