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Quantification of the dynamics of enterovirus 71 infection by experimental-mathematical investigation.

ABSTRACT: Enterovirus 71 (EV71) is the causative agent of hand-foot-and-mouth disease and can trigger neurological disorders. EV71 outbreaks are a major public health concern in Asia-Pacific countries. By performing experimental-mathematical investigation, we demonstrate here that viral productivity and transmissibility but not viral cytotoxicity are drastically different among EV71 strains and can be associated with their epidemiological backgrounds. This is the first report demonstrating the dynamics of nonenveloped virus replication in cell culture using mathematical modeling.

SUBMITTER: Fukuhara M

PROVIDER: S-EPMC3536373 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Quantification of the dynamics of enterovirus 71 infection by experimental-mathematical investigation.

Fukuhara Mitsuko M Iwami Shingo S Sato Kei K Nishimura Yorihiro Y Shimizu Hiroyuki H Aihara Kazuyuki K Koyanagi Yoshio Y

Journal of virology 20121024 1

Enterovirus 71 (EV71) is the causative agent of hand-foot-and-mouth disease and can trigger neurological disorders. EV71 outbreaks are a major public health concern in Asia-Pacific countries. By performing experimental-mathematical investigation, we demonstrate here that viral productivity and transmissibility but not viral cytotoxicity are drastically different among EV71 strains and can be associated with their epidemiological backgrounds. This is the first report demonstrating the dynamics of ...[more]

PMID: 23097444

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First seroepidemiological investigation of human enterovirus 71 in Iran.

Project description:Background and objectivesHuman Enterovirus 71 (EV-A71) is the causative agent for many dermal to neurological diseases especially polio-like paralysis outbreaks around the world. This study, the first of this kind in Iran, aimed to find neutralizing antibodies against EV-A71 in serum of healthy individuals in different age groups based on neutralization test (NT).Materials and methodsIn this cross-sectional study, 547 serum samples were collected from healthy individuals who were referring for routine checkup tests (aged from under 6 months to over 31 years old) to Imam-Khomeini Hospital in Tehran during January-December 2015. Serum samples were examined by NT in cell culture to detect neutralizing antibodies against EV-A71. In the next step, some of the positive samples were subjected to complete titration to determine the exact titer of anti-EV-A71 antibodies.ResultsOf 547 samples, 310 (56.7%) were positive for EV-A71 neutralizing antibody. The presence of the antibody increased with age (p<0.001), and there was a significant statistical relationship between sex and the presence of antibody (p=0.009).ConclusionOur results demonstrated an apparent but limited circulation of EV-A71 in our society. After the worldwide eradication of poliovirus, EV-A71 which can cause polio-likes syndrome, might be the new challenge for our health care system as regard more in depth research is however needed.

| S-EPMC8421584 | biostudies-literature

Immunity to avirulent enterovirus 71 and coxsackie A16 virus protects against enterovirus 71 infection in mice.

Project description:In this study, we sought to determine whether intratypic and intertypic cross-reactivity protected against enterovirus 71 (EV71) infection in a murine infection model. We demonstrate that active immunization of 1-day-old mice with avirulent EV71 strain or coxsackie A16 virus (CA16) by the oral route developed anti-EV71 antibodies with neutralizing activity (1:16 and 1:2, respectively). Splenocytes from both EV71- and CA16-immunized mice proliferated upon EV71 or CA16, but not coxsackie B3 virus (CB3), antigen stimulation. Immunized mice became more resistant to virulent EV71 strain challenge than nonimmunized mice. There was an increase in the percentage of activated splenic T cells and B cells in the immunized mice 2 days after EV71 challenge. The CA16 immune serum reacted with EV71 antigens in an enzyme-linked immunosorbent assay and neutralized EV71 but not CB3 or poliovirus at a titer of 1:4. Passive immunization with the CA16 immune serum reduced the clinical score, diminished the organ viral load, and increased the survival rate of mice upon EV71 challenge. CB3 neither shared in vitro cross-reactivity with EV71 nor provided in vivo protection after both active and passive immunization. These results illustrated that live vaccine is feasible for EV71 and that intertypic cross-reactivity of enteroviruses may provide a way to determine the prevalence of EV71.

| S-EPMC2045469 | biostudies-literature

Fatal case of enterovirus 71 infection, France, 2007.

