A neonatal murine model of coxsackievirus A4 infection for evaluation of vaccines and antiviral drugs

Zhang, Zhenjie; Zhang, Xing-Cheng; Carr, Michael J.; Zhou, Hong; Li, Juan; Liu, Shaoqiong; Liu, Tao; Xing, Weijia; Shi, Weifeng

doi:10.1080/22221751.2019.1673135

Cited by 11 publications

(8 citation statements)

References 49 publications

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“…Moreover, the cytokines in the mice affected the infection efficiency of the virus, which might explain why the clinical isolates of CVA6-W and CVA6 or other enteroviruses could infect younger newborn mice. The IFN-γ concentration in the 3-day-old mice was higher than that of the mice of other ages, which is similar to the findings of existing studies on CVA4 infection model of newborn mice ( 19 ). It was verified that IFN-γ is capable of inducing cells to producing hWARS receptors, so the efficiency of enterovirus infection increases ( 29 ).…”

Section: Discussionsupporting

confidence: 89%

“…Accordingly, an EV71 transgenic mouse model has been developed, which breaks the age limit of mice infected with enterovirus (16). Thus far, newborn mice infection models of enterovirus CVA6, CVA10, and CVA4 have been studied (17)(18)(19), and used to evaluate the effects of antiviral drugs and vaccines. Nevertheless, due to the small age and low weight of newborn mice, the injection dose is limited, and the evaluation effect of antiviral drugs is reduced.…”

Section: Introductionmentioning

confidence: 99%

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A 10-Day-Old Murine Model of Coxsackievirus A6 Infection for the Evaluation of Vaccines and Antiviral Drugs

Jiang¹,

Zhang

Lin³

et al. 2021

Front. Immunol.

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Coxsackievirus A6 (CVA6) is recognized as a major enterovirus type that can cause severe hand, foot, and mouth disease and spread widely among children. Vaccines and antiviral drugs may be developed more effectively based on a stable and easy-to-operate CVA6 mouse infection model. In this study, a wild CVA6-W strain was sub-cultured in newborn mice of different ages (in days), for adaptation. Therefore, a CVA6-A mouse-adapted strain capable of stably infecting the mice was generated, and a fatal model was built. As the result indicated, CVA6-A could infect the 10-day-old mice to generate higher levels of IFN-γ, IL-6, and IL-10. The mice infected with CVA6-A were treated with IFN-α1b at a higher dose, with complete protection. Based on this strain, an animal model with active immunization was built to evaluate antiviral protection by active immunization. The three-day-old mice were pre-immunized with inactivated CVA6 thereby generating IgM and IgG antibodies within 7 days that enabled complete protection of the pre-immunized mice following the CVA6 virus challenge. There were eight mutations in the genome of CVA6-A than in that of CVA6-W, possibly attributed to the virulence of CVA6 in mice. Briefly, the CVA6 infection model of the 10-day-old mice built herein, may serve as an applicable preclinical evaluation model for CVA6 antiviral drugs and vaccine study.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

A 10-Day-Old Murine Model of Coxsackievirus A6 Infection for the Evaluation of Vaccines and Antiviral Drugs

Jiang¹,

Zhang

Lin³

et al. 2021

Front. Immunol.

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“…in one-week-old lactating mice is 100% lethal and highly pathogenic causing serious damage of multiple tissues, including the brain, hearts, lungs and muscles. In parallel with the fact that majority of enterovirus-infected HFMD cases are under 5 years of age ( Sharma et al, 2022 ), neonatal mouse or young animals is usually required for establishing the pathogenic enterovirus infection model ( Zhang et al, 2019 ; Chen Y. et al, 2021 ; Li et al, 2022 ). Previous studies have shown that gerbils younger than 3-weeks were fully susceptible to infection by a clinical CA16 isolate and all died within 5 days of infection at a TCID 50 of 10 5.5 ( Sun et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

The development and characterization of a stable Coxsackievirus A16 infectious clone with Nanoluc reporter gene

Wang

Liu

et al. 2023

Front. Microbiol.

