Abstract 87: The Impact of Coxsackievirus Infection on Cardiac Stem Cells and Postnatal Heart Development
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Coxsackievirus B (CVB) is an enterovirus that causes a self-limited febrile illness in infants, but can also cause myocarditis. Long-term consequences of mild CVB infection are unknown, although an association between heart failure and seropositive status has been previously described. We have shown that early postnatal exposure to doxorubicin depleted c-Kit+ cardiac stem cells (CSCs). Cardiac dysfunction in adult mice only developed after exercise challenge, or experimentally-induced myocardial infarction. We now report that CSCs from neonatal mouse hearts were susceptible to cytopathic CVB infection. To learn if mild CVB infection might deplete the CSC population in the heart, we inoculated newborn BALB/c mice with a recombinant CVB expressing eGFP. We observed CVB-infected CSCs 2 days post-inoculation and documented a reduction in the number of c-Kit+ cells in the hearts of animals at 4 and 11 weeks of age despite the absence of detectable virus. Moreover, CVB infection induced differentiation in the surviving CSCs. These results indicate that CVB can infect CSCs in the neonatal heart and trigger their destruction. Premature differentiation of surviving cells may also explain the reduced CSC population in adult mice. Despite normal histologic features in adult hearts, prolonged exercise challenge elicited cardiac hypertrophy and fibrosis in mice infected with CVB as pups. We suggest that the loss of CSCs after mild neonatal CVB infection may predispose to late-onset heart failure.Keywords:
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Myocarditis and dilated cardiomyopathy (DCM) are common causes of morbidity and mortality in children and adults. Recently, the human coxsackievirus and adenovirus receptor (CAR), a common receptor for coxsackieviruses and adenoviruses, was discovered and its increased expression has been reported in patients with DCM and myocarditis.To measure the expression of CAR in myocardial tissues of patients with DCM and its cellular localization in DCM cases.Formalin-fixed myocardial tissues collected during autopsy from 26 cases of DCM, and 20 cases each of noncardiac disease and cardiac disease other than DCM were included as the test group, and control groups A and B, respectively. Expression of CAR was studied using immunohistochemical staining of myocardial tissue with a CAR-specific rabbit polyclonal antibody. CAR messenger RNA was semiquantified by reverse transcription polymerase chain reaction followed by agarose gel analysis and measurement of band intensity.CAR positivity in DCM cases was found to be 96% (25 of 26) compared with 30% in control group A and 40% in control group B. CAR was found to be expressed in myocytes, endothelial and interstitial cells; however, positivity in myocytes was significantly higher than in other cells in all groups. The site of CAR expression was predominantly the sarcolemma along with cytoplasm in cardiomyocytes.The present study highlighted the increased expression of CAR in DCM cases, with localization in myocytes and endothelial cells.
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Suckling Swiss Webster mice were inoculated with 10(4)TCD50 of coxsackieviruses, group B types 1 or 4. Virulent necrotizing myocarditis resulted in 185 infected mice. Of the latter group, three (14.3%) nurslings on the 17th and 23rd day after inoculations had left ventricular aneurysms postmortem. None of 61 concurrently matched control mice developed aneurysms. Ventricular aneurysm is a suggested but previously undocumented complication of murine, and possibly human necrotizing transmural coxsackievirus myocarditis.
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Coxsackievirus
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SummarySpider monkeys and chimpanzees were given a series of three injections consisting of 17D yellow fever virus, followed by living West Nile virus, followed by a third injection which consisted of formalin-inactivated Russian spring-summer virus vaccine. On the basis of neutralizing antibody responses, the limitation of viremia, or both, developing when the animals were challenged with virulent viruses, these primates were judged to be protected to a considerable extent against Japanese B encephalitis, West Nile virus, St. Louis encephalitis, Murray Valley encephalitis virus, dengue types 1, 2, 3, and 4, two antigenic types of the Russian spring-summer virus complex, and Wesselsbron virus.An isolate of West Nile virus was passed a number of times in chick embryo tissue cultures and purified by the plaque technique. The progeny of two virus plaques, in a concentration of 106 mouse intracerebral lethal doses, did not produce encephalitis in intracerebrally inoculated rhesus monkeys. These attenuated viral preparations, on the basis of intracerebral titrations in mice, had at least 1,000 times the virus concentration that was necessary to produce encephalitis with the parent type. One of these attenuated isolates still produced homologous and heterologous neutralizing antibodies comparable to those of the parent strain. The data indicate that this attenuated West Nile virus did not revert to a more virulent form after alternate intracerebral passages in rhesus monkeys and suckling mice.The TP-21 strain of the Russian spring-summer virus complex was passed a number of times in chick embryo tissue cultures and purified by the plaque technique. The progeny from one of the virus plaques, in a concentration of approximately 300,000 mouse i.c. LD50, did not produce encephalitis when inoculated intracerebrally into rhesus monkeys. When this purified virus isolate of TP-21 was substituted for the formalin-inactivated Russian spring-summer vaccine in the triple vaccination procedure, considerable protection was noted in spider monkeys challenged with four members of the Russian spring-summer group of viruses.
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that recently appeared in Circulation.'This article concerns the long-term follow-
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Suckling Swiss Webster mice were inoculated with 10(4)TCD50 of coxsackieviruses, group B types 1 or 4. Virulent necrotizing myocarditis resulted in 185 infected mice. Of the latter group, three (14.3%) nurslings on the 17th and 23rd day after inoculations had left ventricular aneurysms postmortem. None of 61 concurrently matched control mice developed aneurysms. Ventricular aneurysm is a suggested but previously undocumented complication of murine, and possibly human necrotizing transmural coxsackievirus myocarditis.
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Group A
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