Project description:A fatal case of enterovirus 71 infection with pulmonary edema and rhombencephalitis occurred in Brest, France, in April 2007. The virus was identified as subgenogroup C2. This highly neurotropic enterovirus merits specific surveillance outside the Asia-Pacific region.

| S-EPMC2857235 | biostudies-literature

Computational and experimental studies of salvianolic acid A targets 3C protease to inhibit enterovirus 71 infection.

Project description:Hand, foot, and mouth disease (HFMD) is a common childhood infectious disease caused by enterovirus (EV) infection. EV71 is one of the major pathogens causing hand, foot, and mouth disease and is more likely to cause exacerbation and death than other enteroviruses. Although a monovalent vaccine for EV71 has been developed, there are no clinically available anti-EV71 specific drugs. Here, we performed virtual screening and biological experiments based on the traditional Chinese medicine monomer library. We identified a traditional Chinese medicine monomer, Salvianolic acid A (SA), a polyphenolic compound isolated from Salvia miltiorrhiza. Salvianolic acid A inhibits EV71 virus infection in a concentration-dependent manner, and its antiviral activity is higher than that of other reported natural polyphenols and has a high biosafety. Furthermore, molecular dynamics simulations showed that salvianolic acid A can anchor to E71, a member of the enzyme catalytic triad, and cause H40 to move away from the catalytic center. Meanwhile, molecular mechanics generalized born surface area (MMGBSA) and steered molecular dynamics (SMD) results showed that the P1 group of SA was most easily unbound to the S1 pocket of 3Cpro, which provided theoretical support to further improve the affinity of salvianolic acid A with 3Cpro. These findings suggest that salvianolic acid A is a novel EV71 3Cpro inhibitor with excellent antiviral activity and is a promising candidate for clinical studies.

| S-EPMC10017496 | biostudies-literature

Type III interferon signaling restricts enterovirus 71 infection of goblet cells.

Project description:Recent worldwide outbreaks of enterovirus 71 (EV71) have caused major epidemics of hand, foot, and mouth disease with severe neurological complications, including acute flaccid paralysis. EV71 is transmitted by the enteral route, but little is known about the mechanisms it uses to cross the human gastrointestinal tract. Using primary human intestinal epithelial monolayers, we show that EV71 infects the epithelium from the apical surface, where it preferentially infects goblet cells. We found that EV71 infection did not alter epithelial barrier function but did reduce the expression of goblet cell-derived mucins, suggesting that it alters goblet cell function. We also show that the intestinal epithelium responds to EV71 infection through the selective induction of type III interferons (IFNs), which restrict EV71 replication. Collectively, these findings define the early events associated with EV71 infections of the human intestinal epithelium and show that host IFN signaling controls replication in an IFN-specific manner.

| S-EPMC6402847 | biostudies-other

Animal models of enterovirus 71 infection: applications and limitations.

Project description:Human enterovirus 71 (EV71) has emerged as a neuroinvasive virus that is responsible for several outbreaks in the Asia-Pacific region over the past 15 years. Appropriate animal models are needed to understand EV71 neuropathogenesis better and to facilitate the development of effective vaccines and drugs. Non-human primate models have been used to characterize and evaluate the neurovirulence of EV71 after the early outbreaks in late 1990s. However, these models were not suitable for assessing the neurovirulence level of the virus and were associated with ethical and economic difficulties in terms of broad application. Several strategies have been applied to develop mouse models of EV71 infection, including strategies that employ virus adaption and immunodeficient hosts. Although these mouse models do not closely mimic human disease, they have been applied to determine the pathogenesis of and treatment and prevention of the disease. EV71 receptor-transgenic mouse models have recently been developed and have significantly advanced our understanding of the biological features of the virus and the host-parasite interactions. Overall, each of these models has advantages and disadvantages, and these models are differentially suited for studies of EV71 pathogenesis and/or the pre-clinical testing of antiviral drugs and vaccines. In this paper, we review the characteristics, applications and limitation of these EV71 animal models, including non-human primate and mouse models.

| S-EPMC4013435 | biostudies-literature

lncRNA expression signatures in response to enterovirus 71 infection.

