The cag pathogenicity island (cag PAI) of H. pylori represents one of the most potent virulence factors in GC (Sgouras et al., 2015). CagA has been found in the early 1990s and has a significant correlation with peptic ulcers and GC. H. pylori strains that possess cag PAI have a higher risk of developing gastritis and GC when compared to strains without cag PAI (Tegtmeyer et al., 2011; Haddadi et al., 2020a). H. pylori promotes the infection by attaching or adhering to the gastric epithelium of the host. Adhesions and outer membrane proteins (OMP) assist in this process (Tegtmeyer et al., 2011). The cag PAI is a 40 kb DNA insertion element. It includes 27–31 genes, including also the cagA, cagL, and cagY genes, that encode the Cag type IV secretion system (CagT4SS) proteins (Backert et al., 2015). The CagT4SS proteins seem to function as a syringe-like pilus that injects CagA in gastric epithelial cells (Tegtmeyer et al., 2011; Alfarouk et al., 2019), where CagA undergoes tyrosine phosphorylation by Src family kinases or the Abl kinase at the EPIYA motifs found in the C-terminal area (Odenbreit et al., 2000; Higashi et al., 2004; Poppe et al., 2007; Tammer et al., 2007). Thereafter, the supplied CagA binds to and activates Src homology 2-containing protein tyrosine phosphatase (SHP2) (Odenbreit et al., 2000; Higashi et al., 2004), and the CagA-deregulated SHP2 performs diverse roles, including mitogen-activated protein kinase cascade and the activation of the extracellular regulated kinase (Higashi et al., 2004). The regulation of focal adhesion kinase induces the hummingbird phenomenon, which also leads to the elongation and spreading of gastric epithelial cells (Segal et al., 1996; Tsutsumi et al., 2006; Kwok et al., 2007), regulating the inhibition of Src family kinases via stimulating the C-terminal Src kinase, which in turn generates a response regulation circle for the tyrosine phosphorylation cascade, thereby preserving gastric junctional integrity and epithelial polarity (Saadat et al., 2007; Haddadi et al., 2020b). CagA links to Crk, which induces cell scattering. Additionally, it has been demonstrated that CagA activates the nuclear factor of activated T cells by boosting calcineurin, irrespective of its phosphorylation condition (Yokoyama et al., 2005). CagA inhibits cell–cell adherence regardless of CagA tyrosine phosphorylation by breaking tight junctions and inducing a cell’s loss of polarity through suppressing the PAR1/MARK polarity-regulating kinase (Saadat et al., 2007). H. pylori acquire access to epidermal growth factor receptors (EGFR) and Her2/Neu by interrupting the tight junctions at the basolateral membrane, which might also enable cell injury and mucosal ulceration (Alzahrani et al., 2014). Additionally, within the cell line of human GC, the CagA–SHP2 complex induces cell elongation by extending the activation of ERK and removing phosphate groups from focal adhesion kinase (FAK). FAK plays a role in the processes of cell adhesion and cell migration (Tsutsumi et al., 2006). CagA has been shown to disrupt the E-cadherin–-catenin complex, leading to β-catenin signal activation (Franco et al., 2005). Each of the following mechanisms of CagA potentially contribute to the progression of GC by creating an environment conducive to the neoplastic transformation of epithelial cells (Figure 1) (Chiba et al., 2008).

