A bacterial genotoxin causes virus reactivation and genomic instability in Epstein–Barr virus infected epithelial cells pointing to a role of co‐infection in viral oncogenesis

Abstract

We have addressed the role of bacterial co-infection in viral oncogenesis using as model Epstein-Barr virus (EBV), a human herpesvirus that causes lymphoid malignancies and epithelial cancers. Infection of EBV carrying epithelial cells with the common oral pathogenic Gram-negative bacterium Aggregatibacter actinomycetemcomitans (Aa) triggered reactivation of the productive virus cycle. Using isogenic Aa strains that differ in the production of the cytolethal distending toxin (CDT) and purified catalytically active or inactive toxin, we found that the CDT acts via induction of DNA double strand breaks and activation of the Ataxia Telangectasia Mutated (ATM) kinase. Exposure of EBV-negative epithelial cells to the virus in the presence of sub-lethal doses of CDT was accompanied by the accumulation of latently infected cells exhibiting multiple signs of genomic instability. These findings illustrate a scenario where co-infection with certain bacterial species may favor the establishment of a microenvironment conducive to the EBV-induced malignant transformation of epithelial cells.

Influence of the FIV Status and Chronic Gingivitis on Feline Oral Microbiota

“…One theory is that the deficient immune system could result in physiological changes within the oral cavity that would support an altered microbiome. In humans, studies have found evidence of oral bacteria and their products [21] affecting activation and replication of Epstein-Barr virus and HIV [22], demonstrating that not only what bacteria are present, but also what they produce and how they interact with viruses may be important.…”

Bacterial-Viral Interactions in Human Orodigestive and Female Genital Tract Cancers: A Summary of Epidemiologic and Laboratory Evidence

“…Likewise, EBV can be reactivated by metabolic end products of periodontal pathogen, e.g., butyrate, as demonstrated by increased viral lytic mRNAs, BZLF1 and BGLF5, and ZEBRA protein expression in exposed cells, concomitantly increased acetylated histone H3 [ 57 ]. In addition, Aa CDT has been reported to reactivate latent EBV infection in EBV positive cells and promote latent infection in non-infected cells via causing genomic instability [ 59 ].…”

Delivery, structure, and function of bacterial genotoxins

“…Matching residues are also found in CdtB sequences. The importance of Mg 2+ for CdtB activity was demonstrated in AaCdtB [ 110 ], CjCdtB [ 2 ], EcCDT-II [ 111 , 115 ], HdCDT [ 116 , 117 ], StyCDT [ 74 ] through in vivo chromatin condensation and/or in vitro plasmid degradation assays.…”