Abstract
Coxsackievirus A16 (CVA16) is one of the major pathogens responsible for hand, foot and mouth disease, which affects more than two million children in the Asian-Pacific region annually. Previous studies have shown that scavenger receptor B2 is a functional receptor for CVA16 that facilitates the uncoating process. However, it remains unclear whether other receptors are required for efficient CVA16 infection. In this study, by using a variety of assays we demonstrated that CVA16 utilizes surface heparan sulfate glycosaminoglycans as its attachment receptor. We further showed that five surface-exposed positively charged residues located in a cluster at the five-fold vertex of the virion are critical to heparan sulfate binding and cellular attachment of CVA16. Among the five residues, the arginine at position 166 (R166) of VP1 capsid protein appeared to be the most important for the interaction between CVA16 and heparan sulfate. Alanine substitution at this site (R166A) almost completely abolished heparan sulfate binding and cellular attachment of the virus. Our work achieves insight into the early events of CVA16 infection, thereby providing information that may facilitate the rational design of antiviral drugs and vaccines against CVA16 infection.Emerging Microbes & Infections (2017) 6, e65; doi:10.1038/emi.2017.55; published online 26 July 2017
Highlights
IntroductionCoxsackievirus A16 (CVA16) is one of the major pathogens responsible for hand, foot and mouth disease in infants and young children.[1]A proportion of hand, foot and mouth disease patients infected withCVA16 may present with encephalitis, myocarditis and pneumonitis, which in some cases can be fatal.[2,3,4,5] Efforts have been made toward the development of CVA16 vaccines.[1,6,7,8,9,10]CVA16 is a non-enveloped virus belonging to the Enterovirus genus of the Picornaviridae family.[11,12] The virus contains a singlestranded positive-sense RNA genome ~ 7.4 kb in length,[13] which is encapsidated in a spherical protein shell that consists of 60 copies each of VP1, VP2, VP3 and VP4 subunit proteins.[14,15] Recent studies have identified human scavenger receptor B2 (SCARB2) as an uncoating receptor for both EV71 and CVA16.16,17 another EV71 receptor, human P-selectin glycoprotein ligand-1, which facilitates EV71 infection in Jurkat T cells, does not support CVA16 infection of the same cell line.[18]
Soluble heparin inhibits Coxsackievirus A16 (CVA16) attachment and infection To investigate the role of heparan sulfate-specific GAGs in CVA16 infection, we first examined the effect of pretreatment with soluble heparin sodium salt on the infectivity of CVA16 in RD cells
scavenger receptor B2 (SCARB2) was identified as a functional receptor for CVA16 as well as for EV71.16,17 SCARB2 is a transmembrane protein predominantly expressed in endosomes and lysosomes[33] and is barely present on the cell surface
Summary
Coxsackievirus A16 (CVA16) is one of the major pathogens responsible for hand, foot and mouth disease in infants and young children.[1]A proportion of hand, foot and mouth disease patients infected withCVA16 may present with encephalitis, myocarditis and pneumonitis, which in some cases can be fatal.[2,3,4,5] Efforts have been made toward the development of CVA16 vaccines.[1,6,7,8,9,10]CVA16 is a non-enveloped virus belonging to the Enterovirus genus of the Picornaviridae family.[11,12] The virus contains a singlestranded positive-sense RNA genome ~ 7.4 kb in length,[13] which is encapsidated in a spherical protein shell that consists of 60 copies each of VP1, VP2, VP3 and VP4 subunit proteins.[14,15] Recent studies have identified human scavenger receptor B2 (SCARB2) as an uncoating receptor for both EV71 and CVA16.16,17 another EV71 receptor, human P-selectin glycoprotein ligand-1, which facilitates EV71 infection in Jurkat T cells, does not support CVA16 infection of the same cell line.[18]. Coxsackievirus A16 (CVA16) is one of the major pathogens responsible for hand, foot and mouth disease in infants and young children.[1]. A proportion of hand, foot and mouth disease patients infected with. CVA16 may present with encephalitis, myocarditis and pneumonitis, which in some cases can be fatal.[2,3,4,5] Efforts have been made toward the development of CVA16 vaccines.[1,6,7,8,9,10]. It remains unknown whether other co-receptors are required for efficient CVA16 infection in vitro and in vivo
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