- Protective efficacy of formaldehyde-inactivated whole-virus vaccine and antivirals in a murine model of coxsackievirus A10 infection. [Journal Article]
- JVJ Virol 2017 Apr 19
- Coxsackievirus A10 (CVA10) is one of the major pathogens associated with hand, foot and mouth disease (HFMD). CVA10 infection can cause herpangina and viral pneumonia, which can be complicated by sev...
Coxsackievirus A10 (CVA10) is one of the major pathogens associated with hand, foot and mouth disease (HFMD). CVA10 infection can cause herpangina and viral pneumonia, which can be complicated by severe neurological sequelae. Morbidity and mortality of CVA10-associated HFMD has been increasing in recent years, particularly in the pan-Pacific region. There are limited studies however on the pathogenesis and immunology of CVA10-associated HFMD infections, and few antiviral drugs or vaccines have been reported. In the present study, a cell-adapted CVA10 strain was employed to inoculate intramuscularly five-day-old ICR mice, which developed significant clinical signs including: reduced mobility, lower weight gain and quadriplegia, with significant pathology in the brain, hind limb skeletal muscles and lungs of infected mice in the moribund state. The severity of illness was associated with abnormally high expression of the proinflammatory cytokine IL-6. Antiviral assays demonstrated that ribavirin and gamma interferon administration could significantly inhibit CVA10 replication both in vitro and in vivo In addition, formaldehyde-inactivated CVA10 whole-virus vaccines induced immune responses in adult mice and maternal neutralizing antibodies could be transmitted to neonatal mice providing protection against CVA10 clinical strains. Furthermore, high titer antisera were effective against CVA10 and could relieve early clinical symptoms and improve the survival rates of CVA10-challenged neonatal mice. In summary, we present a novel murine model to study CVA10 pathology which will be extremely useful to develop effective antivirals and vaccines to diminish the burden of HFMD-associated disease.IMPORTANCE Hand, foot and mouth disease cases in infancy, arising from coxsackievirus A10 (CVA10) infections, are typically benign, resolving without any significant adverse events. Severe disease and fatalities can however occur in some children, necessitating the development of vaccines and antiviral therapies. The present study has established a newborn mouse model of CVA10 which, importantly, recapitulates many aspects of human disease, with respect to the neuropathology and skeletal muscle pathology. We found that high levels of the proinflammatory cytokine interleukin 6 correlated with disease severity and that ribavirin and gamma interferon could decrease viral titers in vitro and in vivo Whole-virus vaccines produced immune responses in adult mice and immunized mothers conferred protection to neonates against challenge from CVA10 clinical strains. Passive immunization with high titer antisera could also improve survival rates in newborn animals.
- Viral exanthems: An update on laboratory testing of the adult patient. [Review]
- JAJ Am Acad Dermatol 2017; 76(3):538-550
- Although classic viral exanthems of childhood are well described, they are rarely differentiated in adults. Laboratory techniques for viral identification have advanced without substantial literature...
Although classic viral exanthems of childhood are well described, they are rarely differentiated in adults. Laboratory techniques for viral identification have advanced without substantial literature to suggest how a dermatologist ought to conduct a cost-effective and diagnostic viral panel. Certain clinical features such as petechiae, vesicles, and dusky macular or morbilliform exanthems point strongly toward a viral exanthem. Differentiation of drug and viral causes of morbilliform eruptions has proven difficult. It is possible that with further diagnostic refinement that unnecessary and fruitless workups of an exanthem and unneeded discontinuation of drugs can be avoided. We review viral exanthems based on clinical features and discuss the available and optimal laboratory techniques to assist the dermatologist in a targeted workup.
- Direct-acting antivirals and host-targeting strategies to combat enterovirus infections. [Review]
- COCurr Opin Virol 2017 Apr 12; 24:1-8
- Enteroviruses (e.g., poliovirus, enterovirus-A71, coxsackievirus, enterovirus-D68, rhinovirus) include many human pathogens causative of various mild and more severe diseases, especially in young chi...
