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Coxsackievirus infections [keywords]
- 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.
- Enterovirus/Picornavirus infections. [Journal Article]
- Handb Clin Neurol 2014.:379-416.
The human enteroviruses (EV) comprise one group of the picornavirus family. The best known members are the polioviruses (PV), coxsackieviruses, and echoviruses. They replicate in the oropharynx and gastrointestinal (GI) tract and are primarily spread by fecal-hand-oral contamination. With systemic invasion nonspecific febrile illness occurs as well as specific syndromes (rashes, hand-foot-and-mouth disease, herpangina, pleurodynia, myocarditis/pericarditis, and conjunctivitis). With systemic replication a high level viremia may result in central nervous system (CNS) invasion. EV activity can be endemic in warm climates or epidemic in temperate climates. In temperate climates, because of improved hygiene, newborns were not exposed to EV until they were older, resulting in large epidemics of poliomyelitis, which were finally curtailed with the killed PV vaccines in the 1950s and the live oral PV vaccines in the 1960s. Today, "aseptic" meningitis is the most common neurologic syndrome caused by EV. EV are also the most common cause of viral meningitis. Other EV neurologic syndromes include encephalitis, paralytic disease, persistent infections, and the severe group B coxsackievirus fatal systemic infections of neonates. Newly recognized emerging infections include EV71 rhombencephalitis/brainstem encephalitis and saffold virus (Saf V) meningitis and cerebellitis. Diagnostic clues can come from epidemics, systemic manifestations, household infections, the cerebrospinal fluid picture, and the neurologic syndromes. However, definite diagnosis depends on laboratory methods, primarily nucleic acid amplification. Treatment of acute infections is supportive. Preventive methods include good hygiene and aggressive polio vaccination programs.
- Immunogenicity Studies of Bivalent Inactivated Virions of EV71/CVA16 Formulated with Submicron Emulsion Systems. [Journal Article]
- Biomed Res Int 2014.:670506.
We assessed two strategies for preparing candidate vaccines against hand, foot, and mouth disease (HFMD) caused mainly by infections of enterovirus (EV) 71 and coxsackievirus (CV) A16. We firstly design and optimize the potency of adjuvant combinations of emulsion-based delivery systems, using EV71 candidate vaccine as a model. We then perform immunogenicity studies in mice of EV71/CVA16 antigen combinations formulated with PELC/CpG. A single dose of inactivated EV71 virion (0.2 μ g) emulsified in submicron particles was found (i) to induce potent antigen-specific neutralizing antibody responses and (ii) consistently to elicit broad antibody responses against EV71 neutralization epitopes. A single dose immunogenicity study of bivalent activated EV71/CVA16 virion formulated with either Alum or PELC/CpG adjuvant showed that CVA16 antigen failed to elicit CVA16 neutralizing antibody responses and did not affect EV71-specific neutralizing antibody responses. A boosting dose of emulsified EV71/CVA16 bivalent vaccine candidate was found to be necessary to achieve high seroconversion of CVA16-specific neutralizing antibody responses. The current results are important for the design and development of prophylactic vaccines against HFMD and other emerging infectious diseases.
- Increased IFN-α-Producing Plasmacytoid Dendritic Cells (pDCs) in Human Th1-Mediated Type 1 Diabetes: pDCs Augment Th1 Responses through IFN-α Production. [JOURNAL ARTICLE]
- J Immunol 2014 Jun 27.