All H. pylori isolates release Vacuolation cytotoxin A (VacA) through the type V secretion pathway, which is the main toxin protein that leads to vacuolation once within the cell (Sheu et al., 2003). VacA is an 88 kDa protein composed of the subunits p33 and p55. The p33 (N-terminal, 33 kDa) section creates an inner chloride transport channel, whereas the p55 (C-terminal, 55 kDa) region is essential for toxin adherence to host cells (Boquet and Ricci, 2012). VacA has multiple biological functions. It attaches to host cells and is internalized, resulting in a severe “vacuolation” defined by a collection of giant vesicles exhibiting characteristics of both late endosomes and early lysosomes. It is suggested that this effect is caused by the introduction of VacA channels that selectively allow anions to pass through cell membranes. These channels promote the influx of chloride ions, elevating the concentration of intraluminal chloride. Consequently, this triggers osmotic swelling and the subsequent formation of vacuoles within the cytoplasm of gastric cells. In addition to its vacuolating impacts, it has recently been proven that VacA directly influences mitochondrial function, impedes T-cell proliferation, and induces apoptosis (Rassow and Meinecke, 2012). Stimulation of dynamin-related protein 1 (DRP1) could play a crucial role in VacA-induced mitochondrial disturbance, as the inhibition of DRP1-dependent mitochondrial fission in VacA-intoxicated cells obstructed Bax activation and mitochondrial outer membrane permeabilization (MOMP) and helped prevent death of intoxicated cells (Jain et al., 2011). VacA also could impair the epithelial cells’ tight junctions and inhibit T lymphocyte proliferation and activation in the lamina propria. Autophagy disruption is an additional method through which VacA promotes gastric inflammation (Palframan et al., 2012; Raju et al., 2012). This disruption permits H. pylori to successfully escape the immune system, remain as a chronic infection (Sundrud et al., 2004), and contribute to the development of GC (Palframan et al., 2012; Raju et al., 2012). The existence of vacA genotypes strongly predicted the degree of virulence of cagA-positive H. pylori strains. According to a South East Asian meta-analysis, the vacA s1 allele is commonly detected in cagA H. pylori from East Asia and Western Europe and is linked to the improvement of peptic ulcers (Alzahrani et al., 2014).

H. pylori serine protease high-temperature requirement A (HtrA) is an extremely active protein under severe conditions that destroys misfolded proteins in the bacterial periplasm, consequently enhancing bacterial survival in challenging situations (Hoy et al., 2013). Experimental in vitro infection demonstrated that the HtrA protein cleaves the extracellular domain of E-cadherin, resulting in the disruption of cell junctions in polarized cell monolayers (Hoy et al., 2010). Multiple investigations have identified the H. pylori HtrA protein as an E-cadherin-targeting protease that actively catalyzes the breakdown of the extracellular domain of E-cadherin, thereby breaking cell–cell adhesion and promoting the development of cancer (Hoy et al., 2012; Schmidt et al., 2016a,b; Tegtmeyer et al., 2016).

Blood group antigen-binding adhesin (BabA) is a protein located in the outer membrane of H. pylori. It specifically recognizes Lewis b blood group antigens (Leb) present on the gastric epithelial cells of the host. The presence of BabA in H. pylori strains appears to contribute to increased virulence and a higher likelihood of successful bacterial colonization (Chang et al., 2018). While three alleles of Bab (BabA1, BabA2, and BabB) have been identified, attachment to Leb requires just the BabA2 genotype (Roesler et al., 2014). BabA binds to host epithelial cells to facilitate the translocation of CagA through into host cell by T4SS (Kable et al., 2017). The expression of CagA, VacA, and BabA2 increases the degree of H. pylori infection because these virulence factors operate synchronously. This finding will result in a more intense inflammatory response and an increased risk for GC (Roesler et al., 2014). According to a meta-analysis of case–control studies, babA2 genopositive status is associated with an increased risk of PUD (OR = 2.07) in Western nations but not in Asian ones (Chen et al., 2013).

The significance of sialic acid binding adhesin (SabA), a new outer membrane protein, in the pathophysiology of gastroduodenal disease is becoming more apparent. During the initial phase of infection, the binding of blood group antigen-binding adhesin (BabA) to Lewis b antigen and related fucosylated ABO blood group antigens is likely crucial. Throughout an inflammatory response by the host, there is increased expression of Sialyl-Lewis X, which, in conjunction with SabA, enables a greater adherence of H. pylori to the gastric mucosa (Yoshio, 2008). It has been shown that SabA production is linked to severe intestinal metaplasia, gastric atrophy, and the onset of GC in both industrialized and developing nations; this finding highlights the need for further study of SabA in the latter (Yoshio, 2008). Furthermore, SabA can mimic selectin to activate the neutrophils. This activation leads to the production of reactive oxygen species (ROS), which further enhances the prolongation of the inflammatory response (Unemo et al., 2005). Multiple roles for gamma-glutamyl transpeptidase (GGT) have been established. H. pylori colonization of the gastric mucosa is facilitated, and apoptosis of gastric epithelial cells is induced. Additionally, H. pylori GGT suppress T-cell-mediated immunity and dendritic cell growth and differentiation, hence inducing immunological tolerance. H. pylori carries GGT in its outer membrane vesicles. Increased levels of H₂O₂ and Il-8 synthesis in gastric epithelial cells have been linked to this condition (Gong et al., 2010).

