Pyroptosis induced by enterovirus 71 and coxsackievirus B3 infection affects viral replication and host response

Abstract

Enterovirus 71 (EV71) is the primary causative pathogen of hand, foot, and mouth disease (HFMD), affecting children with severe neurological complications. Pyroptosis is a programmed cell death characterized by cell lysis and inflammatory response. Although proinflammatory response has been implicated to play important roles in EV71-caused diseases, the involvement of pyroptosis in the pathogenesis of EV71 is poorly defined. We show that EV71 infection induced caspase-1 activation. Responding to the activation of caspase-1, the expression and secretion of both IL-1β and IL-18 were increased in EV71-infected cells. The treatment of caspase-1 inhibitor markedly improved the systemic response of the EV71-infected mice. Importantly, caspase-1 inhibitor suppressed EV71 replication in mouse brains. Similarly, pyroptosis was activated by the infection of coxsackievirus B3 (CVB3), an important member of the Enterovirus genus. Caspase-1 activation and the increased expression of IL-18 and NLRP3 were demonstrated in HeLa cells infected with CVB3. Caspase-1 inhibitor also alleviated the overall conditions of virus-infected mice with markedly decreased replication of CVB3 and reduced expression of caspase-1. These results indicate that pyroptosis is involved in the pathogenesis of both EV71 and CVB3 infections, and the treatment of caspase-1 inhibitor is beneficial to the host response during enterovirus infection.

N-Acetyl Cysteine Alleviates Coxsackievirus B-Induced Myocarditis by Suppressing caspase-1

“…As shown in Figure 4A, dramatically increased level of caspase-1 p20, one of the active fragments of caspase-1, was seen in the cells at 12 h of post-infection. As we have demonstrated previously 39 , procaspase-1 and NLRP3, the critical constituents of NLRP3 inflammasome, were also increased due to CVB3 infection ( Figure 4A). These data show that CVB3 infection not only induces the activation of caspase-1, but also increases the level of procaspase-1.…”

“…We previously demonstrated that CVB infection induced caspase-1 activation. surprisingly, we found that inhibition of caspase-1 with specific inhibitors not only alleviated the myocardial inflammation but also significantly inhibited viral replication, suggesting a novel therapeutic strategy against CVB-induced myocarditis 39 . N-acetyl cysteine (NAC), an amino acid derivative, is among the list of essential medicines issued by the World Health Organization 40 .…”

“…Unexpectedly, we found that, in addition to its anti-inflammation and cardio-protective effect, NAC also showed remarkable inhibition on CVB3 replication. To understand its antiviral mechanism, we started by determining the activity of caspase-1, since our previous study showed that CVB3 replication was inhibited by caspase-1 inhibitor 39 .…”

“…Thus, we asked whether NAC regulates cellular components which are essential to viral replication. Our previous study demonstrated that selective caspase-1 inhibitor not only alleviated the inflammation caused by CVB3 infection, but also showed antiviral effect 39 , suggesting the essential role of caspase-1 in CVB3 infection. In the present study, we observed the reduced production of pro-inflammatory cytokines including TNF-, IL-6, IL-1, and IL-18 during the infection of CVB3 in both mouse myocardium ( Figure 1E) and HeLa cells ( Figure S1A) treated with NAC.…”

Orchestrated efforts on host network hijacking: Processes governing virus replication

“…Pyroptosis is characterized by cell lysis and an inflammatory response and may occur as an antiviral immune response to virus infection. For instance, enterovirus 71 (EV71) and coxsackievirus B3 (CVB3) infections activate host pyroptosis, which is accompanied by IL-1β and IL-18 secretion [64]. Necroptosis is marked by rupture of the plasma membrane and release of proinflammatory damage-associated molecular patterns (DAMPs), and plays pro-inflammatory roles against virus infection [65].…”