Coxsackie B (CB) viruses, like other enteroviruses, enter the host through the gastrointestinal tract before dissemination to target organs, such as the heart and brain (14
). In some cases, coxsackievirus transmission may also occur by way of the respiratory tract. Both the intestine and the airway are lined by polarized epithelial cells whose intercellular tight junctions separate the apical and basolateral surfaces and regulate transepithelial solute flow (13
). Coxsackieviruses must either cross or bypass epithelial barriers in the course of infection.
At the cellular level, CB viruses can initiate infection by attaching to the coxsackievirus and adenovirus receptor (CAR), a 46-kDa transmembrane protein that also functions as a receptor for many adenoviruses (3
). CAR expression on transfected nonpermissive rodent cells is sufficient to permit infection by all CB viruses that have been tested (12
In polarized respiratory and intestinal epithelial cells, CAR is absent from the apical surface and is localized to intercellular tight junctions, where it appears to be inaccessible to virus (9
). Polarized colonic epithelial cells resist infection by a prototypic strain of coxsackievirus B3 (CB3), CB3-Nancy, unless tight junctions are disrupted and CAR is exposed (9
), and sequestration of CAR in tight junctions has impeded efforts to use adenovirus vectors for gene delivery to airway epithelium (15
). These observations raise questions about how CB cross mucosal barriers during infection in vivo.
Certain CB viruses interact with an additional cell surface molecule, decay-accelerating factor (DAF, or CD55). Attachment to DAF was first observed with a variant of CB3-Nancy, designated CB3-RD, that had been adapted to growth in rhabdomyosarcoma cells (4
). It has also been observed with other isolates of CB1, CB3, and CB5 (21
)—as well as with hemagglutinating isolates of other enteroviruses (2
)—but not with CB2, CB4, or CB6. Expression of DAF on the surface of transfected rodent cells permits virus attachment but not infection (21
), suggesting that DAF, unlike CAR, is incapable of mediating some important postattachment function during virus entry. Although the role of DAF in infection remains uncertain, the DAF-binding capacity demonstrated by a wide variety of enteroviruses suggests that interaction with DAF may serve an important function during infection. We have found that interaction with DAF permits DAF-binding CB isolates to infect polarized epithelial cells, thus surmounting the obstacle presented by CAR sequestration.