Title: Regulation of H. pylori pili encoded by the cag pathogenicity island Jennifer A. Gaddy, Ph.D. Helicobacter pylori is the predominant colonizing prokaryote in the human gastric niche, causing persistent chronic inflammation. H. pylori infection is a strong risk factor for the development of peptic ulceration and gastric adenocarcinoma. The development of adenocarcinoma is dependent upon a variety of factors including host genetics, diet, and bacterial factors. One specific feature that contributes to bacterial pathogenesis is the H. pylori cag-pathogenicity island (cag-PAI), which encodes a type IV secretion system (T4SS) responsible for the delivery of the oncogenic protein CagA into gastric epithelial cells. The T4SS apparatus spans two bacterial membranes and includes an extracellular organelle referred to as the T4SS pilus. This organelle is proposed to be responsible for compromising the eukaryotic membrane and thereby allowing translocation of CagA. Although the T4SS has an important role in H. pylori pathogenesis and ultimately carcinogenesis, the mechanisms that regulate assembly of this complex molecular machine are largely obscure. This application proposes experiments that will elucidate mechanisms by which assembly and activity of the cag T4SS are regulated. Preliminary results indicate that metals such as iron and zinc contribute to the regulation of the T4SS. We will use high resolution electron microscopy to visualize the T4SS pilus under different conditions of metal availability in conjunction with biochemical and molecular biology techniques to evaluate the expression of pilus components in these conditions. We will also use bacterial genetics as a tool to investigate the contribution of bacterial metal homeostasis to the regulation of the cag-PAI T4SS. Finally, we will translate the laboratory experiments into an in vivo model by utilizing rodent models of infection and manipulating the dietary metal intake to determine the effect of nutrient metal upon disease progression and the regulation of the T4SS within a vertebrate host. This research plan will advance our knowledge in the area of bacterial pathogenesis, and specifically in the contribution of H. pylori virulence factor regulation to gastric diseases such as cancer.
The purpose of this research proposal is to determine the conditions that contribute to the formation of the Helicobacter pylori Cag-pathogenicity island encoded type IV secretion pili. H. pylori is a bacterium that resides in the stomach of about half of the world's population. These bacteria can persist in the gastric niche for decades and contribute to a variety of gastric diseases such as gastritis, peptic ulcer disease, gastric adenocarcinoma and MALT lymphoma. The data derived from the proposed experiments will give vital information on novel virulence attributes which can be identified as potential targets for novel therapeutic strategies. This is particularly important for Veteran populations or deployed troops, who have an increased risk of H. pylori infection.
|Ackerman, Dorothy L; Craft, Kelly M; Doster, Ryan S et al. (2018) Antimicrobial and Antibiofilm Activity of Human Milk Oligosaccharides against Streptococcus agalactiae, Staphylococcus aureus, and Acinetobacter baumannii. ACS Infect Dis 4:315-324|
|Korir, Michelle L; Flaherty, Rebecca A; Rogers, Lisa M et al. (2018) Investigation of the Role That NADH Peroxidase Plays in Oxidative Stress Survival in Group B Streptococcus. Front Microbiol 9:2786|
|Shank, Janette M; Kelley, Brittni R; Jackson, Joseph W et al. (2018) The Host Antimicrobial Protein Calgranulin C Participates in the Control of Campylobacter jejuni Growth via Zinc Sequestration. Infect Immun 86:|
|Skoog, Emma C; Morikis, Vasilios A; Martin, Miriam E et al. (2018) CagY-Dependent Regulation of Type IV Secretion in Helicobacter pylori Is Associated with Alterations in Integrin Binding. MBio 9:|
|Ackerman, Dorothy L; Doster, Ryan S; Weitkamp, Jörn-Hendrik et al. (2017) Human Milk Oligosaccharides Exhibit Antimicrobial and Antibiofilm Properties against Group B Streptococcus. ACS Infect Dis 3:595-605|
|Kothary, Vishesh; Doster, Ryan S; Rogers, Lisa M et al. (2017) Group B Streptococcus Induces Neutrophil Recruitment to Gestational Tissues and Elaboration of Extracellular Traps and Nutritional Immunity. Front Cell Infect Microbiol 7:19|
|Jackson, Emmanuel; Little, Saffron; Franklin, Dana S et al. (2017) Expression, Purification, and Antimicrobial Activity of S100A12. J Vis Exp :|
|Anders, Anjali P; Gaddy, Jennifer A; Doster, Ryan S et al. (2017) Current concepts in maternal-fetal immunology: Recognition and response to microbial pathogens by decidual stromal cells. Am J Reprod Immunol 77:|
|Parker, Robert E; Laut, Clare; Gaddy, Jennifer A et al. (2016) Association between genotypic diversity and biofilm production in group B Streptococcus. BMC Microbiol 16:86|
|Wakeman, Catherine A; Moore, Jessica L; Noto, Michael J et al. (2016) The innate immune protein calprotectin promotes Pseudomonas aeruginosa and Staphylococcus aureus interaction. Nat Commun 7:11951|
Showing the most recent 10 out of 29 publications