Helicobacter pylori Virulence Regulatory Network: Insights into the Host-Environment and Pathogen Interactions

Abstract

Helicobacter pylori (H. pylori) has evolved significant regulatory mechanisms in order to acclimatize in extreme gastric environment of human beings. The virulence machinery of H. pylori is complicated as virulence factors of pathogen not only interact with transcription and translational machinery of host, but also are involved in the progression and development of the disease. The present study is an effort to model virulence mechanism in H. pylori, particularly ferric uptake regulator (FUR) under acidic and iron (Fe) depleted conditions, as well as its effects on the well known virulence factors cytotoxin-associated gene A (cagA) and vacuolating cytotoxin A (vacA) gene. The virulence regulatory network of cagA and vacA is modeled based on an asynchronous kinetic logic formalism introduced by René Thomas. The cagA-vacA virulence regulatory network is then elaborated qualitatively to obtain insights into H. pylori induced pathogenesis. The findings have revealed the significant regulatory pathways through which H. pylori spreads infection to the gastric cells, and also verified that cagA is associated with acute gastritis while vacA is involved in vacuolation, apoptosis and atrophy. Interestingly, both cagA and vacA were found to modulate each other virulence potential which ultimately leads to the state of chrHelicobacter pylori (H. pylori) has evolved significant regulatory mechanisms in order to acclimatize in extreme gastric environment of human beings. The virulence machinery of H. pylori is complicated as virulence factors of pathogen not only interact with transcription and translational machinery of host, but also are involved in the progression and development of the disease. The present study is an effort to model virulence mechanism in H. pylori, particularly ferric uptake regulator (FUR) under acidic and iron (Fe) depleted conditions, as well as its effects on the well known virulence factors cytotoxin-associated gene A (cagA) and vacuolating cytotoxin A (vacA) gene. The virulence regulatory network of cagA and vacA is modeled based on an asynchronous kinetic logic formalism introduced by René Thomas. The cagA-vacA virulence regulatory network is then elaborated qualitatively to obtain insights into H. pylori induced pathogenesis. The findings have revealed the significant regulatory pathways through which H. pylori spreads infection to the gastric cells, and also verified that cagA is associated with acute gastritis while vacA is involved in vacuolation, apoptosis and atrophy. Interestingly, both cagA and vacA were found to modulate each other virulence potential which ultimately leads to the state of chronic gastritis; which in turn drives the pathway smoothly towards gastric adenocarcinoma via the formation of pre-malignant lesions. The proposed strategy can be extended to understand the mechanism of other similar bacterial infections and disease progression. It will also help in the prioritization of potential therapeutic targets to control such serious infections.onic gastritis; which in turn drives the pathway smoothly towards gastric adenocarcinoma via the formation of pre-malignant lesions. The proposed strategy can be extended to understand the mechanism of other similar bacterial infections and disease progression. It will also help in the prioritization of potential therapeutic targets to control such serious infections.