Key Host Pathogen Interaction in Helicobacter Pylori

In this review, we mainly focus on persistence colonization of Helicobacter pylori in the human gut. In recent times we have come across some novel strategies used by this bacterium can be a cause of prolonged existence in human or evolution with another bacterium to optimize its existence. The equilibrium between the bacterium and human cells in response posed a great role in the persistence of the bacterium in its colonization or confer to risk it's into dysfunctional of organs leading to more severe disease like gastric adenocarcinoma, lymphoma, gastric peptic ulcers, and many more. A recently discovered novel factor is the secreted protease HtrA (high temperature requirement A), which has been shown to cleave-off the ectodomain of E-cadherin, an important cellular adhesion protein and tumour suppressor, having crucial consequences for the disturbance of epithelial barrier functions Some of the factor that are essential in the survival of the bacterium Helicobacter pylori in the human gut and leading to a number of severe diseases are:

1) Urease:

It is known that the pH of the human stomach is around 2.5. Since Helicobacter pylori is not an acidophile it is not possible for it to survives in such a harsh environment(.Eaton KA, Brooks CL, Morgan DR, Krakowka S. Essential role of urease in pathogenesis of gastritis induced by Helicobacter pylori in gnotobiotic piglets. Infect Immun 1991; 59:2470-2475 [PMID: 2050411] )

Its colonization in the gut is highly favored by urease enzyme which converts into ammonia and co2.ammonium carbonate which ultimately increases the pH of the stomach and makes for the bacterium to survive in such low ph in the periplasm, therefore, contributing in proton motive force(. Stingl K, Altendorf K, Bakker EP. Acid survival of Helicobacter pylori: how does urease activity trigger cytoplasmic pH homeostasis? Trends Microbiol 2002; 10: 70-74 [PMID:11827807 DOI: 10.1016/S0966-842X(01)02287-9])

Another mechanism via which urease leads to periplasmic buffering can be with the conversion of CO2 into bicarbonate by the action of periplasmic alpha carbonic anhydrase. (Marcus EA, Moshfegh AP, Sachs G, Scott DR. The periplasmic alpha-carbonic anhydrase activity of Helicobacter pylori is essential for acid acclimation. J Bacteriol 2005; 187: 729-738[PMID: 15629943 DOI: 10.1128/JB.187.2.729-738.2005]).

Presence of urease provides strong evidence for the persistence colonization of Helicobacter pylori in the human and perhaps can serve as a evidence that persistence of Helicobacter pylori is not found in any part of the human body since the normal pH of body is above 7. Therefore, further alkalisation of environmental pH can inhibit the growth of the Helicobacter pylori. (Factors that mediate colonization of the human stomach by Helicobacter pylori

2) Helical shape of Helicobacter pylori:

Although it ,may not seem like an inessential factor but it plays a great deal in the pathological process of the bacterium in invasion of the mucous membrane of the bacterium in the human gut. It provides a mechanistic screw-like movement helps in penetration in the epithelium. Apparently genes responsible for the bacterium morphology are as Ccrp89, Ccrp58, Ccrp1142 and Ccrp1143. any deletion or mutation may directly responsible for its colonisation. (Bansal R, Celli JP, Hardcastle JM, Turner BS. The Influence of Mucus Microstructure and Rheology in Helicobacter pylori Infection. Front Immunol 2013; 4: 310 [PMID: 24133493 DOI:10.3389/fimmu.2013.00310])

3) Cag A mediated strategy persists in Helicobacter pylori:

Cag A protein of bacterium has a site that interacts with several host kinases at the site of phosphorylation site. The phosphorylation site consists of amino acid sequence called as EPIGYA.M. Stein, F. Bagnoli, R. Halenbeck, R. Rappuoli, W.J. Fantl, A. Covacci, c-Src/Lyn kinases activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs, Mol. Microbiol. 43 (2002) 971e980 Role of Src kinases and all kinases in the persistence with the Cag A protein in H.pylori: CagA is phosphorylated by Src kinases and can subsequently interfere with intracellular signaling pathways, leading to cell proliferation, cytoskeletal rearrangement, cell-cell adhesion loss, extracellular matrix remodelling, and ß-catenin pathway activation. Based on geographical modification in the sequence of amino acid present in Cag A gene decides the variability on the pathogenicity of the gene present in the bacterium.Cag A has many other effects on epithelial cells when are bound which is it can agitate cell polarity and affects multiple host cell pathways. (Amieva MR, El-Omar EM. 2008. Host-bacterial interactions in Helicobacter pylori infection. Gastroenterology 134:306–323) Cag PAI ( Cag pathogenicity Island) is a locus on the DNA found contains about 30 genes clusters; encode the gene responsible for cagA for glutamate racemase which is believed to be a cause of horizontal gene transfer. The pathogenicity of the bacterium is highly dependent on the inflammatory response of the host cell which is dependent on the presence or absence of the pathogenicity island on the locus of DNA and severity of its outcome. For instance, cag+ can be seen to be associated with the higher ratio of peptic ulcer to gastric ulcer rather than in the individual with negative or intermediate strains of the Helicobacter pylori infections.

4) T4SS type 4 secretory system:

Cag A protein is secreted via the Type IV secretion system (T4SS) into gastric epithelial cells, where it plays a pivotal role in the etiology of Helicobacter pylori-associated gastric cancer. There are essentially 15 genes on the pathogenicity island required for the induction of T4SS, IL-8 and Cag A translocation or nucleotide-binding-oligomerization-domain(NOD1) signaling Key host-pathogen interactions for designing novel interventions against Helicobacter pylori. It is a multisubunit contact-dependent secretion system which is encoded by Cag pathogenicity island and transfers to the host’s cell. The association between T4SS and Cag A is highly linked with the severity of the immunological responses that can often lead to gastric adenocarcinoma and peptic ulceration. (Life in the human stomach: persistence strategies of the bacterial pathogen Helicobacter pylori.)

5) VacA toxin:

Another secretory protein alongside Cag A is Vac A. VacA is a pore-forming toxin that alters the cell function and alters the mitochondria function, it permeates the plasma membrane. Vac A genes are present in every strain of Helicobacter pylori but also causes each strain to possess different magnitude of the pathological process.(Kim IJ, Blanke SR. Remodeling the host environment: modulation of the gastric epithelium by the Helicobacter pylori vacuolating toxin (VacA). Front Cell Infect Microbiol. 2012; 2:37. [PubMed: 22919629] ) situated pathogenic genes can result in programmed cell death, or act as immunosuppressants meaning that they can check T-cells development. Helicobacter pylori have major antigenic determinants which are VacA and GGT (?- glutamyl transpeptidase) both the factors intervene with that dendritic cells maturation as well as suppress the activity of Treg( T-cell regulation) thereby developing toleration against T-cells.Oertli M, Noben M, Engler DB, et al. Helicobacter pylori gamma-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance. Proc Natl Acad Sci U S A. 2013; 110:3047–52. [PubMed: 23382221]

This helps Helicobacter pylori exceptional quality to resist the innate and adaptive immunity by escaping Th1 cells/ Th17 cells- polarized effector cells to adaption and influence of hosts system.Müller A, OertliM, Arnold IC (2011) H. pylori exploits and manipulates innate and adaptive immune cell signaling pathways to establish persistent infection. CellCommun Signal 9(1):25.