Increasing evidence suggests that type 1 IFN (IFN-αβ) is associated with pathogenesis of Th1-mediated type 1 diabetes (T1D). A major source of IFN-αβ is plasmacytoid dendritic cells (pDCs). In this study, we analyzed peripheral blood pDC numbers and functions in at-risk, new-onset, and established T1D patients and controls. We found that subjects at risk for T1D and new-onset and established T1D subjects possessed significantly increased pDCs but similar number of myeloid DCs when compared with controls. pDC numbers were not affected by age in T1D subjects but declined with increasing age in control subjects. It was demonstrated that IFN-α production by PBMCs stimulated with influenza viruses was significantly higher in T1D subjects than in controls, and IFN-α production was correlated with pDC numbers in PBMCs. Of interest, only T1D-associated Coxsackievirus serotype B4 but not B3 induced majority of T1D PBMCs to produce IFN-α, which was confirmed to be secreted by pDCs. Finally, in vitro studies demonstrated IFN-α produced by pDCs augmented Th1 responses, with significantly greater IFN-γ-producing CD4(+) T cells from T1D subjects. These findings indicate that increased pDCs and their IFN-αβ production may be associated with this Th1-mediated autoimmune disease, especially under certain viral infections linked to T1D pathogenesis.
- Coxsackievirus A 16 infection does not interfere with the specific immune response induced by an enterovirus 71 inactivated vaccine in rhesus monkeys. [JOURNAL ARTICLE]
- Vaccine 2014 Jun 20.
Hand, foot and mouth disease is usually caused by enterovirus 71 (EV71) and coxsackievirus A 16 (CA16), which are members of the Picornaviridae family. In the present study, the characteristics of the immune response induced by an EV71 inactivated vaccine (made from human diploid cells) were explored in the presence of CA16 infection, based on the previously established neonatal rhesus monkey model. The typical clinical manifestations, including body temperature, viral viremia and virus shedding in the mouth, pharynx and feces, were characterized. A specific neutralizing antibody assay showed that the specific immune response induced by the EV71 inactivated vaccine was active against EV71 but not against CA16. No remarkable fluctuation in proinflammatory cytokine release was identified in the serum of immunized monkeys with EV71 vaccine and CA16 infections subsequently. The results showed that the specific immune response induced by the EV71 inactivated vaccine is effective against EV71 infection but is not affected by CA16 infection.
- A virus-like particle based bivalent vaccine confers dual protection against enterovirus 71 and coxsackievirus A16 infections in mice. [Journal Article]
- Vaccine 2014 Jul 23; 32(34):4296-303.
Enterovirus 71(EV71) and coxsackievirus A16 (CA16) are responsible for hand, foot and mouth disease which has been prevalent in Asia-Pacific regions, causing significant morbidity and mortality in young children. Co-circulation of and co-infection by both viruses underscores the importance and urgency of developing vaccines against both viruses simultaneously. Here we report the immunogenicity and protective efficacy of a bivalent combination vaccine comprised of EV71 and CA16 virus-like particles (VLPs). We show that monovalent EV71- or CA16-VLPs-elicited serum antibodies exhibited potent neutralization effect on the homotypic virus but little or no effect on the heterotypic one, whereas the antisera against the bivalent vaccine formulation were able to efficiently neutralize both EV71 and CA16, indicating there is no immunological interference between the two antigens with respect to their ability to induce virus-specific neutralizing antibodies. Passive immunization with monovalent VLP vaccines protected mice against a homotypic virus challenge but not heterotypic infection. Surprisingly, antibody-dependent enhancement (ADE) of disease was observed in mice passively transferred with mono-specific anti-CA16 VLP sera and subsequently challenged with EV71. In contrast, the bivalent VLP vaccine conferred full protection against lethal challenge by either EV71 or CA16, thus eliminating the potential of ADE. Taken together, our results demonstrate for the first time that the bivalent VLP approach represents a safe and efficacious vaccine strategy for both EV71 and CA16.
- High-degree atrioventricular block in a child with acute myocarditis. [Journal Article]
- Ochsner J 2014; 14(2):244-7.
Viral myocarditis is a common cause of transient electrocardiogram (EKG) abnormalities in children. The clinical presentation of acute myocarditis ranges from asymptomatic infection to fulminant heart failure and sudden death. Many children present with nonspecific symptoms such as dyspnea or vomiting, frequently leading to misdiagnosis. EKG abnormalities are a sensitive indicator of acute myocarditis and are present in more than 90% of cases.A 13-year-old female suffered a syncopal episode and was found to have high-grade atrioventricular (AV) block caused by acute presumed viral myocarditis. With close monitoring, the EKG abnormalities resolved over the following 48 hours. In this case report, we discuss the incidence, pathogenesis, and outcomes of conduction disturbances in acute myocarditis.High-degree AV block can occur in patients with acute myocarditis, and higher-degree AV block is correlated with greater myocardial injury. Additionally, severity of pathological changes may reflect the reversibility of AV block. In the majority of cases, however, this rhythm disturbance is transient and does not require permanent pacemaker placement.
