The Role of Coinfections in the EBV-Host Broken Equilibrium

Abstract

The Epstein-Barr virus (EBV) is a well-adapted human virus, and its infection is exclusive to our species, generally beginning in the childhood and then persisting throughout the life of most of the affected adults. Although this infection generally remains asymptomatic, EBV can trigger life-threatening conditions under unclear circumstances. The EBV lifecycle is characterized by interactions with other viruses or bacteria, which increases the probability of awakening its pathobiont capacity. For instance, EBV infects B cells with the potential to alter the germinal center reaction (GCR)-an adaptive immune structure wherein mutagenic-driven processes take place. HIV- and Plasmodium falciparum-induced B cell hyperactivation also feeds the GCR. These agents, along with the B cell tropic KSHV, converge in the ontogeny of germinal center (GC) or post-GC lymphomas. EBV oral transmission facilitates interactions with local bacteria and HPV, thereby increasing the risk of periodontal diseases and head and neck carcinomas. It is less clear as to how EBV is localized in the stomach, but together with Helicobacter pylori, they are known to be responsible for gastric cancer. Perhaps this mechanism is reminiscent of the local inflammation that attracts different herpesviruses and enhances graft damage and chances of rejection in transplanted patients. In this review, we discussed the existing evidence suggestive of EBV possessing the potential to synergize or cooperate with these agents to trigger or worsen the disease.

Keywords: EBV; H. pylori; HIV; HPV; P. falciparum; beta herpesvirus; coinfection; immunosuppression; lymphomagenesis; periodontal bacteria.

Figure 1

Shared microenvironments between EBV and other infectious agents. EBV infection’s main portal of entry and exit is the oral mucosa, where it coexists with the periodontal bacteria P. gingivalis and A. actinomycetemcomitans, and HPV. EBV persists in B cells residing in the lymphatic system, where it can cross paths with other infectious agents such as HIV, P. falciparum, or KSHV (here represented in the spleen as an example of a secondary lymph node). From the lymphatic system, EBV-infected cells can infiltrate certain tissues, such as the stomach or cervix, where EBV can intersect with H. pylori and HPV, respectively.

Figure 2

EBV-infected B cells transiting through the germinal center reaction (GCR) cross paths with HIV, P. falciparum, and KSHV. The key convergent mechanisms that potentiate lymphomagenesis are antigen (Ag)-specific and heterologous hyperactivation of B cells, which, upon enhancing the passage through the GCR, increase the likelihood of off-target mutagenesis. Mutated B cells normally die of apoptosis. However, if EBV alone or in conjunction with KSHV resides in these lymphocytes, viral proteins can rescue the cells from dying (illustrated here with LMP1 and vFLIP). In addition, the transformed/mutated B cells should be eliminated by the immune system, but infection-induced exhaustion or senescence causes unpaired immunosurveillance and immunoescape of these cells. The viral products also activate the oncogenic pathways and oncogenic processes and block B cell differentiation into memory cells. Immunosuppression by viral orthologs of cellular cytokines may also contribute to lymphomagenesis. Altogether, these events result in the development of conditions that favor the emergence of lymphomas with a plasmablastic morphology (see text for a more detailed explanation): Burkitt’s lymphoma (BL), Hodgkin’s lymphoma (HL), diffuse large B cell lymphoma (DLBCL), primary effusion lymphoma (PEL), and germinotropic lymphoproliferative disorder (GLPD).

Figure 3

Interactions between EBV and other infectious agents in non-lymphatic organs. The arrival and reactivation of EBV-infected B cells in different tissues may be influenced by ongoing inflammation. Reactivation is better understood by the secretion of butyric acid by oral bacteria. Released viral particles can infect epithelial cells aggravating inflammation and worsening tissue damage. EBV together with H. pylori or HPV alter the expression of methyltransferases (DNMT), which silences the tumor suppressor genes, such as the phosphatase SHP1, rendering the bacterium oncoprotein CagA more active. H. pylori, HPV, and EBV products also enhance the survival of cells. EBV and HPV also turned off the expression of differentiation genes, such as BLIMP1, thus halting cells in the proliferative states to become more permissive for viral persistency, and EBV may favor HPV integration into the host DNA. EBV immunomodulatory mechanisms may help create an immunosuppressive microenvironment that may cooperate with the immunomodulatory mechanisms of other herpesviruses (HHV). Altogether, these interactions promote the appearance of tissue lesions that may be partially responsible for graft rejection and carcinogenesis (see text for details).