The outer membrane proteins of H. pylori [HomB, HopQ, and HopH (OipA)] are linked to the development of GC (Cover, 2016; Braga et al., 2019). No receptor for outer inflammatory protein antigen (OipA) has been discovered (Posselt et al., 2013). OipA, which is encoded by the HopH gene, is an outer membrane protein associated with inflammation. The inflammatory response caused by OipA positive H. pylori strains is greater than that caused by OipA negative strains. This finding raises the probability of developing GC and gastric ulcer disease (Zhang et al., 2014). Patients with precancerous gastric lesions are more likely than individuals with simple gastritis to have OipA in their gastric biopsies (Baj et al., 2021). Furthermore, the Bcl-2 pathway is involved in the apoptotic cascade activation upon OipA binding to gastric cells (Teymournejad et al., 2017). Several proinflammatory cytokines, including IL-6, IL-8, and, IL-1, are believed to be stimulated by OipA. Increased GC risk is a result of its effect on IL-10 secretion and dendritic cell maturation (Teymournejad et al., 2014). The OipA “on,” but not “off,” state has also been observed to be strongly associated with an increased risk of PUD (OR = 3.97) and GC (OR = 2.43), particularly in Western nations, according to a meta-analysis (Liu et al., 2013).

In the adaptability zone of H. pylori, a new gene that is highly homologous to the virB4 gene, named duodenal ulcer stimulating gene A (dupA), has been discovered. Recent evidence indicates that dupA is part of a novel cluster of vir homolog genes expected to generate a new T4SS that contributes to the emergence of H. pylori-related pathologies (Yamaoka, 2008; Fischer et al., 2010). Lu et al. found that infection with dupA-positive strains was substantially linked with duodenal ulcers but inversely correlated with GC after screening 500 H. pylori strains collected from patients in Colombia, Japan, and South Korea (Lu et al., 2005). Even though other studies have not clarified those same research results with dupA, they are particularly appealing considering that other recommended H. pylori virulence genes have also been linked to both GC and ulcer disease, while patients with duodenal ulcers contradictory have a lower risk of developing GC (Hansson et al., 1996). Table 1 summarizes all virulence factors and their role in GC.

A link between a variant of the TLR1 genetic locus (4p14) and H. pylori seroprevalence was found in a meta-analysis conducted in Europe. The observed difference in each person’s susceptibility for H. pylori infection may be partially explained, if verified, by genetic polymorphisms in TLR1. This finding may also support the idea that H. pylori-related carcinogenesis and genetic polymorphisms of TLRs are related (Mayerle et al., 2013). However, research has identified single-nucleotide polymorphisms (SNPs) of TLRs and their associations with the emergence of GC. Lipoarabinomannan (LAM), peptidoglycans, and bacterial lipoproteins all function as signal-transducing receptors through TLR2.

TLR2 was crucial for the release of the pro-inflammatory cytokines IL-1 and IL-6 as well (Obonyo et al., 2007). The promoter activity of TLR2 may be impacted by a polymorphism in TLR2 between positions 196 and 174 caused by a 22-bp deletion. TLR2-196 to -174del polymorphism and the onset of GC were found to be positively correlated in studies from Brazil and Japan, but studies from China and Japan found the link to be negatively correlated (Hishida et al., 2010; Zeng et al., 2011). The results of the other Chinese study showed that neither H. pylori infection nor poor prognoses are linked to TLR2 polymorphism and that the del/del genotype is related to an elevated risk of GC in the southern Chinese population (Huang et al., 2019). The risk of all malignancies increased from −196 to −174del, according to a meta-analysis by Gao et al. (2019).