Project description:Outbreaks of hand, foot, and mouth disease caused by enterovirus 71 (EV71) have become considerable threats to the health of infants and young children. To identify the cellular long noncoding RNAs (lncRNAs) involved in the host response to EV71 infection, we performed comprehensive lncRNA and mRNA profiling in EV71-infected rhabdomyosarcoma cells through microarray. We observed the differential expression of more than 4800 lncRNAs during infection. Further analysis showed 160 regulated enhancer-like lncRNA and nearby mRNA pairs, as well as 313 regulated Rinn's lncRNA [M. Guttman I. Amit, M. Garber, C. French, M.F. Lin, D. Feldser, M. Huarte, O. Zuk, B.W. Carey, J.P. Cassady, M.N. Cabili, R. Jaenisch, T.S. Mikkelsen, T. Jacks, N. Hacohen, B.E. Bernstein, M. Kellis, A. Regev, J.L. Rinn, E.S. Lander. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458 (2009) 223-227, A.M. Khalil, M. Guttman, M. Huarte, M. Garber, A. Raj, D. Rivea Morales, K. Thomas, A. Presser, B.E. Bernstein, A. van Oudenaarden, A. Regev, E.S. Lander, J.L. Rinn. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc. Natl. Acad. Sci. USA 106 (2009) 11667-11672] and nearby mRNA pairs. The results provided information for further research on the prevention and treatment of EV71 infection, as well as on distinguishing severe and mild EV71 cases.

| S-EPMC7092842 | biostudies-literature

Seroepidemiology of Human Enterovirus 71 Infection among Children, Cambodia.

Project description:Enterovirus 71 is reported to have emerged in Cambodia in 2012; at least 54 children with severe encephalitis died during that outbreak. We used serum samples collected during 2000-2011 to show that the virus had been widespread in the country for at least a decade before the 2012 outbreak.

| S-EPMC4696711 | biostudies-literature

Enterovirus 71 infection impairs the reproductive capacity of female mice.

Project description:Enterovirus 71 (EV71) is a major cause of hand, foot and mouth disease (HFMD); however, no clinically approved vaccine or antiviral treatment is currently available for EV71 infection. In the present study, a murine model of EV71 infection was constructed. The clinical isolates of EV71 were amplified in Vero cells and used to challenge adult mice via hydrodynamic injection (HI) and intraperitoneal injection (IP). Following two challenges, >50% of the mice succumbed to EV71 infection. Surviving female mice were identified to have impaired fertility and their litter sizes were significantly decreased compared with the control group. The antibody against EV71-VP1 persisted in the sera of female mice at a high titer for >2 years after challenge. The maternal antibody in the offspring sera also persisted for ~1 year and disappeared after ~2 years. Results from the present study suggest that a high titer of active EV71 was able to impair the reproductivity of adult female mice, and that high levels of maternal antibody persisted in the offspring and protected postnatal mice from EV71-induced mortality. The promising antigenicity, immunogenicity and reactogenicity of EV71 suggests that it a potential vaccine target that may be beneficial to the control of HFMD, through immunizing infants and women of reproductive age.

| S-EPMC5488539 | biostudies-literature

Enterovirus 71 infection with central nervous system involvement, South Korea.

Project description:We assessed neurologic sequelae associated with an enterovirus 71 (EV71) outbreak in South Korea during 2009. Four of 94 patients had high signal intensities at brainstem or cerebellum on magnetic resonance imaging. Two patients died of cardiopulmonary collapse; 2 had severe neurologic sequelae. Severity and case-fatality rates may differ by EV71 genotype or subgenotype.

| S-EPMC3294506 | biostudies-literature

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