Transgenic mouse model for echovirus myocarditis and paralysis

Abstract

Echoviruses have been implicated in multiple human disease syndromes, including aseptic meningitis, paralysis, and heart disease, but no animal model is available for studying the pathogenesis of infection. Production of human integrin very late antigen 2, a receptor for echovirus type 1, in transgenic mice conferred susceptibility to viral infection. Intracerebral inoculation of newborn transgenic mice with echovirus leads to paralysis and wasting. No disease was observed in infected nontransgenic mice. In paralyzed mice significant damage was observed in the outer layers of the cerebrum, and numerous condensed neuronal nuclei were present. In contrast, intracerebral inoculation of adolescent (3-to 4-weekold) transgenic mice with echovirus type 1 did not lead to paralysis but an acute wasting phenotype and myocarditis. These findings establish human very late antigen 2 transgenic mice as a model for echovirus pathogenesis. E choviruses, like polioviruses and coxsackieviruses, are nonenveloped RNA viruses that are members of the Enterovirus group of the family Picornaviridae. It is estimated that 10-15 million illnesses are caused each year by nonpolio enteroviruses in the United States (1). Although the vast majority of these illnesses are not serious, a wide range of potentially fatal human diseases, including aseptic meningitis, encephalitis, paralysis, type I diabetes mellitus, and myocarditis, have been associated with echovirus infections (2).Members of the enteric cytopathogenic human orphan group of viruses (echoviruses) were initially distinguished from coxsackieviruses by their inability to replicate and cause disease in newborn mice (3). Because a small animal model is not available, much of what is known about echovirus pathogenesis is inferred from epidemiological surveillance studies and mouse models for coxsackievirus and poliovirus pathogenesis. As is the case for poliovirus, the cellular receptor is most likely a major determinant of the restricted host range of echoviruses (4-7). A receptor molecule that is both sufficient and necessary to mediate virus binding and entry has been identified for only 1 of the 31 echovirus serotypes, echovirus type 1 (EV1) (8). A cellular receptor for EV1 is human very late antigen 2 (VLA-2), a heterodimer comprising one ␣2 subunit and one ␤1 subunit (integrin ␣2͞␤1). EV1 interacts with the collagen binding I domain of human ␣2 integrin subunits (9). Although EV1 binding and entry are mediated solely by the ␣2 subunit, association of an ␣2 subunit with a ␤1 subunit is required for proper transport of ␣2͞␤1 integrin to the cell surface (10). Production of the ␣2 polypeptide in rodent cells is sufficient to render these cells susceptible to infection by EV1, indicating that human-␣2͞mouse-␤1 heterodimers can serve as functional EV1 receptors (8, 11). Widespread cell and tissue synthesis of integrin ␣2͞␤1 is consistent with the hypothesis that many target organs are involved in EV1 pathogenesis (12).Transgenic mice that produce human cell receptors for infectious ag...

Coxsackievirus Targets Proliferating Neuronal Progenitor Cells in the Neonatal CNS

“…Figure 9 also makes clear one prediction of our model: the combination of diminished cellular proliferation after exiting the SVZ and virusinduced lysis of mature cells implies that the final destinations of those infected progenitor cells (e.g., the OB or cerebral cortex) should be depleted of mature neurons, as we observed in the glomerular layer (Fig. 3) and as has been reported in a transgenic model of echovirus infection (Hughes et al, 2003). We are currently investigating the magnitude of this depletion throughout the neonatal CNS; if extensive, it could contribute to the neurodevelopmental deficits that have been identified in survivors of fetal CVB infections (Euscher et al, 2001;Genen et al, 2004).…”

Surface Proteins ofStreptococcus agalactiaeand Related Proteins in Other Bacterial Pathogens

“…However, results obtained with animal models must be interpreted with caution, and lack of evidence that a bacterial component contributes to virulence in an animal model does not exclude the possibility that it is of major importance in human infections. In the future, the use of transgenic mice may facilitate studies of some aspects of the infectious process, as described in other systems (100,143,207).…”

Enterovirus 70 Receptor Utilization Is Controlled by Capsid Residues That Also Regulate Host Range and Cytopathogenicity

“…These animal models have proven valuable for studying the pathogenesis of poliomyelitis (15,34), measles (3,9,16,28,33), and echovirus paralysis and myocarditis (17). At least one cell receptor for EV70 is decay accelerating factor (DAF), also known as CD55 (19).…”