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

ABSTRACT: Coxsackievirus A4 (CVA4) infection can cause hand, foot and mouth disease (HFMD), an epidemic illness affecting neonatal and paediatric cohorts, which can develop to severe neurological disease with high mortality. In this study, we established the first ICR mouse model of CVA4 infection for the evaluation of inactivated vaccines and antiviral drug screening. The CVA4 YT226R strain was selected to infect the neonatal mice and three infectious factors were optimized to establish the infection model. The 3-day-old neonatal mice exhibited clinical symptoms such as hind limb paralysis and death. The severe inflammatory reactions were closely related to the abnormal expression of the acute phase response proinflammatory cytokine IL-6 and an imbalance in the IFN-?/IL-4 ratio. Importantly, the inactivated CVA4 whole-virus vaccine induced humoral immune responses in adult females and the maternal antibodies afforded mice complete protection against lethal dose challenges of homologous or heterologous CVA4 strains. Both IFN-?2a and antiserum inhibited the replication of CVA4 and increased the survival rates of neonatal mice during the early stages of infection. This neonatal murine model of CVA4 infection will be useful for the development of prophylactic and therapeutic vaccines and for screening of antiviral drugs targeting CVA4 to decrease morbidity and mortality.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC6792045 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Zhang Zhenjie Z Zhang Xingcheng X Carr Michael J MJ Zhou Hong H Li Juan J Liu Shaoqiong S Liu Tao T Xing Weijia W Shi Weifeng W

Emerging microbes & infections 20190101 1

Coxsackievirus A4 (CVA4) infection can cause hand, foot and mouth disease (HFMD), an epidemic illness affecting neonatal and paediatric cohorts, which can develop to severe neurological disease with high mortality. In this study, we established the first ICR mouse model of CVA4 infection for the evaluation of inactivated vaccines and antiviral drug screening. The CVA4 YT226R strain was selected to infect the neonatal mice and three infectious factors were optimized to establish the infection mod ...[more]

PMID: 31595827

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Project description: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 105.5 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.

Project description:BackgroundTransient constrictive pericarditis (TCP) is a distinct constrictive pericarditis (CP) subtype characterized by acute pericardial inflammation and transient constrictive physiology. If left untreated, it may progress to irreversible CP requiring pericardiectomy. However, making an early diagnosis of TCP remains difficult.Case presentationA 51-year-old man presented with fever, chest pain, and dyspnea following preceding flu symptoms. An initial investigation suggested right-sided heart failure. Laboratory results revealed elevated inflammatory markers and hepatic enzyme levels. Echocardiography revealed pericardial effusion with a normal ejection fraction and diastolic ventricular septal bounce suggestive of pericardial constriction. Computed tomography suggested acute descending mediastinitis with pericarditis and pleuritis; however, detailed examinations ruled out this possibility. The constellation of increased serological inflammation, pericardial thickness/effusion, and constrictive physiology suggested TCP, confirmed by cardiac magnetic resonance (CMR) and hemodynamic studies. CMR also revealed coexistent myocarditis. After a thorough assessment for the cause of TCP, a viral etiology was suspected. Paired serology for virus antibody titers revealed a significant increase only in coxsackievirus A4 (CVA4) titers. With prompt anti-inflammatory treatment, the patient's pericardial structure and function and concomitant inflammation of the surrounding tissues were nearly completely recovered, leading to a final diagnosis of TCP caused by CVA4. The subsequent clinical course was uneventful without recurrence at the 1-year follow-up.ConclusionsHere we described the first case of TCP caused by CVA4 concurrent with mediastinitis, myocarditis, and pleuritis, all of which were successfully resolved with anti-inflammatory treatment. Acute mediastinitis secondary to TCP is rare. This case highlights the clinical importance of assessing pericardial diseases as a source of acute mediastinitis and considering CVA4 as an etiology of TCP. An evaluation including multimodal cardiac imaging and serology for virus antibody titers may be useful for an exploratory diagnosis of TCP in right-sided heart failure patients with pericardial effusion.

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

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

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