The Long and Complicated Relationship between Epstein-Barr Virus and Epithelial Cells

Abstract

The roles of epithelial cells in infection and persistence of the EpsteinBarr virus (EBV) have long been difficult to resolve. However, recent developments have reinforced the conclusion that these cells are a major site of virus replication and raised the possibility that, like papillomaviruses, EBV has evolved to take advantage of epithelial differentiation to ensure survival, persistence, and spread.KEYWORDS Epstein-Barr virus, epithelial cells, tropism E pstein-Barr virus (EBV) is well known as a human lymphotropic herpesvirus that was isolated from a Burkitt's lymphoma in the early 1960s (1). It is a well-described causal agent of infectious mononucleosis and an important player in the development of lymphoid tumors. It is well used as a tool for immortalizing human B cells. Soon after its discovery, an association between EBV and epithelial malignancies was revealed (2) and the presence of the virus was confirmed within epithelial cells of nasopharyngeal carcinoma (3). Yet, as late as 2005, a distinguished speaker at an international herpesvirus meeting declared that epithelial cells were not relevant to the general biology of EBV. How was that possible, and where are we today? EARLY WORKEarly works described EBV DNA and RNA in squamous epithelial cells shed in the oral cavity during acute infectious mononucleosis (4, 5). Thus, the model with B cells as the reservoir of latent EBV and epithelial cells as the site of productive lytic replication in vivo was developed. However, additional support for the routine involvement of epithelial cells in primary and persistent infections was, for many years, quite elusive. In the absence of any obvious lesions, such as those seen in herpes simplex infections, the finding of an infected cell in the oral cavity was much like looking for the proverbial needle in the haystack. Compounding the problem was the difficulty in infecting epithelial cells in vitro. With the advent of the AIDS epidemic, oral hairy leukoplakia appeared, which was the first and remains the only disease caused entirely by productive replication of EBV. Oral hairy leukoplakia, which is an epithelial hyperplasia typically found on the lateral tongue (6), is full of and driven by EBV lytic replication (7,8). This bolstered the case for epithelial cells in the oral cavity being responsible for the production of cell-free virus in saliva, but still, normal epithelial cells were readily found to contain virus only in individuals coinfected with the human immunodeficiency virus (9). For a while, the model of persistence pivoted toward the idea that in the absence of malignancy or other underlying disease, B cells alone are involved in infection (10).Three sets of observations subsequently helped spur a return to the yin-and-yang description of epithelial and B cell infection. Despite the uncertainty about the role of epithelial cells in EBV biology, its presence in epithelial cells of patients with nasopharyngeal carcinoma and gastric cancer indicates that EBV remains important for understanding...

Upsetting the Balance: When Viruses Manipulate Cell Polarity Control

“…EBV infection is generally found in B-lymphocytes, but the virus is also thought to infect polarized epithelium through the formation of direct adhesions between the B cells and the basolateral surface of epithelial cells [110,111], utilizing the endocytic recycling pathways of both donor and recipient cell to facilitate direct cell-cell transmission of the virus [112,113]. It has also been suggested that the virus exploits the endosomal machinery to cross the epithelial cells of the oral mucosa, without initiating an infection, to directly infect the B lymphocyes in the underlying dermis [112,114].…”

Presence of lytic Epstein‐Barr virus infection in nasopharyngeal carcinoma

“…In particular, the time and site of EBV involvement during tumor development is still circumstantial and controversial. For example, it remains unknown whether NPC tumor cells are infected by cell‐free EBV or by transferred infection from EBV‐positive memory B cells via the cell‐cell contact manner …”

“…For example, it remains unknown whether NPC tumor cells are infected by cell-free EBV or by transferred infection from EBV-positive memory B cells via the cell-cell contact manner. 8 Chromogenic in situ hybridization (ISH) of EBER has been reported to be the gold standard for detection of EBV-infected cells. [9][10][11] The reliable detection is somewhat hampered by the lack of robustness and sensitivity of this technique.…”

B Cell Receptor-Responsive miR-141 and viral miR-BART9 promote Epstein-Barr Virus Reactivation Through FOXO3 Inhibition

“…The EBV lytic stage is essentially required for horizontal transmission and lifelong persistence, and has a poorly understood role in the development of viral malignancies (7). In addition to epithelial cells in the oropharynx (8), resting peripheral blood and tonsil memory B cells are thought to serve as reservoirs for latent EBV (2, 9), while mature B cell trafficking through the GC and terminal differentiation into CD38+ plasma cells can trigger EBV reactivation (10). In vitro, cross-linking of surface immunoglobulins (Ig) on freshly isolated EBV-positive B cells (11) or latently infected BL cells (12) functionally mimics antigen interactions and stimulates virus reactivation.…”