Research Projects

Helicobacter pylori is an archetype persistent pathogen colonizing majority of people worldwide. This persistent infection and chronic inflammation cause various associated pathologies in infected people. Most of the people with H. pylori infection experience mild gastritis while 10-20% forms peptic ulcer, 1-2% develops gastric cancer and mucosa associated lymphoid tissue (MALT) lymphoma. H. pylori infection activates several toll-like receptors (TLRs) for signalling to produce several pro- and anti-inflammatory cytokines. H. pylori infection induces pro-inflammatory T-helper-1 (Th1) cells, M1 macrophages, humoral immunity producing B-cells and anti-inflammatory T-regulatory (T-reg) cells and M2 macrophages in the colonized area. H. pylori flagellin is mutated in the TLR5 binding domain and evades the interaction. Interestingly, our studies discovered that H. pylori harbours two TLR5 ligands in the Type IV secretion system (T4SS) pilus and activates TLR5 only when the pilus formed. H. pylori expresses varied LPSs on the cell surface and that found to activate TLR2, TLR4 and TLR10 in different proportion. H. pylori found to upregulate NLRP3 inflammasome components in immune cells, but activation is regulated. All the above facts show that H. pylori survival at the gastric mucosa depends on the concerted interplay of various host and bacterial factors. In this project, we are going to study the H. pylori mediated Interleukin-1β (IL-1β) expression dynamics and NLRP3 inflammasome regulation in the context of diet-derived signalling molecules (DSMs) and microbiota including probiotics. IL-1β signalling and gene polymorphisms are implicated in the development of gastric cancer. Therefore, NLRP3 inflammasome driven IL-1β secretion is of paramount importance in the H. pylori infection. Our previous studies demonstrated that H. pylori induced the first signalling or priming in NLRP3 inflammasome formation. However, it was not able to provide a second signal for critical activation of NLRP3 inflammasome in human immune cells, but application of exogenous activators relieved this inhibition. The gastric lumen is open to several environmental factors such as diet, metabolites, microbiota, passenger microbes, pollutants etc. that may have inflammasome regulating potential. This aspect of biology will be studied in our project along with the mechanistic control of IL1B mRNA expression and protein production. This is relevant in the Indian context of low prevalence of gastric cancer even with high H. pylori colonization in the population. A diet related factor has been long hypothesized for this enigma. The outcome of this project may open the possibility of therapeutic intervention on inflammation, resolution, and even gastric cancer.