TLR4 is normally found in the gastric mucosa and epithelial cells in two distinct parts: the apical and basolateral compartments. In GC tissues, TLR4 expression is increased, leading to enhanced responsiveness to lipopolysaccharide (LPS) from H. pylori. This increased response activates the NF-κB pathway and promotes the activation of the IL-8 promoter. TLR4 is highly polarized and expressed in the apical and basolateral compartments of normal gastric mucosa and gastric epithelial cells. In GC tissues, TLR4 expression is increased, and this confers LPS responsiveness, which enhances the activation of the NF- κB and IL-8 promoters in response to stimulation with H. pylori LPS. When LPS binds to TLR4 in gastric epithelial cells, TLR4 signaling is activated, which leads to the production of inflammatory mediators including IL-8 and TNF-α, which are essential for the progression of tumor. Studies have revealed that TLR4 is overexpressed in gastric epithelia and that it is also elevated in the monocytes and macrophages of superficial gastritis in cases of GC (Figure 2) (Ito et al., 2020). According to a new study, H. pylori attaches to human annexins using LPS in order to prevent TLR4 signaling (Schmidinger et al., 2022). TLR4 polymorphism (Asp299Gly) can reduce responsiveness to H. pylori-LPS by lowering the affinity of bacterial ligands for binding. These modifications may contribute to the development of long-lasting infections, following chronic inflammation, and cancer. There are contradictions in the relationship between the incidence of GC and TLR4 polymorphism. According to the findings of a Japanese investigation, the TLR4 + 3,725 G/C polymorphism was a risk factor for severe gastric atrophy in Japanese people who were seropositive for H. pylori. The relevance of the differences in host innate immunity caused by TLR4 polymorphism as genetic predispositions to gastric precancerous lesions in Eastern Asian groups with similar backgrounds was highlighted by these results (Hishida et al., 2009). Another Japanese investigation found that having the TLR4 + 3,725 C allele and the miR-146a rs2910164 G/G variant together improved the likelihood of severe gastric atrophy in H. pylori-infected Japanese participants (Hishida et al., 2011). The correlation between the TLR4 Asp299Gly and TLR2-196 to -174del polymorphism and the likelihood of developing GC was also supported by a study from China (Castaño-Rodríguez et al., 2013). TRL4 gene variants, however, were not connected to gastric carcinogenesis in Caucasians, indicating that this gene variant should not be used as a potential biomarker to identify people at higher risk of developing GC (Kupcinskas et al., 2011).

Despite the fact that H. pylori flagellin has been proposed as a TLR5 ligand, its activity as a TLR5 activator is modest, indicating a potential mechanism that contributes to H. pylori persistence (Lee et al., 2003; Smith et al., 2003; Gewirtz et al., 2004). Through an ERK-dependent mechanism, flagellin-activated TLR5 increases the proliferation of GC cells (Song et al., 2011). Due to its tendency to interfere with ligand recognition, the TLR5rs5744174 polymorphism has also been linked to an increased risk of gastric carcinogenesis in Chinese patients, allowing H. pylori to survive in the stomach (Zeng et al., 2011). Two more TLR5 polymorphisms (rs1640827 and rs17163737), according to a recent Chinese study, were linked to H. pylori infection and a high risk of GC (Xu et al., 2017). In intracellular vesicles such the endosome, lysosome, and endoplasmic reticulum, TLR3, TLR7, TLR8, and TLR9 are present. They play a major role in the identification of microbial nucleic acids (Kawai and Akira, 2009; Kawai and Akira, 2011).

TLR8 on dendritic cells, which is endosomally localized, may detect the RNA of H. pylori. TLR9 can be activated by an inflammatory milieu that comprises cells without polarity, promoting proinflammatory cascades that ultimately lead to the development of GC (Schmaußer et al., 2004; Wang et al., 2014). One study found that H. pylori’s specific TLR-9 activation is dependent on the cag T4SS but not on virD4 coupling proteins or virD2 relaxases (Tegtmeyer et al., 2022). As the only receptor with dual pro-and anti-inflammatory functions, TLR9 plays a dichotomous role. The microenvironment, particularly the presence of H. pylori, affects its function (Meliț et al., 2019). A functional receptor called TLR10 participates in the innate immune reaction to H. pylori infection (Nagashima et al., 2015). The TLR10 rs10004195 polymorphism may be important for gastric pathophysiology and H. pylori susceptibility (Tongtawee et al., 2018). Discovering diagnostic/predictive biomarkers and therapeutic targets for GC needs to be the subject of further studies on the regulation of TLRs in H. pylori-associated gastric carcinogenesis.