6) Motility:

It has been seen that possession of flagella has been a key factor in the colonization and persistence in human gut. Presence of flagellar appendages helps bacteria in motility confers endurance. Evidence from the mutant bacteria with absent flagella has affected its motility thus in its aftereffects in its host. Flagella drives it into the mucuos of host epithelium making it even easier for it to survive it in such atmosphere since Helicobacter pylori is not an acidophile it drive towards more hospitable environment that is towards mucous membrane of gastric epithelium and abundance of ammonium carbonate and neutral ph, amino acid and cholesterol via chemotactic properties.(beyond the stomach).
For full motility in the bacterium expression of two proteins are very crucial i.e., Fla A and FlaB regulated by Flh A. Any mutants with the absence in this protein may lead to variability in movement, infection and therefore, persistence. It has been found that functional of flagella is regulated by quorum sensing with the help of pheromones such as autoinducer-2 in response change in environment (.Rader BA, Campagna SR, Semmelhack MF, Bassler BL, Guillemin K. The quorum-sensing molecule autoinducer2 regulates motility and flagellar morphogenesis in Helicobacter pylori. J Bacteriol 2007; 189: 6109-6117 [PMID:17586631 DOI: 10.1128/JB.00246-07]45 ) (Shen F, Hobley L, Doherty N, Loh JT, Cover TL, Sockett RE, Hardie KR, Atherton JC. In Helicobacter pylori autoinducer-2, but not LuxS/McCabe catalyzed reverse transsulphuration, regulates motility through modulation of flagellar gene transcription. BMC Microbiol 2010; 10: 210 [PMID: 20691071DOI: ????? Further studies revealed that mutant with hyper-motile phenotype from glycosylation of elevated in Fla A protein was seen to be increased activation of NF-?B hence increased infection. (Asakura H, Churin Y, Bauer B, Boettcher JP, Bar-*tfeld S, Hashii N, Kawasaki N, Mollenkopf HJ, Jungblut PR, Brinkmann V, Meyer TF. Helicobacter pylori HP0518 affect flagellin glycosylation to alter bacterial motility. Mol Microbiol2010; 78: 1130-1144 [PMID: 21091500 DOI: 10.1111/j.1365-2958.2010.07393.x])

7) TNF-a All strains of Helicobacter pylori are believed to contain TNF-a factor which is encoded by gene Tipa gene which along with various chemokines such as NF-?B.for new genes involved in the induction of TNF-a gene expression in gastric epithelial cells and identified a new gene encoding a TNF-a inducing protein, which we named IPA. ( M. Suganuma, M. Kurusu, K. Suzuki, et al., New tumor necrosis factor-inducing protein released from Helicobacter pylori for gastric cancer progression, J. Cancer Res. Clin. Oncol. 131 (2005) 305–313. )TNF-a inducing Tip gene which in the invasion in the host body induces higher inflammation of epithelium and increases the risk of gastric cancer. Top gene is found on the Cag Pathogenicity Island. It is unique since it as no resemblance to the other secretory proteins like urease, Cag A, Vac and it is independent of T4SS as well as of CagPAI. These findings indicate that colonization of Helicobacter was made effortless leading to entering into the host's system and act upon. (M. Suganuma, K. Yamaguchi, Y. Ono, et al., TNF-a-inducing protein, a carcinogenic factor secreted by H. pylori, enters gastric cancer cells, Int. J.Cancer 123 (2008) 117–122)

8) Mandatory chemotaxis for Persistence:

Rather then infecting helicobacter pylori persists in the anatomical niche of the epithelial lumen of the human gut. The mechanism is constantly evolving with increased pathogenicity. ( Helicobacter and Salmonella persistent infection strategiesDenise M. Monack) Chemotaxis by sensing a little or ample change in pH are guiding factors in the movement of the bacterium and colonization. Proteins like Che A, CheW, CheY, and ChePep are responsible for chemotactic properties in the bacterium. Further studies also led to believe that mutant mice lack ChePep protein could colonize into the lumen while when compared to the wildtype species ?ChePep had less of the virulence on the host to the ones carrying ChePep with an enhanced sense of direction-routed infection. ( Terry K, Williams SM, Connolly L, Ottemann KM. 2005. Chemotaxis plays multiple roles during Helicobacter pylori animal infection. Infect Immun 73: 803–811.)