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Coxsackievirus infections [keywords]
- Prospect and challenges for the development of multivalent vaccines against hand, foot and mouth diseases. [REVIEW]
- Vaccine 2014 Sep 10.
Enterovirus 71 (EV71), an emerging neurotropic virus and coxsackieviruses (CV) are the major causative agents of hand, foot and mouth diseases (HFMD). These viruses have become a serious public health threat in the Asia Pacific region. Formalin-inactivated EV71 (FI-EV71) vaccines have been developed, evaluated in human clinical trials and were found to elicit full protection against EV71. Their failure to prevent CVA16 infections could compromise the acceptability of monovalent EV71 vaccines. Bivalent FI-EV71/FI-CVA16 vaccines have been found to elicit strong neutralizing antibody responses against both viruses in animal models but did not protect against CVA6 and CVA10 viral infections in cell culture neutralization assay. In this review, we discuss the critical bottlenecks in the development of multivalent HFMD vaccines, including the selection of vaccine strains, animal models to assess vaccine potency, the definition of end-points for efficacy trials, and the need for improved manufacturing processes to produce affordable vaccines.
- AUF1 is recruited to the stress granules induced by coxsackievirus B3. [JOURNAL ARTICLE]
- Virus Res 2014 Aug 19.
Stress granules (SGs) are cytoplasmic granules that are formed in cells when stress occurs. In this study, we found that SGs formed in cells infected with coxsackievirus B3 (CVB3), evidenced with the co-localization of some accepted SG markers in the viral infection-induced granules. We further discovered that adenosine-uridine (AU)-rich element RNA binding factor 1 (AUF1), which can bind to mRNAs and regulate their translation, was recruited to the SGs in response to high dose of CVB3 by detecting the co-localization of AUF1 with SG markers. Similar results were also observed in the enterovirus 71 (EV71)-infected cells. Finally, we demonstrated that AUF1 was also recruited to arsenite-induced SGs, suggesting that the recruitment of AUF1 to SG is not a specific response to viral infection. In summary, our data indicate that both CVB3 and EV71 infections can induce SG formation, and AUF1 is a novel SG component upon the viral infections. Our findings may shed light on understanding the picornavirus-host interaction.
- ER stress, autophagy, and RNA viruses. [Journal Article, Review]
- Front Microbiol 2014.:388.
Endoplasmic reticulum (ER) stress is a general term for representing the pathway by which various stimuli affect ER functions. ER stress induces the evolutionarily conserved signaling pathways, called the unfolded protein response (UPR), which compromises the stimulus and then determines whether the cell survives or dies. In recent years, ongoing research has suggested that these pathways may be linked to the autophagic response, which plays a key role in the cell's response to various stressors. Autophagy performs a self-digestion function, and its activation protects cells against certain pathogens. However, the link between the UPR and autophagy may be more complicated. These two systems may act dependently, or the induction of one system may interfere with the other. Experimental studies have found that different viruses modulate these mechanisms to allow them to escape the host immune response or, worse, to exploit the host's defense to their advantage; thus, this topic is a critical area in antiviral research. In this review, we summarize the current knowledge about how RNA viruses, including influenza virus, poliovirus, coxsackievirus, enterovirus 71, Japanese encephalitis virus, hepatitis C virus, and dengue virus, regulate these processes. We also discuss recent discoveries and how these will produce novel strategies for antiviral treatment.
- [Epidemiology of hand, foot, and mouth disease and genetic characterization of enterovirus A71: a survey from 2007 to 2012 in Linyi of Shandong Province, China]. [English Abstract, Journal Article]
- Bing Du Xue Bao 2014 May; 30(3):246-52.
To investigate the epidemiology of hand, foot, and mouth disease (HFMD) and the genetic characteristics of enterovirus A71 (EV-A71) in Linyi of Shandong Province, China during 2007-2012. The number of reported HFMD cases were obtained from the National Notifiable Disease Reporting System (NNDRS) were analyzed by descriptive epidemiology method; the VP1 region of EV-A71 isolated from HFMD patients in Linyi was amplified and sequenced. Finally, the genetic variability and phylogenecity of VP1 sequences of EV-A71 were analyzed by MEGA 5.0. The results showed that HFMD incidence was reported in each year from 2007 to 2012 in Linyi, and the highest incidence and mortality were reported in 2009, when there were total 14697 cases and 9 of death. The reported incidence was 140.28/100000, and the mortality was 0.086/100000. The peak incidence usually occurred between April and July, and the summit occurred in May. Scattered children accounted for 77.37%-92.00% of all cases. The peak age was 2.5 years during 2007-2009 and 1.5 years during 2010-2012. A total of 1365 laboratory-confirmed HFMD cases were reported in the 6 consecutive years, accounting for 2.98% of the gross number. Among these reports, the ratio of EV-A71 was 44.18%, and the ratio of coxsackievirus A16 (CVA16) was 46.59%. All EV-A71 strains isolated in Linyi during 2007-2012 belonged to the C4a evolutionary branch of C4 genotype. In conclusion, HFMD outbreaks occurred every year in Linyi during 2007-2012. Incidence varied significantly among different counties. The peak incidence in each year lasted from April to July. Most of the patients were children under 3 years of age, and scattered children took the highest proportion. Co-circulation of EV-A71 and CVA16 was the major cause of HFMD in each year. Since the first report of HFMD prevalence caused by EV-A71 (C4a) in 2007, the virus has been prevalent continuously in Linyi for 6 years.
