Innate and adaptive immune responses against picornaviruses and their counteractions: An overview

Picornaviruses, small positive-stranded RNA viruses, cause a wide range of diseases which is based on their differential tissue and cell type tropisms. This diversity is reflected by the immune responses, both innate and adaptive, induced after infection, and the subsequent interactions of the viruses with the immune system. The defense mechanisms of the host and the countermeasures of the virus significantly contribute to the pathogenesis of the infections. Important human pathogens are poliovirus, coxsackievirus, human rhinovirus and hepatitis A virus. These viruses are the beststudied members of the family, and in this review we want to present the major aspects of the reciprocal effects between the immune system and these viruses.

Rupintrivir is a promising candidate for treating severe cases of Enterovirus-71 infection

AIM:To evaluate the suitability of rupintrivir against Enterovirus 71(EV71)induced severe clinical symptoms using computational methods. METHODS:The structure of EV71 3C protease was predicted by homology modeling.The binding free energies between rupintrivir and EV71 3C and human rhinovirus 3C protease were computed by molecular dynamics and molecular mechanics Poisson-Boltzmann/ surface area and molecular mechanics generalized-born/ surface area methods.EV71 3C fragments obtained from clinical samples collected during May to July 2008 in Shanghai were amplified by reverse-transcription and polymerase chain reaction and sequenced. RESULTS:We observed that rupintrivir had favorable binding affinity with EV71 3C protease(-10.76 kcal/mol). The variability of the 3C protein sequence in isolates of various outbreaks,including those obtained in our hospital from May to July 2008,were also analyzed to validate the conservation of the drug binding pocket. CONCLUSION:Rupintrivir,whose safety profiles had been proved,is an attractive candidate and can be quickly utilized for treating severe EV71 infection.

EGCG-S Impacts Oxidative Stress and Infection of Enterovirus 69 in Lung Cells

Enteroviruses are responsible for emerging diseases which cause diverse symptoms and may result in neurological complications. An antiviral with multiple mechanisms of action can help prevent enterovirus mediated disease despite differences in the pathogenesis between enteroviruses, including the recently identified enterovirus 69 (EV-69) for which pathogenesis is not well understood. This study investigated the efficacy of epigallocatechin-3-gallate stearate (EGCG-S), a modified form of the antioxidant green tea catechin epigallocatechin-3-gallate (EGCG), in inhibiting EV-69 infection of lung fibroblast cells in vitro. Treatment with EGCG-S resulted in moderate protection from EV-69 mediated cytotoxicity as demonstrated by increased metabolic activity as well as maintenance of cell morphology and mitochondrial function. These effects were correlated with reduced hydrogen peroxide production in infected cells following EGCG-S treatment with concentrations less than 100 μM, suggesting a role for inhibition of EV-69 mediated oxidative stress. This study provides insight into characteristics of EV-69 infection as well as the efficacy of EGCG-S mediated inhibition of EV-69 infection.

Enterovirus A71 antivirals:Past,present,and future

Enterovirus A71(EV-A71)is a significant human pathogen,especially in children.EV-A71 infection is one of the leading causes of hand,foot,and mouth diseases(HFMD),and can lead to neurological complications such as acute flaccid myelitis(AFM)in severe cases.Although three EV-A71 vaccines are available in China,they are not broadly protective and have reduced efficacy against emerging strains.There is currently no approved antiviral for EV-A71.Significant progress has been made in developing antivirals against EV-A71 by targeting both viral proteins and host factors.However,viral capsid inhibitors and protease inhibitors failed in clinical trials of human rhinovirus infection due to limited efficacy or side effects.This review discusses major discoveries in EV-A71 antiviral development,analyzes the advantages and limitations of each drug target,and highlights the knowledge gaps that need to be addressed to advance the field forward.

Heat inactivation of foot-and-mouth disease virus,swine vesicular disease virus and classical swine fever virus when air-dried on plastic and glass surfaces

Foot-and-mouth disease virus(FMDV),swine vesicular disease virus(SVDV)and classical swine fever virus(CSFV)all cause important animal diseases.FMDV affects many different cloven-hoofed animals,whereas SVDV and CSFV are restricted to domestic and feral pigs together with wild boar.Europe is normally free of these diseases,but occasionally outbreaks happen,which can cause huge economic losses.Handling of these viruses,in particular FMDV and CSFV,is only allowed within high containment laboratories and stables.Periodically such facilities need to be decommissioned for repair or closing down,which is done by cleaning and chemical disinfection,followed by fumigation due to residual risk from virus on surfaces in inaccessible places.However,building materials in older laboratories or stables that have housed infected animals may not be well-suited for fumigation.Heat treatment is another way of inactivating viruses.In this study,we have determined the survival of infectivity in air-dried virus samples on glass and plastic surfaces incubated at room temperature or heated to 70°C for 1,2,3,5 and 7 days.Each of the tested viruses was inactivated to below the limit of detection after 24 h or 48 h of incubation at 70°C;in contrast,some of these viruses were still infectious after 7 days of incubation at room temperature.This study provides important information that can be used in relation to decontamination of buildings and in risk-assessments.

Porcine Picornavirus 3C Protease Degrades PRDX6 to Impair PRDX6-mediated Antiviral Function

Peroxiredoxin-6(PRDX6)is an antioxidant enzyme with both the activities of peroxidase and phospholipase A2(PLA2),which is involved in regulation of many cellular reactions.However,the function of PRDX6 during virus infection remains unknown.In this study,we found that the abundance of PRDX6 protein was dramatically decreased in foot-and-mouth disease virus(FMDV)infected cells.Overexpression of PRDX6 inhibited FMDV replication.In contrast,knockdown of PRDX6 expression promoted FMDV replication,suggesting an antiviral role of PRDX6.To explore whether the activity of peroxidase and PLA2 was associated with PRDX6-mediated antiviral function,a specific inhibitor of PLA2(MJ33)and a specific inhibitor of peroxidase activity(mercaptosuccinate)were used to treat the cells before FMDV infection.The results showed that incubation of MJ33 but not mercaptosuccinate promoted FMDV replication.Meanwhile,overexpression of PRDX6 slightly enhanced type I interferon signaling.We further determined that the viral 3Cprowas responsible for degradation of PRDX6,and 3Cpro-induced reduction of PRDX6 was independent of the proteasome,lysosome,and caspase pathways.The protease activity of 3Cprowas required for induction of PRDX6 reduction.Besides,PRDX6 suppressed the replication of another porcine picornavirus Senecavirus A(SVA),and the 3Cproof SVA induced the reduction of PRDX6 through its proteolytic activity as well.Together,our results suggested that PRDX6 plays an important antiviral role during porcine picornavirus infection,and the viral 3Cproinduces the degradation of PRDX6 to overcome PRDX6-mediated antiviral function.