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.
Highlights
Helicobacter pylori (H. pylori) affects more than 50% of the world’s population and the infection is more prevalent in developing countries (~90%) in comparison to the developed world (~20%)
Two types of biological regulation i.e. either positive regulation or activation and negative regulation or inactivation are the essential interactions between genes or/and products of biological regulatory network (BRN). Both types of biological regulation are a function of sigmoidal curve (Ahmad, et al, 2012). our study studies the pathogenic nature of H. pylori in gastric carcinogenesis pertaining to the regulatory expression of cytotoxin-associated gene A (cagA) and vacuolating cytotoxin A (vacA), this regulatory expression along with other associated factors is referred to as virulence regulatory network (VRN), which has been constructed by logical modeling based on Kinetic logic formalism and with the help of existing experimental evidences
Apo-form ferric uptake regulator (Fur) regulates the expression of outer-membrane proteins, iron storage protein and most important virulence factors; cagA and vacA while in Fe co-factoredform, Fur regulated the expression of flagellar genes and genes implicated in iron homeostasis like frpB1,exbB2, fec1and fec2 (Ernst, et al, 2005)
Summary
Helicobacter pylori (H. pylori) affects more than 50% of the world’s population and the infection is more prevalent in developing countries (~90%) in comparison to the developed world (~20%). Fur in H. pylori has acquired the ability to bind the promoter of other host genes independent of the complex (Apo-Fur) and regulates the transcription process (Bereswill, et al, 2000, Delany, et al, 2003, Ernst, et al, 2005). This dual property of Fur broadens its regulatory control on the expression of genes, which in turn equip the bacterium to adapt in environment with low iron levels
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