Enteroviruses (e.g., poliovirus, enterovirus-A71, coxsackievirus, enterovirus-D68, rhinovirus) include many human pathogens causative of various mild and more severe diseases, especially in young children. Unfortunately, antiviral drugs to treat enterovirus infections have not been approved yet. Over the past decades, several direct-acting inhibitors have been developed, including capsid binders, which block virus entry, and inhibitors of viral enzymes required for genome replication. Capsid binders and protease inhibitors have been clinically evaluated, but failed due to limited efficacy or toxicity issues. As an alternative approach, host-targeting inhibitors with potential broad-spectrum activity have been identified. Furthermore, drug repurposing screens have recently uncovered promising new inhibitors with disparate viral and host targets. Together, these findings raise hope for the development of (broad-range) anti-enteroviral drugs.
- Understanding the mechanism of the broad-spectrum antiviral favipiravir (T-705): key role of the F1 motif of the viral polymerase. [Journal Article]
- JVJ Virol 2017 Apr 05
- Favipiravir (T-705) is a broad-spectrum antiviral agent that has been approved in Japan for treatment of influenza virus infections. T-705 also inhibits the replication of various RNA viruses includi...
Favipiravir (T-705) is a broad-spectrum antiviral agent that has been approved in Japan for treatment of influenza virus infections. T-705 also inhibits the replication of various RNA viruses including chikungunya virus (CHIKV). We demonstrated earlier that the K291R mutation in the F1 motif of the RNA-dependent RNA polymerase (RdRp) of CHIKV is responsible for low-level resistance to T-705. Interestingly, this lysine is highly conserved in the RdRp of positive-sense single-stranded RNA [+ssRNA] viruses. To obtain insights into the unique broad-spectrum antiviral activity of T-705, we explored the role of this lysine using another +ssRNA virus, namely Coxsackievirus B3 (CVB3). Introduction of the corresponding K-to-R substitution in the CVB3 RdRp (K159R) resulted in a non-viable virus. Replication competence of the K159R variant was restored by spontaneous acquisition of an A239G substitution in the RdRp. A mutagenesis analysis at position K159 identified K159M as the only other viable variant, which had also acquired the A239G substitution. The K159 substitutions markedly decreased the processivity of the purified viral RdRp, which was restored by introduction of the A239G mutation. The K159R-A239G and K159M-A239G variants proved, surprisingly, more susceptible to T-705 than the wild-type virus and exhibited lower fidelity in polymerase assays. Furthermore, the K159R-A239G variant was found to be highly attenuated in mice. We thus demonstrate that the conserved lysine in the F1 motif of the RdRp of +ssRNA viruses is involved in the broad-spectrum antiviral activity of T-705 and that it is a key amino acid for the proper functioning of the enzyme.IMPORTANCE In this study, we report the key role of a highly conserved lysine residue of the viral polymerase in the broad-spectrum antiviral activity of favipiravir (T-705) against positive single-stranded RNA viruses. Substitutions of this conserved lysine have a major negative impact on the functionality of the RdRp. Furthermore we show that this lysine is involved in the fidelity of the RdRp and that the RdRp fidelity influences the sensitivity of the virus for the antiviral efficacy of T-705. Consequently, these results provide insights into the mechanism of the antiviral activity of T-705 and may lay the basis for the design of novel chemical scaffolds that may be endowed with a more potent broad-spectrum antiviral activity than T-705.
- Amylmetacresol/2,4-dichlorobenzyl alcohol, hexylresorcinol, or carrageenan lozenges as active treatments for sore throat. [Journal Article]
- IJInt J Gen Med 2017; 10:53-60
- Up to 80% of sore throats are caused by viruses. Several over the counter products are available which provide symptomatic, not causal relief. For such lozenges, containing the antiseptics and local ...
