Abstract
Hand, foot, and mouth disease (HFMD) is a febrile exanthematous disease with typical or atypical symptoms. Typical HFMD is usually caused by enterovirus 71 (EV71) or coxsackievirus A16, while atypical HFMD is usually caused by coxsackievirus A6 (CA6). In recent years, worldwide outbreaks of CA6-associated HFMD have dramatically increased, although the pathogenic mechanism of CA6 is still unclear. EV71 has been established to induce caspase-dependent apoptosis, but in this study, we demonstrate that CA6 infection promotes a distinct pathway of cell death that involves loss of cell membrane integrity. Necrostatin-1, an inhibitor of necroptosis, blocks the cell death induced by CA6 infection, but Z-DEVD-FMK, an inhibitor of caspase-3, has no effect on CA6-induced cell death. Furthermore, CA6 infection up-regulates the expression of the necroptosis signaling molecule RIPK3. Importantly, necrostatin-1 inhibits CA6 viral production, as assessed by its ability to inhibit levels of VP1 protein and genomic RNA and infectious particles. CA6-induced necroptosis is not dependent on the generation of reactive oxygen species; however, viral 3D protein can directly bind RIPK3, which is suggestive of a direct mechanism of necroptosis induction. Therefore, these results indicate that CA6 induces a mechanism of RIPK3-dependent necroptosis for viral production that is distinct from the mechanism of apoptosis induced by typical HFMD viruses.
Highlights
Hand, food, and mouth disease (HFMD) is a highly contagious disease caused by enterovirus infection
Given that enterovirus 71 (EV71), a causative agent for typical HFMD, is known to induce an obvious cytopathic effect in RD cells (Chang et al, 2004; Lu et al, 2013; Song et al, 2018), we sought to determine whether coxsackievirus A6 (CA6), a causative agent for atypical HFMD, induces a cytopathic effect
At 24 h post infection, EV71 decreased the cell number from 4.83 ± 0.45 × 105 to 1.93 ± 0.15 × 105 (Figure 1B). These results suggest that CA6 can induce a cytopathic effect, the time course for CA6-mediated cytopathy is extended relative to the time course for EV71mediated cytopathy
Summary
Food, and mouth disease (HFMD) is a highly contagious disease caused by enterovirus infection. It especially poses a health problem in young children under 5 years of age worldwide. Outbreaks of CA6-associated HFMD have markedly increased worldwide, and especially in China (Gao et al, 2016; Laga et al, 2016; Li J.S. et al, 2016; Li W. et al, 2016; Mirand et al, 2016; Anh et al, 2018; Wang S.H. et al, 2018; Du et al, 2019). Vaccines and drug have been developed for HFMD, they principally target EV71 and CA16; strategies for preventing and treating CA6-related-HFMD are scarce, and the current understanding of the pathogenic mechanism of CA6 remains limited.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