- [Immunoprotective effect of inactivated coxsackievirus A16 vaccine in mice]. [English Abstract, Journal Article, Research Support, Non-U.S. Gov't]
- Bing Du Xue Bao 2014 May; 30(3):226-32.
This study aims to construct inactivated coxsackievirus A16 (CVA16) vaccine and to investigate its protective effect in ICR mice. A clinical isolate of CVA16, 521-01T, was cultured in VERO cells, inactivated by formaldehyde, and purified by ultracentrifugation for vaccine preparation. Purity and other characteristics of the vaccine were determined by SDS-PAGE and Western blot. Female ICR mice were subcutaneously inoculated with inactivated CVA16 or Al(OH)3-absorbed CVA16, followed by booster immunization at the end of 2 and 4 weeks. CVA16-specific IgG titers in serum were determined by ELISA, and titers of neutralizing antibodies were determined by viral neutralization assay. The immunity of T lymphocytes was evaluated by IFN-gamma ELISPOT assay. The protective effect was evaluated by challenging the neonatal offspring (< 48 hours) of vaccinated female mice with 1 000 LD50 of CVA16 521-01T. The mortality rates of different groups were compared. The results showed that Al(OH)3 +CVA16 could induce high titers of specific IgG antibodies in ICR mice. After being boosted two times, the serum IgG antibody titer could reach up to 1 : 1 x 10(5) (P = 0.000), and neutralizing antibody titer was higher than 1 : 256. Additionally, more spot forming cells were induced in the immunized groups than in the negative controls. The maternal antibodies showed protective effect in 100% of the neonatal mice challenged with 1 000 LD50 of CVA16 521-01T. The inactivated CVA16 vaccine has ideal immunogenicity and immunoprotective effect. This research lays a foundation for the development and evaluation of CVA16 vaccines.
- Coxsackievirus can persist in murine pancreas by deletion of 5' terminal genomic sequences. [JOURNAL ARTICLE]
- J Med Virol 2014 Aug 11.
Enterovirus infections are generally acute and rapidly cleared by the host immune response. Enteroviruses can at times persist in immunologically intact individuals after the rise of the type-specific neutralizing immune response. The mechanism of enterovirus persistence was shown in group B coxsackieviruses (CVB) to be due to naturally-occurring deletions at the 5' terminus of the genome which variably impact the stem-loop secondary structure called domain I. These deletions result in much slower viral replication and a loss of measurable cytopathic effect when such 5' terminally deleted (TD) viruses are assayed in cell culture. The existence and persistence of CVB-TD long after the acute phase of infection has been documented in hearts of experimentally inoculated mice and naturally infected humans but to date, the existence of TD enteroviral populations have not been documented in any other organ. Enteroviral infections have been shown to impact type 1 diabetes (T1D) onset in humans as well as in the non-obese diabetic mouse model of T1D. The first step to studying the potential impact of CVB-TD on T1D etiology is to determine whether CVB-TD populations can arise in the pancreas. After inoculation of NOD diabetic mice with CVB, viral RNA persists in the absence of cytopathic virus in pancreas weeks past the acute infectious period. Analysis of viral genomic 5' termini by RT-PCR showed CVB-TD populations displace the parental population during persistent replication in murine pancreata. J. Med. Virol. 9999: XX-XX, 2014. © 2014 Wiley Periodicals, Inc.
- Induction and suppression of innate antiviral responses by picornaviruses. [JOURNAL ARTICLE]
- Cytokine Growth Factor Rev 2014 Jul 18.
The family Picornaviridae comprises of small, non-enveloped, positive-strand RNA viruses and contains many human and animal pathogens including enteroviruses (e.g. poliovirus, coxsackievirus, enterovirus 71 and rhinovirus), cardioviruses (e.g. encephalomyocarditis virus), hepatitis A virus and foot-and-mouth disease virus. Picornavirus infections activate a cytosolic RNA sensor, MDA5, which in turn, induces a type I interferon response, a crucial component of antiviral immunity. Moreover, picornaviruses activate the formation of stress granules (SGs), large aggregates of preassembled mRNPs (messenger ribonucleoprotein particles) to temporarily store these molecules upon cellular stress. Meanwhile, picornaviruses actively suppress these antiviral responses to ensure efficient replication. In this review we provide an overview of the induction and suppression of the MDA5-mediated IFN-α/β response and the cellular stress pathway by picornaviruses.
