Pancreatic expression of interferon-γ protects mice from lethal coxsackievirus B3 infection and subsequent myocarditis

Horwitz, Marc S.; Cava, Antonio La; Fine, Cody; Rodrı́guez, Enrique; Ilic, Alex; Sarvetnick, Nora

doi:10.1038/76277

Cited by 155 publications

(179 citation statements)

References 20 publications

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“…No age-dependent difference in ␣2 mRNA levels was detected in heart tissue. In mice infected with coxsackievirus B3 the immune system both prevents viral replication and exacerbates myocardial damage (26)(27)(28). Age-dependent immune status may be a critical determinant of myocardial disease during EV1 infection of ␣2 and ␣2͞␤1 transgenic mice.…”

Section: Discussionmentioning

confidence: 99%

Transgenic mouse model for echovirus myocarditis and paralysis

Hughes

Thaker

Racaniello

2003

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Section: Discussionmentioning

confidence: 99%

Transgenic mouse model for echovirus myocarditis and paralysis

Hughes

Thaker

Racaniello

2003

Proc. Natl. Acad. Sci. U.S.A.

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“…39 In this model, IFN-␥ expression was limited to the pancreas and was not expressed in the heart. 39 The protective mechanism proposed was that viral infection in the heart was subdued, and therefore, myosin was not released from the lysis of infected myocytes and induction of autoimmune heart disease would not occur. Protection was attributed to the antiviral effect of IFN-␥.…”

Section: Influence Of Cytokines On Myocarditis and Th1/ Th2 Immune Rementioning

confidence: 99%

“…In the study of the transgenic animals, viremia was reduced in the heart. 39 Other factors besides reduction of viremia may play a role in protection against viral-induced autoimmune myocarditis. In the study reported herein, in the absence of viral infection but in the presence of immunization with cardiac myosin, IFN-␥ protected against myocarditis presumably by controlling the expression of IL-4 by T cells.…”

Section: Influence Of Cytokines On Myocarditis and Th1/ Th2 Immune Rementioning

confidence: 99%

“…37 Nevertheless, it is debated as to whether or not mimicry between coxsackieviruses and cardiac myosin plays a role in the pathogenesis of myocarditis. 38,39 There is strong evidence that cardiac myosin is a dominant autoantigen in autoimmune myocarditis 23 and viral-induced myocarditis. 25 Cardiac myosin-induced myocarditis histologically resembles the viral-induced disease.…”

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Cardiac Myosin and the TH1/TH2 Paradigm in Autoimmune Myocarditis

Cunningham

2001

The American Journal of Pathology

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“…The resulting high-level viremia enables the virus to invade other organs, notably the heart, brain, and liver, and morbidity and mortality are generally the result of damage to these other organs. The pancreatic infection appears to be critical to multiorgan pathogenesis, because when the pancreatic infection is suppressed, mice are protected from consequent myocarditis (4,5). This dependence on a viremic phase for infection of organs makes CVB an appropriate target to evaluate the efficacy of erythrocyte-bound receptor.…”

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confidence: 99%

The erythrocyte viral trap: Transgenic expression of viral receptor on erythrocytes attenuates coxsackievirus B infection

Asher

Cerny²,

Finberg³

2005

Proc. Natl. Acad. Sci. U.S.A.

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Viruses rely on attachment to specific cell surface receptors to infect host cells. Selective expression of viral receptors has the potential to attenuate infection of susceptible tissues by redirecting virus to cells that cannot support viral replication. We propose that erythrocytes are an ideal instrument for this strategy, because they are present in vast numbers, permeate every organ, and cannot serve as hosts for viral propagation. To test this hypothesis, we generated a transgenic mouse, termed globin transcription factor 1 (GATA1)-coxsackie and adenovirus receptor (CAR), that expressed the CAR on erythrocytes. Coxsackievirus group B (CVB) adhered to the surface of CAR-expressing erythrocytes and was rendered noninfectious. Upon infection with CVB, GATA1-CAR mice had diminished viremia and reduced viral replication in heart, brain, and liver. Furthermore, when faced with a CVB challenge that was lethal to WT littermates, the survival of GATA1-CAR mice was prolonged, and their ultimate mortality was reduced. The GATA1-CAR mouse model presented here demonstrates that erythrocyte expression of CAR limits CVB pathogenesis. Erythrocytes also may be coated with a variety of receptors by nontransgenic methods, making this a very flexible model for the treatment of infectious diseases in humans.coxsackie and adenovirus receptor ͉ virus receptor V iruses infect cells through attachment to specific host cell membrane receptors. These receptors mediate adhesion of the virus and facilitate its entry into the cell. The expression pattern of the specific receptors for a virus is thus a major determinant of viral tropism. Viruses cannot attack cells that do not bear the appropriate receptors, but they will attempt to infect cells that do, even if those cells are not suitable for viral propagation. If the receptor-expressing cell cannot support replication of the virus, then the virus will spend itself fruitlessly in an attempt to infect it. This idea can be advantageously applied by using selective expression of viral receptors to redirect virus to nonproductive cells, thus protecting susceptible tissues. We propose that erythrocytes are the ideal instrument for this strategy, because these cells are present in vast numbers, permeate every organ, are easily manipulated, are relatively disposable, and cannot serve as hosts for viral replication.Erythrocytes are simultaneously the most numerous and the simplest cells in the body. In their mature form, they lack the nuclei and organelles required to replicate nucleic acids and elaborate proteins. Because viruses depend on the use of the host cell machinery to replicate, erythrocytes are invulnerable to viral infection. The redirection of virus to erythrocytes has the potential to attenuate infection by leading virions to a dead end, leaving fewer infectious particles free to invade susceptible tissues. We hypothesized that the transgenic expression of viral receptor on erythrocytes would overwhelm the virus with decoy targets and thereby limit pathogenesis. Coxsackievirus ...

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Pancreatic expression of interferon-γ protects mice from lethal coxsackievirus B3 infection and subsequent myocarditis

Cited by 155 publications

References 20 publications

Transgenic mouse model for echovirus myocarditis and paralysis

Transgenic mouse model for echovirus myocarditis and paralysis

Cardiac Myosin and the TH1/TH2 Paradigm in Autoimmune Myocarditis

The erythrocyte viral trap: Transgenic expression of viral receptor on erythrocytes attenuates coxsackievirus B infection

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