- Cellular microRNAs and Picornaviral Infections. [REVIEW]
- RNA Biol 2014 Jun 12; 11(7)
microRNAs (miRNAs) are a subtype of short, endogenous, and non-coding RNAs, which post-transcriptionally regulate gene expression. The miRNA-mediated gene silencing mechanism is involved in a wide spectrum of biological processes, such as cellular proliferation, differentiation, and immune responses. Picornaviridae is a large family of RNA viruses, which includes a number of causative agents of many human and animal diseases viz., poliovirus, foot-and-mouth disease virus (FMDV), and coxsackievirus B3 (CVB3). Accumulated evidences have demonstrated that replication of picornaviruses can be regulated by miRNAs and picornaviral infections can alter the expression of cellular miRNAs. Herein, we outline the intricate interactions between miRNAs and picornaviral infections.
- Prevalence and Characterization of Enterovirus Infections among Pediatric Patients with Hand Foot Mouth Disease, Herpangina and Influenza Like Illness in Thailand, 2012. [JOURNAL ARTICLE]
- PLoS One 2014; 9(6):e98888.
Hand, foot, and mouth disease (HFMD) and herpangina are common infectious diseases caused by several genotypes of human enterovirus species A and frequently occurring in young children. This study was aimed at analyzing enteroviruses from patients with these diseases in Thailand in 2012. Detection and genotype determination of enteroviruses were accomplished by reverse transcription-polymerase chain reaction and sequencing of the VP1 region. Enterovirus-positive samples were differentiated into 17 genotypes (coxsackievirus A4 (CAV4), A5, A6, A8, A9, A10, A12, A16, A21, B1, B2, B4, B5, echovirus 7, 16, 25 and Enterovirus 71). The result showed CAV6 (33.5%), followed by CAV16 (9.4%) and EV71 (8.8%) as the most frequent genotypes in HFMD, CAV8 (19.3%) in herpangina and CAV6 (1.5%) in influenza like illness. Enterovirus infections were most prevalent during July with 34.4% in HFMD, 39.8% in herpangina and 1.6% in ILI. The higher enterovirus infection associated with HFMD and herpangina occurred in infants over one year-old. This represents the first report describing the circulation of multiple enteroviruses in Thailand.
- First report of a Chinese strain of coxsackie B3 virus infection in a newborn in Germany in 2011: a case report. [JOURNAL ARTICLE]
- J Med Case Rep 2014 May 27; 8(1):164.
Enteroviruses commonly encounter babies and children and infections present in a wide variety of symptoms ranging from asymptomatic infection, benign illness, and aseptic meningitis, hand-foot-and-mouth disease to severe life-threatening disease. Some newborns develop severe disease in the first 2 weeks of life and long-term sequelae may occur among survivors.We present a case report of a Caucasian newborn baby boy with severe encephalitis and systemic coxsackievirus B3 infection. The coincidence of maternal infection as well as previous mild respiratory illness in his sister suggests either prenatal or horizontal postnatal transmission. An electroencephalogram showed a severe pathologic pattern with theta-delta-rhythm and spike-wave complexes on both hemispheres. We also observed an unusual prolonged viremia for a period of 6 weeks. Due to the lack of specific antiviral treatment options, the supportive management included ventilation and medical treatment of seizures. Phylogenetic analysis revealed a genogroup D2 virus previously exclusively detected in China and now described in Europe for the first time.Enteroviral infection is an important differential diagnosis in neonatal encephalitis. Prolonged viremia must be taken into account and might correlate with disease severity. The newly observed enterovirus genotype D2 is spreading from Asia to other continents.