Sensing Bacterial-Induced DNA Damaging Effects via Natural Killer Group 2 Member D Immune Receptor: From Dysbiosis to Autoimmunity and Carcinogenesis

Abstract

The human genome is constantly exposed to exogenous and endogenous DNA damaging factors that frequently cause DNA damages. Unless repaired, damaged DNA can result in deleterious mutations capable of causing malignant transformation. Accordingly, cells have developed an advanced and effective surveillance system, the DNA damage response (DDR) pathway, which maintains genetic integrity. In addition to well-defined outcomes, such as cell cycle arrest, apoptosis, and senescence, another consequence of DDR activation is the induction of natural killer group 2 member D ligands (NKG2D-Ls) on the surface of stressed cells. Consequently, NKG2D-Ls-expressing cells are recognized and eliminated by NKG2D receptor-expressing immune cells, including NK cells, and various subsets of T-cells. Recent pieces of evidence indicate that commensal microbial imbalance (known as dysbiosis) can trigger DDR activation in host cells, which may result in sustained inflammatory responses. Therefore, dysbiosis can be seen as an important source of DNA damage agents that may be partially responsible for the overexpression of NKG2D-Ls on intestinal epithelial cells that is frequently observed in patients with inflammatory bowel disease and other disorders associated with altered human microbiota, including the development of colorectal cancer. In this article, we discuss recent evidence that appears to link an altered human microbiota with autoimmunity and carcinogenesis via the activation of DDR signals and the induction of NKG2D-Ls in stressed cells.

Escherichia coli, a common constituent of benign prostate hyperplasia‐associated microbiota induces inflammation and DNA damage in prostate epithelial cells

“…Studies have attempted to dissect the underlying mechanism behind the initiation and progression of PC in the context of inflammation 7,13 . The inflammatory milieu in association with the presence of microorganisms in BPH/prostatitis/PC involves oncogenic mechanisms like oxidative stress 10,14 and DNA damage 15‐19 . Inflammatory signaling involving nuclear factor‐κB (NF‐κB) 20‐22 and cyclooxygenase‐2 (COX2) 23,24 is also reported to be intricate in PC pathogenesis.…”

Lectin-Dependent Diversity of Natural Killer Populations and Communications Against Tumors and Viruses

“…It may be used upon search the ways and strategies of fight against tumors (also throuph antiviral action). As a result, increase of a number of effective NK cells and NKP and their intratumor-tissue expansion (expansion of needed NK cell types and complex NKP combinations) take place [8,11,13,30]. Actions of NKP are in the synergistic accordance to protective actions of the complement system [18].…”

NK-cells that identify glycopatterns and their anti-tumor potential against a background of epidemically significant viral infections

“…It can be applied to work out strategies aimed at fighting against tumors including those incorporating antiviral effects. As a result, essential NK-cell types and populations grow in number and their expansion inside a tumor takes place [11,14,15,27]. Effects produced by NK-populations are coordinated with the complement system [21].…”

“…*Targeted application of NKG2D+-populations against tumors with the use of NKG2D-receptors belonging to supervisory effector NK-cells which act in a stand-by mode and monitor occurrence / initiation of tumor ligands on stress cells as such ligands are tumor precursors [8,14]. And here cells that express NKG2D-ligands (as it happens in case of super-expression of sets in stress cells insides the intestines) are recognized and eliminated by supervisory cells and it is aimed at preventing carcinogenesis, for example, rectum cancer [14].…”

“…There are also promising preventive and therapeutic possibilities to prevent dysbiotic states of mucosal biotopes in open cavities from transforming into tumor ones, including participation of NKG2D/ NKG2D-ligands NK-populations system that activates DDRpathway (DNA damage response) as well as effects produced by probiotic lectins with cytokine-like activities [5,13,14]. Since probiotic lectins, in case of microbe-virus dysbiosis, can be selectively aimed at opportunistic pathogens (including those changed under inflammation) and can also act as probiotics when probiotic cellular microflora is absent in mucosal biotopes against HPV occurrence in them which is a potential inducer of vaginal cancer, one can predict that there can be anti-cancer / antiviral synergy of probiotic lectins and NKG2D-caused cytotoxicity that reduces susceptibility to cancer [5,13,38].…”