Epstein-Barr Virus Infection of Langerhans Cell Precursors as a Mechanism of Oral Epithelial Entry, Persistence, and Reactivation

Abstract

Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus associated with many malignant and nonmalignant human diseases. Life-long latent EBV persistence occurs in blood-borne B lymphocytes, while EBV intermittently productively replicates in mucosal epithelia. Although several models have previously been proposed, the mechanism of EBV transition between these two reservoirs of infection has not been determined. In this study, we present the first evidence demonstrating that EBV latently infects a unique subset of blood-borne mononuclear cells that are direct precursors to Langerhans cells and that EBV both latently and productively infects oral epithelium-resident cells that are likely Langerhans cells. These data form the basis of a proposed new model of EBV transition from blood to oral epithelium in which EBV-infected Langerhans cell precursors serve to transport EBV to the oral epithelium as they migrate and differentiate into oral Langerhans cells. This new model contributes fresh insight into the natural history of EBV infection and the pathogenesis of EBV-associated epithelial disease. Epstein-Barr virus (EBV) is a human herpesvirus that ultimately infects 95% of adults worldwide. EBV is transmitted via mucosal fluids and establishes life-long persistent infection.Although persistent infection is asymptomatic in most people, EBV is associated with benign syndromes, including infectious mononucleosis and oral hairy leukoplakia, and a wide variety of both lymphoid and mucosal epithelial malignancies. Persistent latent EBV infection occurs in memory B lymphocytes that circulate in blood (22). While latent EBV infection also occurs in some epithelial malignancies (29), EBV infection of epithelial cells typically results in productive replication, as demonstrated in oral hairy leukoplakia (9) and in normal oral epithelium (8,10,48).Three different models have previously been proposed to explain the transition of EBV from the latent reservoir of infection in blood-borne B lymphocytes to sites of productive replication in oral epithelium. Model 1 proposes that B lymphocytes carrying latent EBV infection migrate from the blood to the epithelium, where the EBV reactivates and infects adjacent epithelial cells (12), but evidence of intraepithelial B lymphocytes in normal oral epithelium or in oral hairy leukoplakia is lacking (30, 33). Model 2 proposes that EBV virions produced by B lymphocytes in the oral submucosa bind submucosal EBV-specific dimeric immunoglobulin A (IgA) and enter basal oral epithelial cells by endocytosis via the polymeric Ig receptor (37), but the polymeric Ig receptor is not expressed in oral epithelium (23). Model 3 proposes that EBV virions produced by B lymphocytes in oral lymphoid tissues (26) gain access to and infect middle-and upper-layer oral epithelial cells as a result of microscopic traumatic epithelial injury, such as that which occurs during mastication. However, this model is contradicted by evidence that EBV transitions into oral epithelium as cell-associated latent infecti...

TLR9 Contributes to the Recognition of EBV by Primary Monocytes and Plasmacytoid Dendritic Cells

“…It has been reported that EBV infects subclasses of DCs, such as skin resident Langerhans cells and follicular DCs (20,21,23). However, although we detected the presence of a viral genome in EBV-treated pDCs, we did not obtain convincing results supporting the ability of EBV to establish infection in these cells.…”

“…First, it was demonstrated that EBV has the capacity to infect monocytes and DCs (2,(19)(20)(21)(22)(23). In addition, infection of monocytes by EBV was reported to inhibit their development into DCs (24), a process that may affect normal regulation of EBV-host interactions because DCs are known to play a crucial role in the induction of primary T cell response against viruses, including EBV (25,26).…”

Detection of EBV genomes in plasmablasts/plasma cells and non-B cells in the blood of most patients with EBV lymphoproliferative disorders by using Immuno-FISH

“…For example, EBV infects pre-Langerhans cells in the peripheral blood. 16 However, we did not detect EBV DNA in pre-Langerhans cells (CD1a ϩ CD11c ϩ , and CD14 Ϫ ) or in basophils (CD123 ϩ ) in PBMCs from 4 patients who had EBV in non-B, non-T, non-monocyte cells (patients 12, 15, 16, and 20), using Immuno-FISH (data not shown). Infection of non-B, non-T, non-monocyte cells may be more common in immunocompromised persons.…”

“…2,[7][8][9][10][11] However, EBV can infect cells other than B cells, including T cells, natural killer (NK) cells, monocytes, and pre-Langerhans cells. [12][13][14][15][16] Several techniques have been developed to detect EBV in cells. In situ hybridization using a probe that detects the EBV-encoded RNAs (EBERs) is considered the best test for localizing latent EBV in tissue samples.…”

Efficient replication of Epstein–Barr virus in stratified epithelium in vitro

“…Infection of suprabasal cells where UPR is activated likely would preclude the establishment of a persistent latent infection and instead would result in productive infection. This situation could arise as an artifact of our system in which the virus might not access the basal surface efficiently or result from the lack of other cell types that might play a role in infection from the basal surface (42,43). Alternatively, a receptor or coreceptor might be expressed more efficiently on differentiated cells; although some investigators observe increased infection in more differentiated keratinocytes (9), others do not (8).…”