Up to 80% of sore throats are caused by viruses. Several over the counter products are available which provide symptomatic, not causal relief. For such lozenges, containing the antiseptics and local anesthetics amylmetacresol (AMC) and 2,4-dichlorobenzyl alcohol (DCBA) or hexylresorcinol (HR), recently an additional virucidal effect was published. Therefore, we tested a set of Strepsils(®) lozenges, containing either HR (Max [#2]) or AMC/DCBA (Original [#3], Extra Strong [#4], Warm [#5], Orange and Vitamin C [#6], Sugar free Lemon [#7], Children/Strawberry [#8] and Soothing Honey and Lemon [#9]) for their antiviral efficiency against representatives of respiratory viruses known to cause sore throat: human rhinovirus (HRV) 1a, HRV8, influenza virus A H1N1n, Coxsackievirus A10, and human coronavirus (hCoV) OC43. The lozenges were tested head to head with Coldamaris(®) lozenges (#1), which contain the patented antiviral iota-carrageenan. None of the tested AMC/DCBA or HR containing lozenges shows any antiviral effectiveness against HRV8 at the tested concentrations, whereas all are moderately active against HRV1a. Only lozenge #5 shows any activity against hCoV OC43 and Coxsackievirus A10 at the tested concentrations. Similarly, only lozenge #3 is moderately active against influenza A H1N1n virus. The data indicates that neither the isolated effect of the active ingredients nor the pH but rather one or more of the excipients of the specific formulations are responsible for the antiviral effect of some of the AMC/DCBA or HR containing lozenges. In contrast, carrageenan-containing lozenges are highly active against all viruses tested. In another experiment, we showed that binding and inactivation of virus particles by iota-carrageenan are fast and highly effective. During the residence time of the lozenge in the mouth, the viral titer is reduced by 85% and 91% for influenza A virus and hCoV OC43, respectively. Carrageenan-containing lozenges are, therefore, suitable as causative therapy against viral infections of the throat.
- A Neonatal Murine Model of Coxsackievirus A6 Infection for Evaluation of Antiviral and Vaccine Efficacy. [Journal Article]
- JVJ Virol 2017 May 01; 91(9)
- Hand, foot, and mouth disease (HFMD) is a global health concern. Family Picornaviridae members, particularly enterovirus A71 (EVA71) and coxsackievirus A16 (CVA16), are the primary etiological agents...
Hand, foot, and mouth disease (HFMD) is a global health concern. Family Picornaviridae members, particularly enterovirus A71 (EVA71) and coxsackievirus A16 (CVA16), are the primary etiological agents of HFMD; however, a third enterovirus A species, CVA6, has been recently associated with epidemic outbreaks. Study of the pathogenesis of CVA6 infection and development of antivirals and vaccines are hindered by a lack of appropriate animal models. We have developed and characterized a murine model of CVA6 infection that was employed to evaluate the antiviral activities of different drugs and the protective efficacies of CVA6-inactivated vaccines. Neonatal mice were susceptible to CVA6 infection via intramuscular inoculation, and the susceptibility of mice to CVA6 infection was age and dose dependent. Five-day-old mice infected with 10(5.5) 50% tissue culture infective doses of the CVA6 WF057R strain consistently exhibited clinical signs, including reduced mobility, lower weight gain, and quadriplegia with significant pathology in the brain, hind limb skeletal muscles, and lungs of the infected mice in the moribund state. Immunohistochemical analysis and quantitative reverse transcription-PCR (qRT-PCR) analyses showed high viral loads (11 log10/mg) in skeletal muscle, and elevated levels of interleukin-6 (IL-6; >2,000 pg/ml) were associated with severe viral pneumonia and encephalitis. Ribavirin and gamma interferon administered prophylactically diminished CVA6-associated pathology in vivo, and treatment with IL-6 accelerated the death of neonatal mice. Both specific anti-CVA6 serum and maternal antibody play important roles in controlling CVA6 infection and viral replication. Collectively, these findings indicate that this neonatal murine model will be invaluable in future studies to develop CVA6-specific antivirals and vaccines.IMPORTANCE Although coxsackievirus A6 (CVA6) infections are commonly mild and self-limiting, a small proportion of children may have serious complications, such as encephalitis, acute flaccid paralysis, and neurorespiratory syndrome, leading to fatalities. We have established a mouse model of CVA6 infection by inoculation of neonatal mice with a CVA6 clinical isolate that produced consistent pathological outcomes. Here, using this model of CVA6 infection, we found that high levels of IL-6 were associated with severe viral pneumonia and encephalitis, as in an evaluation of antiviral efficacy in vivo, IL-6 had no protective effect and instead accelerated death in neonatal mice. We demonstrated that, as antiviral drugs, both gamma interferon and ribavirin played important protective roles in the early stages of infection, with increased survival in treated neonatal mice challenged with CVA6. Moreover, active and passive immunization with the inactivated vaccines and anti-CVA6 serum also protected mice against homologous challenge infections.
- Genetic variation in chromosome Y regulates susceptibility to influenza A virus infection. [Journal Article]
- PNProc Natl Acad Sci U S A 2017 Mar 28; 114(13):3491-3496
- Males of many species, ranging from humans to insects, are more susceptible than females to parasitic, fungal, bacterial, and viral infections. One mechanism that has been proposed to account for thi...
