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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Veterans Administration (IK2)
Project #
5IK2BX001701-02
Application #
8682782
Study Section
Infectious Diseases B (INFB)
Project Start
2013-07-01
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Veterans Health Administration
Department
Type
DUNS #
City
Nashville
State
TN
Country
United States
Zip Code
37212
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
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
Johnson, Jeremiah G; Gaddy, Jennifer A; DiRita, Victor J (2016) The PAS Domain-Containing Protein HeuR Regulates Heme Uptake in Campylobacter jejuni. MBio 7:
Shaffer, Carrie L; Good, James A D; Kumar, Santosh et al. (2016) Peptidomimetic Small Molecules Disrupt Type IV Secretion System Activity in Diverse Bacterial Pathogens. MBio 7:e00221-16
Haley, Kathryn P; Gaddy, Jennifer A (2016) Nutrition and Helicobacter pylori: Host Diet and Nutritional Immunity Influence Bacterial Virulence and Disease Outcome. Gastroenterol Res Pract 2016:3019362
Hurlow, J; Blanz, E; Gaddy, J A (2016) Clinical investigation of biofilm in non-healing wounds by high resolution microscopy techniques. J Wound Care 25 Suppl 9:S11-22
Guevara, Claudia; Zhang, Chengxian; Gaddy, Jennifer A et al. (2016) Highly differentiated human airway epithelial cells: a model to study host cell-parasite interactions in pertussis. Infect Dis (Lond) 48:177-88
Haley, Kathryn P; Gaddy, Jennifer A (2015) Metalloregulation of Helicobacter pylori physiology and pathogenesis. Front Microbiol 6:911
Gaddy, Jennifer A; Radin, Jana N; Cullen, Thomas W et al. (2015) Helicobacter pylori Resists the Antimicrobial Activity of Calprotectin via Lipid A Modification and Associated Biofilm Formation. MBio 6:e01349-15

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