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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.

SUBMITTER: Fahimi F

PROVIDER: S-EPMC5439391 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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

Fahimi Farnaz F Tohidkia Mohammad Reza MR Fouladi Mehdi M Aghabeygi Reza R Samadi Naser N Omidi Yadollah Y

BioImpacts : BI 20170330 1

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 ...[more]

PMID: 28546954

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Project description:Adoptive cell transfer against solid tumors faces challenges to overcome tumor microenvironment (TME), which plays as a physical barrier and provides immuno-suppressive conditions. Classical cytotoxicity assays are widely used to measure killing ability of the engineered cytotoxic lymphocytes as therapeutics, but the results cannot represent the performance in clinical application due to the absence of the TME. This paper describes a 3D cytotoxicity assay using an injection molded plastic array culture (CACI-IMPACT) device for 3D cytotoxicity assay to assess killing abilities of cytotoxic lymphocytes in 3D microenvironment through a spatiotemporal analysis of the lymphocytes and cancer cells embedded in 3D extra cellular matrix (ECM). Rail-based microfluidic design was integrated within a single 96-well and the wells were rectangularly arrayed in 2 × 6 to enhance the experimental throughput. The rail-based microstructures facilitate hydrogel patterning with simple pipetting so that hydrogel pre-solution aspirated with 10 ?l pipette can be patterned in 10 wells within 30 s. To demonstrate 3D cytotoxicity assay, we patterned HeLa cells encapsulated by collagen gel and observed infiltration, migration and cytotoxic activity of NK-92 cells against HeLa cells in the collagen matrix. We found that 3D ECM significantly reduced migration of cytotoxic lymphocytes and access to cancer cells, resulting in lower cytotoxicity compared with 2D assays. In dense ECM, the physical barrier function of the 3D matrix was enhanced, but the cytotoxic lymphocytes effectively killed cancer cells once they contacted with cancer cells. The results implied ECM significantly influences migration and cytotoxicity of cytotoxic lymphocytes. Hence, the CACI-IMPACT platform, enabling high-throughput 3D co-culture of cytotoxic lymphocyte with cancer cells, has the potential to be used for pre-clinical evaluation of cytotoxic lymphocytes engineered for immunotherapy against solid tumors.

Dataset Information

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

Publications

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

Similar Datasets

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