According to Iqra Jan et al., H. pylori infection enhances IL-6, IL-10, and TGF-b in the physical excursion, even though the critical function of the cytokine to signal in the induction of epigenetic corrections within GC is yet unclear. Although IL-1 and IL-6 help overactivate the JAK/STAT passage, H. pylori infection causes the disablement of the inhibitor of cytokine signaling one (CS1) gene between the promoter’s amazing methylation and the promoter’s area. Furthermore, H. pylori-mediated epigenetic turn of CS1 within harmony by the over-activation of the inflammatory cytokines group of the JAK/STAT passage on GC (Sheh et al., 2010). Predictive models for virulence gene play a significant role in clinical consequences. In other words, cytotoxin-associated gene A (cagA) and phosphor glucosamine mutase gene (glmM) are the critical genes in the H. pylori pathogenicity pathway (Torres et al., 1998; Beevers et al., 2004; Šebunova et al., 2018).

Several immune cells including macrophages, monocytes, mast cells, neutrophils, Th17, Th2, and Th1 produce the cytokines in H. pylori-induced GC. For example, TNF-a, TGF-b, IFN-g, CXCL12, CXCL4, IL-10, IL-17, IL-23, IL-1, IL-2, and IL-6 cytokines are secreted in widespread blood circulation (Vorobjova et al., 1998; Niu et al., 2020). Gastric epithelial cells have many specific membrane receptors that pass on the signal conveyed through various cytokines inside the cell (Zhuang et al., 2012). The cytokine’s role in different types of cells is their attachment to related membrane receivers and their adjustment of downstream factors to signal cascade (Bockerstett and DiPaolo, 2017). Multiplex cytokines stimulate Janus kinase 2 (JAK2) and lead to the signal phosphorylate converter. Furthermore, these cytokine activators of transcription 3 (STAT3) such as phosphorylated STAT3 enter the nucleic acid regulatory sequences and leads to GC development (Pandey et al., 2018). The suppressor of cytokine signaling-1 (SOCS1), reacting to phosphoserine, acts within the JAK kinase pathway to regulate the stimulation of STAT proteins or another signaling transitional intermediates in the JAK/STAT signaling cascade. Furthermore, the SOCS1 has been suggested to be in charge of GC. IL6 and TFGb are essential for controlling the expression of SOCS1.

According to Kosuke Sakitani et al., the real-time RT-PCR results in vitro show that H. pylori increase protein expression in infectious stomach cells. Next, in a time-dependent procedure, the Western blotting analysis showed that H. pylori induced interleukin-32 in the GC cell lines (Censini et al., 1996). IL-1 and TNF-α have been introduced to highly induce IL-32 in a few cell lines (Bockerstett and DiPaolo, 2017).

According to research, cytokines produced by epithelial cells, particularly IL-33, play a role in the development of GC. IL-33 is expressed in gastric epithelium, specifically in surface mucous cells. It binds to ST2 (IL1RL1) receptor and activates the NF-kB and MAPK signaling pathways through its subsidiary protein IL-1RAP. In a study by Bockerstett et al., inflammation, atrophy, and metaplasia in the fundus of the stomach were induced via an IL-13-dependent mechanism. IL-6 and IL-11, members of the IL-6 family of cytokines, along with gp130 signaling, were found to be connected to JAK–STAT signaling pathways and contributed to atrophic gastritis. Additionally, cytokines from the IL-12 family, particularly IL-23, were observed to be altered in GC patients. It should be noted that gp130 signaling is frequently disrupted in GC. These discoveries have highlighted the significance of IL-33, IL-11, and other cytokines in GC (Bockerstett and DiPaolo, 2017).

