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.
Highlights
Enteroviruses is a group of small single-strand, positive-sensed RNA viruses in the Enterovirus genus of Picornaviridae family[1,2,3]
Diseases caused by the infection of enterovirus 71 (EV71) and coxsackievirus B (CVB) are common among children and young adults[34,35]
A series of severe complications are related to enterovirus infection such as meningitis, encephalitis, acute flaccid paralysis, and myocarditis[5,36]
Summary
Enteroviruses is a group of small single-strand, positive-sensed RNA viruses in the Enterovirus genus of Picornaviridae family[1,2,3] Some enteroviruses such as enterovirus 71 (EV71) and coxsackievirus B (CVB) can lead to severe diseases such as aseptic meningitis, brainstem encephalitis, myocarditis, and pancreatitis[4,5]. Viral myocarditis caused by CVB infection can progress to cardiomyopathy, which may lead to heart failure and require heart transplantation[11] To date, it remains unclear about the pathogenesis of both EV71 and CVB infection. Pyroptosis most frequently occurs during the infection of intracellular pathogens and it is likely to form part of the defense mechanisms of the host against infection[20] In this process, cells recognize intracellular pathogens through a number of pattern-recognition receptors (PRRs) and form multi-protein complex, the inflammasome, which activates www.nature.com/scientificreports/. Our results demonstrated that pyroptosis is involved in the pathogenesis of both EV71 and CVB3 infection
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