Our goal is to define how Helicobacter pylori (Hp) impairs the host's immune response to establish a lifelong infection. Hp infects the gastric mucosa of >50% of the world's population. This bacterium is a causal agent for chronic gastritis, duodenal and gastric ulcers. Hp is also linked to gastric cancer. The mechanisms that allow persistent infection for decades and cause disease are not known. The inability of the host response to clear Hp infection suggests inhibition of the immune response. The CD4+ lymphocytes in the Hp-infected gastric mucosa are hyporesponsive and the mechanisms responsible are unclear. Our preliminary studies showed that Hp induces gastric epithelial expression of novel co-inhibitory receptors and cytokines that may inhibit antigen specific CD4+ T cells as well as the induction of T regulatory cells that suppress effector T cells. These data led us to hypothesize that Hp impairs protective T cell immunity using the epithelium as a mediator. To test the hypothesis we will: (1). Determine the mechanism(s) used by Hp to induce on gastric epithelial cells (GECs) the expression of B7 family ligands that inhibit CD4+T cells. We will investigate mechanisms behind the Hp induction of the expression by GECs of B7 family co-inhibitors of T cells. The expression of these ligands by GEC will be assessed by independent methods that include RT-PCR, western blot analysis, flow cytometry and functional analysis of suppression of T cells. (2). Determine the contact-independent mechanisms involved in inhibition CD4+ T cell function by gastric epithelial cells during Hp infection. We will examine the production by GECs of a cytokine (IL-16) that specifically acts on cells expressing CD4+ and inhibits their proliferation and function. Evaluation will be by ELISA, intracytoplasmic staining and specific function. Also, Hp-infected GECs will be examined for their release of exosomes that will be characterized for the expression of B7 family proteins and will be assessed for their inhibitory activity on T cells. (3). Determine the mechanisms whereby Hp-infected gastric epithelial cells influence the balance of T regulatory cells and Th17 cells. We will investigate how Hp-infected GECs support the induction of T reg cells from naove T cells populations. As Th17 are developmentally linked to T regs and are found in the Hp-infected gastric mucosa, the effect of Hp-infected GECs on Th17 induction will also be examined. The T cells that develop will be phenotypically (flow cytometry) and functionally (cytokine and bioassay) characterized. (4). Determine whether the mechanisms of Hp immune avoidance characterized in vitro are also involved in vivo in a mouse model of Hp infection. The role of B7 family members in T cell inhibition and/or T reg or Th17 expansion will be assessed in vivo by the infection of B7-H1-/- or B7-H1-/-/B7-DC-/- knockout mice. Also, antibody blocking of IL-16 in vivo will be investigated to determine its role in T cell hyporesponsiveness. The results from these studies will provide important insights into underlying causes that prevent the host to clear Hp infection, allowing the infection to remain chronic for decades and contribute to immune evasion by tumors.
Helicobacter pylori is a common human pathogen and infection with this bacterium causes gastritis and may lead to stomach ulcer and cancer. The objective of these studies is to define how H. pylori avoids clearance by the human immune response and becomes established as a chronic infection. Specifically, we will examine how H. pylori induces the expression by stomach epithelial cells of mediators that have immunoinhibitory effects, which could represent potential therapeutic targets for the important diseases associated with this infection.
| Lina, Taslima T; Alzahrani, Shatha; House, Jennifer et al. (2015) Helicobacter pylori cag pathogenicity island's role in B7-H1 induction and immune evasion. PLoS One 10:e0121841 |
| Alzahrani, Shatha; Lina, Taslima T; Gonzalez, Jazmin et al. (2014) Effect of Helicobacter pylori on gastric epithelial cells. World J Gastroenterol 20:12767-80 |
| Lina, Taslima T; Alzahrani, Shatha; Gonzalez, Jazmin et al. (2014) Immune evasion strategies used by Helicobacter pylori. World J Gastroenterol 20:12753-66 |
| Lina, Taslima T; Pinchuk, Irina V; House, Jennifer et al. (2013) CagA-dependent downregulation of B7-H2 expression on gastric mucosa and inhibition of Th17 responses during Helicobacter pylori infection. J Immunol 191:3838-46 |
| Beswick, Ellen J; Pinchuk, Iryna V; Earley, Rachel B et al. (2011) Role of gastric epithelial cell-derived transforming growth factor beta in reduced CD4+ T cell proliferation and development of regulatory T cells during Helicobacter pylori infection. Infect Immun 79:2737-45 |