Males of many species, ranging from humans to insects, are more susceptible than females to parasitic, fungal, bacterial, and viral infections. One mechanism that has been proposed to account for this difference is the immunocompetence handicap model, which posits that the greater infectious disease burden in males is due to testosterone, which drives the development of secondary male sex characteristics at the expense of suppressing immunity. However, emerging data suggest that cell-intrinsic (chromosome X and Y) sex-specific factors also may contribute to the sex differences in infectious disease burden. Using a murine model of influenza A virus (IAV) infection and a panel of chromosome Y (ChrY) consomic strains on the C57BL/6J background, we present data showing that genetic variation in ChrY influences IAV pathogenesis in males. Specific ChrY variants increase susceptibility to IAV in males and augment pathogenic immune responses in the lung, including activation of proinflammatory IL-17-producing γδ T cells, without affecting viral replication. In addition, susceptibility to IAV segregates independent of copy number variation in multicopy ChrY gene families that influence susceptibility to other immunopathological phenotypes, including survival after infection with coxsackievirus B3. These results demonstrate a critical role for genetic variation in ChrY in regulating susceptibility to infectious disease.
- [Genotype distribution of human enteroviruses isolated from swage in Shanghai during year 2013-2014]. [Journal Article]
- ZYZhonghua Yu Fang Yi Xue Za Zhi 2017 Feb 06; 51(2):154-159
- CONCLUSIONS: Poliovirus was identified as a vaccine strain in environmental surveillance from June 2013 to April 2014 in Shanghai. Several transmission strains of ECHO6 and CVB5 were identified, which were the dominant serotypes.
- Adenovirus type 4 respiratory infections with a concurrent outbreak of coxsackievirus A21 among United States Army Basic Trainees, a retrospective viral etiology study using next-generation sequencing. [Journal Article]
- JMJ Med Virol 2017 Feb 15
- Human adenoviruses (HAdV), in particular types 4 and 7, frequently cause acute respiratory disease (ARD) during basic military training. HAdV4 and HAdV7 vaccines reduced the ARD risk in U.S. military...
Human adenoviruses (HAdV), in particular types 4 and 7, frequently cause acute respiratory disease (ARD) during basic military training. HAdV4 and HAdV7 vaccines reduced the ARD risk in U.S. military. It is important to identify other respiratory pathogens and assess their potential impact on military readiness. In 2002, during a period when the HAdV vaccines were not available, throat swabs were taken from trainees (n = 184) with respiratory infections at Fort Jackson, South Carolina. Viral etiology was investigated initially with viral culture and neutralization assay and recently in this study by sequencing the viral isolates. Viral culture and neutralization assays identified 90 HAdV4 isolates and 27 additional cultures that showed viral cytopathic effects (CPE), including some with picornavirus-like CPE. Next-generation sequencing confirmed these results and determined viral genotypes, including 77 HAdV4, 4 HAdV3, 1 HAdV2, 17 coxsackievirus A21 (CAV21), and 1 enterovirus D68. Two samples were positive for both HAdV4 and CAV21. The identified genotypes are phylogenetically close to but distinct from those found during other years or in other military/non-military sites. HAdV4 is the predominant respiratory pathogen in unvaccinated military trainee. HAdV4 has temporal and demographic variability. CAV21 is a significant respiratory pathogen and needs to be evaluated for its current significance in military basic trainees.
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- Coxsackie Myocarditis and Hepatitis with Reactivated Epstein-Bar Virus (EBV): A Case Report. [Case Reports]
- AJAm J Case Rep 2017 Feb 15; 18:166-169
- CONCLUSIONS: Coxsackie B virus myocarditis is rarely recognized and reported by the general internist in clinical practice, so we would like present our experience with an interesting clinical presentation of the viral prodrome. An estimated 95% people in the US are infected with Epstein-Barr virus by adulthood, but it remains dormant in memory B lymphocytes. Recirculation of these B cells in lymphoid tissue stimulated by antigens, which in our case is coxsackie B virus; they differentiate into plasma cells, and the production of Z Epstein-Barr replication activator protein (ZEBRA) increases viral replication, thus explaining the positive EBV DNA measured by PCR.