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

Abstract

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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