Adaptation and Virulence of Enterovirus-A71

Abstract

Outbreaks of hand, foot, and mouth disease caused by enterovirus-A71 (EV-A71) can result in many deaths, due to central nervous system complications. Outbreaks with many fatalities have occurred sporadically in the Asia-Pacific region and have become a serious public health concern. It is hypothesized that virulent mutations in the EV-A71 genome cause these occasional outbreaks. Analysis of EV-A71 neurovirulence determinants is important, but there are no virulence determinants that are widely accepted among researchers. This is because most studies have been done in artificially infected mouse models and because EV-A71 mutates very quickly to adapt to the artificial host environment. Although EV-A71 uses multiple receptors for infection, it is clear that adaptation-related mutations alter the binding specificity of the receptors and allow the virus to adopt the best entry route for each environment. Such mutations have confused interpretations of virulence in animal models. This article will discuss how environment-adapted mutations in EV-A71 occur, how they affect virulence, and how such mutations can be avoided. We also discuss future perspectives for EV-A71 virulence research.

Keywords: adaptation; enterovirus-A71; infection animal model; mutation; virulence determinant.

Figure 1

Selective infection of cultured cells by HS-binding mutants. (Left panel) Normal cell lines, such as RD-A, show low cell surface expression of SCARB2 and high expression of HS. Therefore, the infection efficiency of wild-type HS-nonbinding mutants is low. By contrast, a small number of HS-binding mutants emerge during replication and efficiently infect cells through HS; thus, HS-binding mutants become dominant. (Right panel) In RD-∆EXT1+hSCARB2 cells, selective infection by HS-binding mutants is less likely to occur because the expression of SCARB2 and HS, responsible for such infection bias, is optimized.

Figure 2

The binding site of VP2-149 and hSCARB2. The 3D structure of the EV-A71 capsid protomer (VP1, VP2, and VP3 in blue, green, and red, respectively) and the ectodomain of hSCARB2 (orange) are shown in cartoon representation. VP2-149 is shown as a cyan stick, and hSCARB2 residues 158A, 159M, 162A, and 163Y are shown as gray sticks. This figure was produced using Protein Data Base 6I2K.

Figure 3

The HS-binding mutation controls in vitro (cultured cells) and in vivo adaptations, whereas the VP2-149 mutation controls adaptation to rodents. Human/in vivo indicates infection of human patients, human/in vitro indicates infection of human-derived cell lines, monkey/tg/in vivo indicates infection of cynomolgus monkeys and hSCARB2-tg mice, rodent/in vivo indicates infection of suckling mice, and rodent/in vitro indicates infection of rodent cell lines.