Research Article: The Impact of Juvenile Coxsackievirus Infection on Cardiac Progenitor Cells and Postnatal Heart Development

Date Published: July 31, 2014

Publisher: Public Library of Science

Author(s): Jon Sin, Jenna M. Puccini, Chengqun Huang, Mathias H. Konstandin, Paul E. Gilbert, Mark A. Sussman, Roberta A. Gottlieb, Ralph Feuer, Thomas E. Lane.


Coxsackievirus B (CVB) is an enterovirus that most commonly causes a self-limited febrile illness in infants, but cases of severe infection can manifest in acute myocarditis. Chronic consequences of mild CVB infection are unknown, though there is an epidemiologic association between early subclinical infections and late heart failure, raising the possibility of subtle damage leading to late-onset dysfunction, or chronic ongoing injury due to inflammatory reactions during latent infection. Here we describe a mouse model of juvenile infection with a subclinical dose of coxsackievirus B3 (CVB3) which showed no evident symptoms, either immediately following infection or in adult mice. However following physiological or pharmacologically-induced cardiac stress, juvenile-infected adult mice underwent cardiac hypertrophy and dilation indicative of progression to heart failure. Evaluation of the vasculature in the hearts of adult mice subjected to cardiac stress showed a compensatory increase in CD31+ blood vessel formation, although this effect was suppressed in juvenile-infected mice. Moreover, CVB3 efficiently infected juvenile c-kit+ cells, and cardiac progenitor cell numbers were reduced in the hearts of juvenile-infected adult mice. These results suggest that the exhausted cardiac progenitor cell pool following juvenile CVB3 infection may impair the heart’s ability to increase capillary density to adapt to increased load.

Partial Text

Coxsackieviruses (CV) are common human pathogens that typically cause a self-limited infection and mild symptoms such as fever, rash, and upper-respiratory complications. Though CV can also cause severe inflammatory diseases including myocarditis, a disease that can lead to dilated cardiomyopathy [1], [2], [3], the manifestation of a cardiac disease phenotype has been documented to be extremely rare (∼5% of infected patients) [4]. Collapse and death of young individuals during exertion can result from catastrophic dysfunction of the electrical pathways in the heart associated with unrevealed CV infection [5], [6]. Additionally, 70–80% of individuals with end-stage idiopathic dilated cardiomyopathy have detectable levels of CV RNA in the myocardium without any history of antecedent viral myocarditis [7], [8], [9]. These findings raise the possibility that mild infection with CV can cause subtle but lasting injury, although it is unclear whether such enduring damage is immune-mediated or due to virus-mediated cytopathic effects. Previous studies suggest that coxsackievirus B3 (CVB3) may exhibit unique tropism for undifferentiated cells such as neural and hematopoietic progenitor cells thereby altering cell lineage commitment or diminishing their restorative capacity [10], [11], [12], [13], [14], [15], [16], [17]. Infection of progenitor cells may also enhance virus dissemination in a process referred to autophagosome-mediated exit without lysis (AWOL) [18], [19]. Based on these observations, we hypothesized that CVB3 also infects cardiac progenitor cells which might lead to long-term consequences for heart development and function. Of note, the mechanistic basis and causal link between juvenile CVB3 infection and adult-onset dilated cardiomyopathy has not been previously inspected.

Coxsackieviruses (CV) are enteroviruses that most commonly cause a mild self-limited infection characterized by fever, upper-respiratory symptoms, and rash. In rare cases coxsackievirus B (CVB) infection can give rise to severe inflammatory diseases such as pancreatitis, meningo-encephalitis, and myocarditis. Studies of patients with end-stage idiopathic dilated cardiomyopathy have revealed detectable CVB RNA in the hearts of 70–80% of the cases, despite the absence of a history of viral myocarditis [8], [9]. This observation has raised the concern that mild CVB infection may contribute to long-term cardiac sequelae. Possible mechanisms have not been verified, although some studies have suggested autoimmune mechanisms which include superantigen expression, molecular mimicry, or bystander damage [39]. Dilated cardiomyopathy is the final common pathway of many pathologic processes, in which an enlarged ventricular cavity and thinned ventricular wall, results in poor contractility, low ejection fraction, and in many cases diastolic dysfunction due to fibrosis. These signs of disease may be preceded by many years of compensated cardiac hypertrophy characterized by thickening and enlargement of the ventricles before decompensation develops. While CVB-associated myocarditis is clearly linked to heart failure, the notion that mild CVB infection in childhood could predispose to heart failure in adults has not been previously examined. Based on our previous observation that neonatal exposure to the cardiotoxic anthracycline doxorubicin (DOX) resulted in late-onset heart failure through depletion of cardiac progenitor cells (CPCs), we hypothesized that juvenile CVB infection might reveal similar sequelae if progenitor cells in the heart were susceptible to infection similar to previous findings in the central nervous system and bone marrow [15], [17].




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