- The Impact of Juvenile Coxsackievirus Infection on Cardiac Progenitor Cells and Postnatal Heart Development. [JOURNAL ARTICLE]
- PLoS Pathog 2014 Jul; 10(7):e1004249.
Coxsackievirus B (CVB) is an enterovirus that most commonly causes a self-limited febrile illness in infants, but cases of severe infection can manifest in acute myocarditis. Chronic consequences of mild CVB infection are unknown, though there is an epidemiologic association between early subclinical infections and late heart failure, raising the possibility of subtle damage leading to late-onset dysfunction, or chronic ongoing injury due to inflammatory reactions during latent infection. Here we describe a mouse model of juvenile infection with a subclinical dose of coxsackievirus B3 (CVB3) which showed no evident symptoms, either immediately following infection or in adult mice. However following physiological or pharmacologically-induced cardiac stress, juvenile-infected adult mice underwent cardiac hypertrophy and dilation indicative of progression to heart failure. Evaluation of the vasculature in the hearts of adult mice subjected to cardiac stress showed a compensatory increase in CD31+ blood vessel formation, although this effect was suppressed in juvenile-infected mice. Moreover, CVB3 efficiently infected juvenile c-kit+ cells, and cardiac progenitor cell numbers were reduced in the hearts of juvenile-infected adult mice. These results suggest that the exhausted cardiac progenitor cell pool following juvenile CVB3 infection may impair the heart's ability to increase capillary density to adapt to increased load.
- [Group enterovirus infection due to coxsackievirus A16 in Northwestern Russia]. [English Abstract, Journal Article]
- Zh Mikrobiol Epidemiol Immunobiol 2014 Mar-Apr; (2):51-8.
Study features of epidemic process and etiology of oral cavity and limb enterovirus exanthema group diseases in a number of territories of Northwestern Russia.Isolation and identification of non-poliomyelitis enteroviruses from material of patients was carried out according to WHO recommendations. Phenotyping and phylogenetic analysis of enteroviruses was carried out.In 3 territories of Northwestern Russia oral cavity and limb enterovirus group diseases were registered. Children aged less than 14 years, predominately aged less than 3 years, were shown to be involved in the epidemic process. Coxsackie A16 enteroviruses from 27 samples of patients were isolated in cell cultures and identified by using specific sera. Coxsackie A16 enteroviruses from 16 samples were identified by using partial sequencing of VP1 genome area. Phylogenetic analysis has shown that the identified Coxsackie A16 viruses distributed among 2 phylogenetic groups.Coxsackie A16 enteroviruses that had never been detected in the region previously were established to be the etiologic factor of oral cavity and limb enterovirus exanthema group disease in the 3 territories of Northwestern Russia. The data obtained give evidence on the necessity of epidemiologic and virological control for enterovirus infection with the aim of obtaining novel information on the circulation of non-poliomyelitis enteroviruses in the population and the establishment of development patterns for epidemic process of this infection.
- Identification of Luteolin as Enterovirus 71 and Coxsackievirus A16 Inhibitors through Reporter Viruses and Cell Viability-Based Screening. [JOURNAL ARTICLE]
- Viruses 2014; 6(7):2778-2795.
Hand, foot and mouth disease (HFMD) is a common pediatric illness mainly caused by infection with enterovirus 71 (EV71) and coxsackievirus A16 (CA16). The frequent HFMD outbreaks have become a serious public health problem. Currently, no vaccine or antiviral drug for EV71/CA16 infections has been approved. In this study, a two-step screening platform consisting of reporter virus-based assays and cell viability‑based assays was developed to identify potential inhibitors of EV71/CA16 infection. Two types of reporter viruses, a pseudovirus containing luciferase-encoding RNA replicons encapsidated by viral capsid proteins and a full-length reporter virus containing enhanced green fluorescent protein, were used for primary screening of 400 highly purified natural compounds. Thereafter, a cell viability-based secondary screen was performed for the identified hits to confirm their antiviral activities. Three compounds (luteolin, galangin, and quercetin) were identified, among which luteolin exhibited the most potent inhibition of viral infection. In the cell viability assay and plaque reduction assay, luteolin showed similar 50% effective concentration (EC50) values of about 10 μM. Luteolin targeted the post-attachment stage of EV71 and CA16 infection by inhibiting viral RNA replication. This study suggests that luteolin may serve as a lead compound to develop potent anti-EV71 and CA16 drugs.