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Coxsackievirus A16 (CA16) belongs to the Human Enterovirus A species, which is a common pathogen causing hand, foot, and mouth disease in children. Currently, specific vaccines and drugs against CA16 are unavailable, and there is an unmet need to further understand the virus and invent effective treatment. Constructing a CA16 infectious clone with a reporter gene will greatly facilitate its virological studies. Here, we first reported the construction of a CA16 infectious clone (rCA16) whose progeny is highly replicative and virulent in suckling mice. On the basis of rCA16, we further inserted a NanoLuc (Nluc) reporter gene and made the rCA16-Nluc clone. We found that the Nluc gene in rCA16-Nluc is stable during continuous growing in Vero cells and thus allowed detection of a steady luciferase signal in rCA16-Nluc-infected Vero cells over 10 passages. Its application in antivirals characterization and high-throughput screening is exemplified by measuring IC50, CC50, and selection index of guanidine hydrochloride, ribavirin, chloroquine, and ammonium chloride against CA16. Finally, we showed that rCA16-Nluc based assay greatly simplified the CA16 neutralizing antibody tests. Thus, these two CA16 infectious clones will be robust tools for future enterovirus studies and antivirals development.

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“…Strategies have included using clinical isolates [ 21 , 22 ] or mouse adaptation strains [ 23 , 24 ], and using immunodeficient mice [ 21 ] as well as receptor-transgenic mice [ 26 , 27 ]. Mouse models have also been reported for other enteroviruses associated with HFMD, such as CV-A16, CV-A6, CV-A10, CV-A4 and CV-A5 [ 28–37 , 45 , 46 ]. However, the challenging viruses used infected suckling mice younger than 3–5 days in most reports.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of a coxsackievirus A6 vaccine candidate in an actively immunized mouse model

Qian

Wei

Jin

et al. 2021

Emerging Microbes & Infections

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Coxsackievirus A6 (CV-A6) has been emerging as a major pathogen of hand, foot and mouth disease (HFMD). Study on the pathogenesis of CV-A6 infection and development of vaccines is hindered by a lack of appropriate animal models. Here, we report an actively immunized-challenged mouse model to evaluate the efficacy of a Vero-cell-based, inactivated CV-A6 vaccine candidate. The neonatal Kunming mice were inoculated with a purified, formaldehyde-inactivated CV-A6 vaccine on days 3 and 9, followed by challenging on day 14 with a naturally selected virulent strain at a lethal dose. Within 14 days postchallenge, all mice in the immunized groups survived, while 100% of the Alum-only inoculated mice died. Neutralizing antibodies (NtAbs) were detected in the serum of immunized suckling mice, and the NtAb levels correlated with the survival rate of the challenged mice. The virus loads in organs were reduced, and pathological changes and viral protein expression were weak in the immunized mice compared with those in Alum-only inoculated control mice. Elevated levels of interleukin-4, 6, interferon γ and tumour necrosis factor α were also observed in Alum-only control mice compared with immunized mice. Importantly, the virulent CV-A6 challenge strain was selected quickly and conveniently from a RD cell virus stock characterized with the natural multi-genotypes. The virulent determinants were mapped to V124M and I242 V at VP1. Together, our results indicated that this actively immunized mouse model is invaluable for future studies to develop multivalent vaccines containing the major component of CV-A6 against HFMD.

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A neonatal murine model of coxsackievirus A4 infection for evaluation of vaccines and antiviral drugs

Cited by 11 publications

References 49 publications

A 10-Day-Old Murine Model of Coxsackievirus A6 Infection for the Evaluation of Vaccines and Antiviral Drugs

A 10-Day-Old Murine Model of Coxsackievirus A6 Infection for the Evaluation of Vaccines and Antiviral Drugs

The development and characterization of a stable Coxsackievirus A16 infectious clone with Nanoluc reporter gene

Efficacy of a coxsackievirus A6 vaccine candidate in an actively immunized mouse model

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