The mechanism of H. pylori for the induction of pro-inflammatory cytokines is presumed to be the outer membrane adhesion proteins such as OipA and BabA, which induced IL-6 to IL-11 production via elimination; however, the mechanism is unclear (Sugimoto et al., 2011). One of the immunosuppression T-cell stimulation permits the durability of the bacterial infection. Finally, NF-B stimulates by targeting T-cells (Takeshima et al., 2009). The CagA2 duty offers a position in NF-B and IL-8 activation (Backert and Naumann, 2010). Although CagA does not show to be the leading player in H. pylori-induced IL-12 generation, it exclusively seems to be a H. pylori strain (Viala et al., 2004). Furthermore, stimulating cytokine rescue, H. pylori motivates the generation of growth elements, for example, granulocyte-macrophage colony-stimulating factor (GM-CSF) and oxygen/nitrogen species (ROS/RNS) cyclooxygenase-2 (COX-2). H. pylori-induced GC and persuadable nitric oxide synthase (iNOS) generate prostaglandin E2 and nitric oxide (Cho et al., 2010). LPS of H. pylori plays a prominent role in transforming iNOS, leading to an increased NO release (Cavallo et al., 2011). No synthesis can be regulated between host arginase and H. pylori arginases II (Gobert et al., 2011). In culture, H. pylori sound waves influenced oxidative bursts from neutrophils and monocytes (Hansen et al., 1999; Marta et al., 2020). HP-NAP induces ROS release from neutrophils and promotes recruitment of other leukocytes to the site of infection by stimulating the production of chemokines such as CXCL8, CCL3, and CCL4 (Dundon et al., 2002).

NF-κB is the primary regulator in the inflammatory response and adjusts many cellular proceedings necessary in H. pylori-induced GC (Figure 3) (Orlowski and Baldwin, 2002). Various pro-inflammatory triggers can activate NF-κB, including TLR activation with pathogens generated by cytokines through both common and non-common pathways (Hayden and Ghosh, 2008). In the common pathway, the different ligands bind to receptors causing the stimulation of the IB kinase (IKK), which contains IKK, and NEMO/IKK. This kinase mixes phosphorylates and destroys the suppressor of IB, ultimately leading to cell growth (Chen and Greene, 2004).

In the uncommon pathway, this signal from receptors causes the activation of NF-κB inducing kinase (NK) and IKK, which, in turn, phosphorylates p100 and converts it into p52. Then H. pylori infection activates NF-κB in both pathways (Lamb and Chen, 2010; Sun, 2011). Through the common pathway, NF-κB is activated. However, in immune cells, such as B-lymphocytes, H. pylori infection stimulates NF-κB, and the connector was challenging to remove and appears too plentiful. The host cells banded to TLR2 or TLR4 are recognized by H. pylori LPS, and then H. pylori induces NF-κB stimulation and inflammatory response (Evans et al., 1995). According to Mandell et al. (2004), not only was H. pylori LPS a very weak activator of TLRs but it also aids the bacteria’s sustainability and has a low-degree inflammation through the stomach (Mandell et al., 2004). Despite this finding, H. pylori LPS could be significant in activating inflammatory pathways in leukocytes, responding to bacterial colonization. According to previous investigations, macrophages and monocytes illustrate the value of TLRs in gastric epithelial cells (Maeda et al., 2001; Obonyo et al., 2007). Peptidoglycan in H. pylori was an effective molecule identified by stomach epithelial cells and nucleotide oligomerization domain 1(NOD1) (Grubman et al., 2010). Then, NOD1 signaling activates MAPKs. In conclusion, inflammatory cytokines, such as IL-32 and IL-8, can be useful for drug treatment. The investigation of gene-targeted mice showed that Th1 cytokines drawback GC induced by H. pylori (Smythies et al., 2000). The H. pylori -induced GC discharged peptidyl-prolyl cis (Kumar et al., 2021). Table 2 summarizes all host factors and their role in GC.

Bacterial colonization is not possible in the stomach lumen because of its acidic pH. As a result, the lower bowl, which has a normal or slightly alkaline pH, has the largest bacterial population. The production of gastric acid in the stomach results in a pH of 1–2, which inhibits bacterial colonization in this area (Sr et al., 2005; Schreiber et al., 2006). To prevent bacterial infection, the mucous membrane layer of the stomach works as a physical barrier against bacterial invasion and accumulates host antimicrobials. In gastric lumen, mucins transform to a gel state at low pH (Rawla and Barsouk, 2019; Alipour, 2021), which traps bacteria (Celli et al., 2009) H. pylori produces urease to alter acidity and reduce mucus concentration by ammonium ions. Therefore, suitable conditions are provided for the entry of H. pylori (Sidebotham et al., 2003). These situations emphasize the importance of H. pylori in managing its interaction with lumen gastric lumen epithelium until it is able to evade the host immune system defense and stay alive in this condition (Suarez et al., 2006).

