CagA VagA toxins are released and remain attached to

CagA Pathogenicity Island is a region in the Hpylori genome consisting of 40kb.

It consist of 31 potential coding regionwhich are homologous to genes of other bacteria species and encodes fordifferent types of Type IV Secretary Systems (T4SS)12656466. This T4SS is very important in the attainment ofvirulence by H pylori because the translocation of CagA proteins, peptidoglycanand other bacteria factors into the host cells is dependent on some of itscomponents which form syringe-like structures67682169. Some of these T4SS components also confervirulence through the modulation of host immune responses to suite bacterialpersisting hence augmenting host inflammatory responses.1.

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5.1.1. CagAgeneCagA gene is a gene that encodes for a 140kDa CagAprotein and it acts a marker for Cagpai. H pylori strains are known to be CagA-(no CagA PI) which are less virulent and the more virulent CagA+ strain (withcagpai). Once injected into the host cells, host cell kinases phosphorylatesthe tyrosine residues of these cagA protein which then interact with hostproteins responsible for cell growth, cell motility and cell polarity hencecausing morphological and hence functional changes of the epithelial cells69. This interaction between cagA and host proteinsis achieved by cagA phosphorylation dependent and phosphorylation-independentmechanisms316320.

Phosphorylated cagA protein also stimulates increaseIL-8 expression, a pro-inflammatory cytokine resulting in pronounceinflammatory response and cytoskeletal rearrangement which may lead to gastriccancer7071. 1.5.1.2. VagA gene.H pylori vagA gene found in almost all strains  with a high degree of allelic diversity encodesfor the vagA vacuolating cytotoxin, a 95kDa protein which is highly immunogenicand stimulates enormous vacuolation in epithelial cells in vitro727374. Upon entry into the host cell, the VagA toxinsare released and remain attached to the host cell surface receptors where theyengage in the formation of membrane channels, endosomal disruption,interference of cytoskeleton dependent cell functions, induction of apoptosisand modification of host immune responses7576.

These membrane channels causes the release of urea,anions, nutrients and cations from host cell hence disrupting cell integrityand contributing to the pathogenesis of peptic ulcer diseases7778.1.5.1.3.  Duodenalulcer promoting gene (dupA)dupA gene located in the plasticity region of Hpylori genome encodes for the dupA protein, a virulence factor which has beenfound to be associated with increase expression levels of IL-8 and other CD14+mononuclear pro-inflammatory cytokines such as IL-12p40, IL-12p70 and IL-2379808182.

These observation suggests the involvement of thedupA gene in gastric inflammation. There are controversial studies about thedupA involvement H pylori pathogenesis and it has been attributed to thediversity of the dupA and the fact that many studies failed to consider vir genesadjacent to the dupA which is also needed for its function 79. More studies is needed for the characterisationthis virulence factor.1.5.

1.4.Inducedby contact with epithelial geneIt consist of a virulent iceA1 and and virulent iceA2allelic variants. IceA1 are upregulated upon H pylori contact with gastricepithelial cells and it encodes for a CTAG- specific restriction endonuclease,a homologue of nlaIIIR which a Neisseria lactamica gene8382. Some studies showed the association of iceA1 withpeptic ulcer diseases and increase stimulation of IL-88485. Its action is independent of vagA and cagA levelsbut the role of its endonuclease activities is yet to be established.1.

5.2.      H pylori Enzymes.1.5.2.1.

Urease In order to successfully colonise and persist inthe stomach mucosa, H pylori produces urease, an enzyme which hydrolysis ureato ammonia and carbon dioxide. The excess ammonia produced buffers the acidic pHof the stomach and also forms carcinogenic agents together with neutrophilsmetabolites, a potential cause of gastric cancers86878889. Urease also induces inflammation through theproduction of pro-inflammatory cytokines and the recruitments of neutrophilsand monocytes in the stomach mucosa90. 1.5.2.2.

Catalase. Catalase is an enzyme with a recyclable oxidizablemethionine residue used to quench the oxidant hydrogen peroxide. H pyloriproduces catalase as a defence tragedy against host mediated oxidative stress andother harmful oxidants through this recyclable methionine hence increasingcolonization and persistence91.

1.5.3.     Lipopolysaccharide. Lipopolysaccharidesexpressed on the surface of H pylori aids in immune evasion and subsequentcolonisation of the host due to the presence of fucosylated oligosaccharideantigen (bacterial Lewis antigen) on its O-specific chain92. This bacterial Lewis is known to act as a mimicto the closely related human Lewis antigen hence causing persistence andpossible autoimmune responses leading to increase virulence12.  1.

5.4.     HOPs AdhesinsIn order to obtain stability against mucosalmoulting in the gastric lumen, H pylori expresses various types of outermembrane proteins known as Hop adhesins which have specific receptors on thesurface of gastric epithelial cells.

These adhesins are not only implicated inattachment but helps the bacterium to have good access to nutrients releasedfrom damaged epithelial cells69. 1.5.

4.1. Sialic acid-binding adhesion (SabAAdhesin)SabA is a 70kDa adhesion protein which bindssialylated dimeric lewis x antigen through a selection-mimicry mechanism on thesurface of mucosa epithelial cells826993. Sialylation of lewis antigen to sialylated lewisantigen x is known to occurs increasingly during chronic tissue inflammationand carcinomas, suggesting the role of SabA in these disease states andmaintenance of colonisation9495.

Sialylated carbohydrates are also found on thesurface of granulocytes which binds SabA leading to oxidative stress on thecells96. Moreso, SabA is also implicated in haemagglutination through its binding to siLex a ntigens on the surface of redblood cells961.5.4.2.Outer membrane inflammatoryproteins (OipA)OipA also known as HopH is a 34kDa protein with apro-inflammatory function achieved through the phosphorylation of cagPAIassociated signalling pathways6421. Its function was evident as increase mucosa IL-8expression rate together with enormous neutrophils infiltration were observedto be concomitant with OipA.

More so, 70% of chronic gastritis cases were foundharbouring this protein as compared to 95.5% of duodenal cancer cases82