Pleiotropic cytotoxicity of VacA toxin in host cells and its impact on immunotherapy

Abstract

Introduction: In the recent decades, a number of studies have highlighted the importance of Helicobacter pylori in the initiation and development of peptic ulcer and gastric cancer. Some potential virulence factors (e.g., urease, CagA, VacA, BabA) are exploited by this microorganism, facilitating its persistence through evading human defense mechanisms. Among these toxins and enzymes, vacuolating toxin A (VacA) is of a great importance in the pathogenesis of H. pylori. VacA toxin shows different pattern of cytotoxicity through binding to different cell surface receptors in various cells. Methods: To highlight attempts in treatment for H. pylori infection, here, we discussed the VacA potential as a candidate for development of vaccine and targeted immunotherapy. Furthermore, we reviewed the related literature to provide key insights on association of the genetic variants of VacA with the toxicity of the toxin in cells. Results: A number of investigations on the receptor(s) binding of VacA toxin confirmed the pleiotropic nature of VacA that uses a unique mechanism for internalization through some membrane components such as lipid rafts and glycophosphatidylinositol (GPI)-anchored proteins (GPI-AP). Considering the high potency of VacA toxin in the clinical presentations in infection and assisting persistence and colonization of H. pylori, it is considered as one of the pivotal components in production vaccines and monoclonal antibodies (mAbs). Conclusion: It is possible to generate mAbs with a considerable potential to convert into secretory immunoglobulins that could penetrate into the niche of H. pylori and inhibit its normal functionalities. Further, conjugation of H. pylori targeting Ab fragments with the toxic agents or drug delivery systems (DDSs) offers new generation of H. pylori treatments.

Association of Helicobacter pylori vacA genotypes and peptic ulcer in Iranian population: a systematic review and meta-analysis

“…Endocytosis of VacA into the host cell leads to some events such as vacuoles formation, releasing cytochrome c from mitochondria, and apoptosis. In addition, VacA toxin by impressing on different receptors leads to alteration in signaling pathways of MAPK/p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2) (18,(66)(67)(68). Functional weight of…”

“…VacA toxin is about 88 kDa, and forms two subunits p33 and p55. The p33 domain which contains residues 1-33 in N-terminal region (as signal sequence) of VacA toxin, and creates vacuole in host cell (66,69). On the other, p55 domain acts as binding domain of toxin to the cell surface (66).…”

Pathogenicity of Helicobacter pylori in cancer development and impacts of vaccination

“…Several variable regions within the H. pylori genome have already been identified, including "plasticity zone" and "cytotoxin-associated gene" (Cag) pathogenicity island. The Cag island encodes a few structural proteins that required for assembling four secretion systems, effective on the translocation of the H. pylori products (e.g., immune dominant 120-145 kDa CagA protein) [24] within the host gastric epithelial cells [25]. The H. pylori genome also encodes several adhesion proteins that are important for ensuring tight contact between H. pylori and gastric epithelial cells.…”

“…Among those, CagA and its pathogenicity region (Cag PAI), and VacA (vacuolating cytotoxin A) are deemed as the significant pathogenic factors, which will be discussed in the following sections ( Fig. 2) [24].…”

“…H. pylori secrete the vacuolating cytotoxin (VacA) via a type V auto transport release system [24]. VacA is an 88 kDa, constituting p33 and p55 subunits, in which the p33 protein (N-terminal, 33 kDa) forms an inner channel for the chloride transportation and the p55 protein (C-terminal, 55 kDa) is responsible for the presentation of toxin into the host cells [35].…”