Epithelial cell polarization is a determinant in the infectious outcome of immunoglobulin A-mediated entry by Epstein-Barr virus

Abstract

Diseases of the nasopharyngeal epithelium due to Epstein-Barr virus (EBV) infection typically occur in chronic virus carriers with preexisting virus-specific antibodies. In vitro studies have shown that EBV-specific immunoglobulin A (IgA) promotes infection of human epithelial cells, otherwise refractory to EBV, via the polymeric immunoglobulin receptor (pIgR). To determine if EBV similarly exploits IgA transport mechanisms in vivo, we examined the fate of IgA-EBV complexes in the blood of mice, where pIgR-mediated transcytosis of IgA immune complexes through hepatocytes eliminates exogenous antigens from the circulation. By PCR analysis we showed hepatobiliary transport of IgA-EBV in viremic mice, but without detectable hepatocellular infection by immunostaining. Because efficient transport of EBV immune complexes might avert an infectious outcome, we modulated the transcytotic pathway in polarized Madin-Darby canine kidney (MDCK) cells transfected with pIgR to determine the effect on viral antigen expression. Like hepatocytes in vivo, MDCK cells in polarized monolayers translocatedIgA-EBV from the basal cell face into apical medium without evidence for infection. However, when exposed to IgA-EBV as unpolarized single-cell suspensions, MDCK cells expressed EBV immediate-early and early antigens. These results suggest that pIgR-mediated transcytosis of pIgA-EBV through epithelium facilitates endogenous spread of EBV in long-term virus carriers, with infection being confined to cells with altered polarity from prior cytopathology.

Patterned Entry and Egress by Epstein–Barr Virus in Polarized CR2-Positive Epithelial Cells

“…Since patterned viral entry in polarized cells reflects asymmetric distribution of viral receptors (Fuller et al, 1984;Clayson and Compans, 1988;Rossen et al, 1994), evidence for enhanced apical infectivity despite the general dispersal of CR2 to all cell surfaces supports the existence of an endogenous EBV coreceptor segregated apically on CR2-transfected MDCK cells. Existence of such a coreceptor may explain the disparate outcomes of IgA-mediated entry by EBV reported in earlier studies using this same cell system (Gan et al, 1997). Under polarized conditions where the polymeric immunoglobulin receptor (pIgR) is partitioned basolaterally, EBV/IgA immune complexes were transcytosed by pIgR through MDCK cells without evidence for infection.…”

“…Moreover, transfection of the CR2 molecule into numerous cell types confers susceptibility to infection (Ahearn et al, 1988;Li et al, 1992;Knox et al, 1996). In earlier work using the Madin-Darby canine kidney (MDCK) epithelial cell line, we demonstrated that epithelial cell polarity was a key determinant in the infectious outcome of immunoglobulin A-mediated entry of EBV (Gan et al, 1997). In this report, using MDCK cells stably transfected with the EBV receptor CR2, we provide evidence for preferential direction of viral entry and release in polarized cells that may elucidate EBV exchange between epithelial cells and lymphocytes at the time of primary infection.…”

Entry of viruses through the epithelial barrier: pathogenic trickery

“…surface protein that is present in latently infected people. The complex binds to the POLY-IMMUNOGLOBULIN RECEPTOR at the basal surface of epithelial cells, and is endocytosed and delivered apically without infection 6 . By contrast, in non-polarized cells, the entry of IgA-EBV leads to infection.…”

Transport of viruses through fetal membranes: An in vitro model of perinatal transmission

“…Virus penetration through the fetal membrane may involve transcytosis of internalized virus particles. Immunoglobulin A-mediated transcytosis through polarized cell monolayers via the immunoglobulin receptor has been described for Epstein-Barr virus without evi- dence of infection [Gan et al, 1997]. Receptor-mediated transcytosis has been proposed for the transport of HIV through epithelial monolayers, too.…”