Helicobacter pylori Membrane Vesicles Stimulate Innate Pro- and Anti-Inflammatory Responses and Induce Apoptosis in Jurkat T Cells

Abstract

Persistent Helicobacter pylori infection induces chronic inflammation in the human gastric mucosa, which is associated with development of peptic ulceration, gastric atrophy, and gastric adenocarcinoma. It has been postulated that secretion of immunomodulatory molecules by H. pylori facilitates bacterial persistence, and membrane vesicles (MV), which have the potential to cross the gastric epithelial barrier, may mediate delivery of these molecules to host immune cells. However, bacterial MV effects on human immune cells remain largely uncharacterized to date. In the present study, we investigated the immunomodulatory effects of H. pylori MV with and without the vacuolating cytotoxin, VacA, which inhibits human T cell activity. We show a high degree of variability in the toxin content of vesicles between two H. pylori strains (SS1 and 60190). Vesicles from the more toxigenic 60190 strain contain more VacA (s1i1 type) than vesicles from the SS1 strain (s2i2 VacA), but engineering the SS1 strain to produce s1i1 VacA did not increase the toxin content of its vesicles. Vesicles from all strains tested, including a 60190 isogenic mutant null for VacA, strongly induced interleukin-10 (IL-10) and IL-6 production by human peripheral blood mononuclear cells independently of the infection status of the donor. Finally, we show that H. pylori MV induce T cell apoptosis and that this is enhanced by, but not completely dependent on, the carriage of VacA. Together, these findings suggest a role for H. pylori MV in the stimulation of innate pro-and anti-inflammatory responses and in the suppression of T cell immunity.

Immune modulation by bacterial outer membrane vesicles

“…For example, H. pylori OMVs suppress T cell responses by inducing apoptosis through a pathway that involves caspase 3 and caspase 7 (REF. 44). The authors demonstrated that the VacA toxin associated with H. pylori OMVs 12,67,90 enhanced, but was not essential for, the induction of apoptosis in T cells from a Jurkat cell line 44 .…”

“…44). The authors demonstrated that the VacA toxin associated with H. pylori OMVs 12,67,90 enhanced, but was not essential for, the induction of apoptosis in T cells from a Jurkat cell line 44 . Similarly, opacity-associated (Opa) proteins in N. meningitidis OMVs inhibit T cell activation and proliferation by binding to human carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) on CD4 + T cells to create a zone of immunosuppression at the site of infection 91 .…”

“…Stimulation of monocytes and macrophages with N. meningitidis OMVs induces their production of CCL2, CCL3 and CCL5 (also known as RANTES), CXCL8, IL-1β, IL-6, IL-10, IL-12p40, IL-12p70 and TNF 43 . Similarly, H. pylori OMVs promote IL-6 production by human peripheral blood mononuclear cells 44 , and Salmonella spp. OMVs induce the production of TNF and nitric oxide (NO) by mouse macrophages 45 .…”

“…In addition to having pro-inflammatory effects, OMVs can have an anti-inflammatory role that benefits the pathogen of origin or that promotes secondary bacterial infections. For example, H. pylori OMVs induce the production of the immunosuppressive cytokine IL-10 by human peripheral blood mononuclear cells to limit inflammation and facilitate bacterial survival 44 . P. gingivalis OMVs facilitate the loss of CD14 expression on macrophages, rendering these cells unresponsive to TLR4 signalling induced by secondary E. coli LPS stimulation 48 .…”

Helicobacter pylori vacuolating toxin

“…vesicles (OMVs; Figure 19.3), a mechanism exploited by several Gram-negative bacteria for virulence factor delivery to host cells [37][38][39]. OMVs thus may represent an important vehicle in delivering VacA and other H. pylori antigens to either epithelial or nonepithelial gastric cells, where they exert their pathogenic actions [39][40][41][42]. Moreover, surface-associated VacA can be delivered to host gastric cells through a contact-dependent mechanism [36].…”