The initial attachment of H. pylori to surface receptors on the host gastric epithelial cell is the most crucial event in the development of cancer. Cag A and Vac A, the two important protein toxins that are expressed by pathogenicity island (PAI), are essential for bacterial maintenance and entrance through gastric lumen (Nejati et al., 2018). Cag A is phosphorylated after entering the cell, causing cell proliferation as well as the destruction of strong connections between the adjacent cells (Talebkhan et al., 2008). The presence of Cag A increases the risk of peptic ulcers or GC by 50–70% (Al-Ghoul et al., 2004). Cag A-positive bacteria strains have been highly linked to an increased risk of GC in recent years (Ghotaslou et al., 2018). VacA is actually a toxin that causes cavities in cell membranes that cause vacuoles to form in the cell, and H. pylori damages the host cell with the help of this toxin. All strains of H. pylori have the vacA gene, of which only 50–60% show cytotoxic activity (Soleimani et al., 2016). This factor stimulates vacuole production and ultimately causes cell death through apoptosis (Nejati et al., 2018). VacA also increases the permeability of epithelial cells, which provides nutrients for bacterial growth. This toxin causes erosion of the epithelial cells (Wang et al., 2008).

Given that many pathogens cause the survival of H. pylori, the main factor is that H. pylori impair innate immune responses. Important barriers that can be said to escape H. pylori from the immune system include mucus secreted by epithelial cells and innate immune cells (Chmiela et al., 2017). The recognition of conserved pathogen-related molecular patterns (PAMPs) by pattern recognition receptors on epithelial and innate immunity cells in lamina propria of gastric lumen begins with immunological responses against H. pylori, which are subsequently followed by adaptive immune responses (Fukata and Abreu, 2009; Mogensen, 2009). Innate immunity in eukaryotes is known as the first line of defense against infections. The main categories of PPRs that identify PAMPs are TLRs-like receptors. Bacterial LPS, peptidoglycans, lipoproteins, lipoic acid, and CpG-rich regions not methylated from DNA are the main targets of TLRs (Takeda and Akira, 2004). Adaptor proteins are activated by TLRs, which then activate nuclear factor NF-κB, interferon regulatory factor (IRF), and activator protein-1 (AP-1). The release of inflammatory cytokines and chemokines, as well as INF-α and INF-β, is triggered when these transcription factors are activated (Kawasaki and Kawai, 2014). TLRs are unable to recognize H. pylori due to a variety of PRRs that are required to identify other Gram-negative gut infections (Peek et al., 2010).

In the immunological response to H. pylori, CD 4+ T cells are more important than CD8 T cells as adaptive immune factor cells. H. pylori infection has been associated with CD4 + T cell subsets such as Th1, Th17 and (regulatory T cells) Tregs. Th1 cell activation causes the production of interferon alpha and gamma; Th7 cells also activate interleukins 17, 22, and 21 (Bagheri et al., 2018). The neutrophil-activated protein H. pylori (HP-NAP) causes neutrophils and monocytes to generate IL-12, which boosts Th1 responses and increases the production of interferon-gamma (Amedei et al., 2014). Th17 cells appear to be critical for H. pylori clearance by attracting neutrophils (Luzza et al., 2000). One of the causes of H. pylori infection is that the responses of the effective T cells are mainly disrupted during the infection, leading to a low response of the T cells. T cell proliferation is inhibited by VacA in two ways; first, Vac A interacts with an unknown receptor on T cells, which inhibits cell growth by rearranging actin. Second, Vac A attaches to mitochondria and cause apoptosis and inhibits T-cell growth through this route (Abadi, 2017). The extraordinary induction of Tregs by microbial antigens could be a way for H. pylori to evade the immune system (Oertli et al., 2013). Tregs, which are defined by the expression of transcription factor FOXP3, CD25, and the production of IL-10, may modulate the gastric mucosal inflammatory response to H. pylori. Other T cell’s cytokine production and proliferation can be suppressed by Tregs (Algood and Cover, 2006).