H. pylori, a Gram-negative, microaerophilic, helical bacterium, is considered one of the most successful human pathogens (Camilo et al., 2017). Recent data indicates a global H. pylori prevalence of approximately 43.1% between 2011 and 2022 (Li et al., 2023), with a slightly higher infection rate of 44.2% in China (Ren et al., 2022), surpassing the global average. Infection typically occurs in early childhood, with a global pediatric infection rate of 32.3% (Kalach et al., 2017). Despite eliciting strong innate and adaptive immune responses in hosts, H. pylori persists, inducing chronic inflammation that can lead to gastritis, peptic ulcers, and malignancies such as mucosa-associated lymphoid tissue (MALT) lymphomas and gastric adenocarcinomas (Baj et al., 2021; Yang and Hu, 2022). Chronic gastritis, often asymptomatic, is predominantly caused by H. pylori infection, which is also a principal cause of gastric and duodenal ulcers. Notably, H. pylori infection is a major independent risk factor for gastric cancer, with approximately 1-2% of those infected progressing to cancer. Gastric cancer is currently the sixth most common cancer and the fourth leading cause of cancer-related deaths globally, posing a significant health threat (Salvatori et al., 2023).

H. pylori maintains a stable presence in specific ecological niches within the stomach, a capability intricately linked to its array of virulence factors. Urease activity disrupts the gastric acid barrier, facilitating survival in acidic conditions (Stingl et al., 2002). H. pylori’s motility, mediated by its flagella (Gu, 2017), further promotes colonization on the gastric mucosal surface. Outer membrane proteins like BabA, SabA, AlpA/B, and OipA, along with lipopolysaccharides (LPS), mediate adherence to gastric epithelial cells (Tshibangu-Kabamba and Yamaoka, 2021; Valkonen et al., 1994), contributing to colonization and pathogenesis. The vacuolating cytotoxin A (VacA) disrupts cellular integrity by inducing vacuole formation, while the high-temperature requirement A protease (HtrA) cleaves key intercellular adhesion proteins like E-cadherin, occluding and claudin-8, impairing epithelial barrier functions (Ansari and Yamaoka, 2020; Albrecht et al., 2018). Notably, Cag pathogenicity island (PAI)-encoded virulence factor CagA manipulates signaling pathways such as ERK/MAPK, NF-KB, leading to pathologic alterations in cell morphology, adhesion, polarity, proliferation, and motility (Wang et al., 2023). Additionally, the presence of CagA-positive H. pylori infection has been closely associated with the severity of gastric cancer and adverse clinical outcomes in affected patients (Parsonnet et al., 1997). Host factors including environmental influences and genetic polymorphisms may also augment H. pylori’s colonization efficiency and susceptibility to related diseases. The traditional quadruple therapy, including proton pump inhibitors, amoxicillin, clarithromycin, and bismuth agents, has long been recommended as the first-line treatment for global H. pylori eradication (Lu et al., 2023). However, rising antibiotic resistance has reduced eradication rates, with recent rates falling below 80% in many countries (Tshibangu-Kabamba and Yamaoka, 2021), necessitating the development of novel therapeutic strategies.

H. pylori infection presents a significant clinical challenge, as this bacterium can establish persistent colonization within the host despite a robust immune response, leading to a reduced eradication success rate in patients (Karkhah et al., 2019). Existing studies have revealed strategies employed by H. pylori to evade the host’s immune system through specific molecular mechanisms, but a comprehensive understanding of these mechanisms is still limited, especially in terms of how they are precisely regulated to adapt to different host environments. Furthermore, the mechanisms by which host genetic and physiological factors influence the immune evasion response of H. pylori remain unclear and warrant further investigation. Multiple potential therapeutic targets have been identified in the mechanisms of H. pylori ‘s evasion of immune responses. Additionally, vaccines targeting H. pylori have shown promising results in preclinical trials, with these vaccines preventing infection by activating and modulating immune cell phenotypes, demonstrating significant potential for future development (Friedrich and Gerhard, 2023). This review will explore the strategies employed by H. pylori to manipulate the host’s immune system for chronic colonization ( Figure 1 ), and emphasize the importance of new therapeutic strategies and H. pylori vaccines targeting these mechanisms.

The gastric cavity possesses an extremely acidic pH (typically between 1 to 2), which is not an ideal environment for bacterial colonization (Ramsay and Carr, 2011). Additionally, the gastric mucosal layer serves as a physical barrier that not only prevents bacterial penetration into deeper tissues but also entraps antimicrobial compounds within the host, thereby enhancing resistance to bacterial infections (Shimizu et al., 1996). Therefore, H. pylori ‘s initial colonization in the stomach relies on its urease activity and motility to buffer its cytoplasm and escape from the gastric lumen into the mucous layer, reaching a more favorable environment with a higher pH (Table 1).

The urease produced by H. pylori hydrolyzes urea present in the stomach into ammonia and carbon dioxide. The ammonia neutralizes gastric acid, forming ammonium ions, thereby providing a more neutral microenvironment conducive to bacterial survival (Stingl et al., 2002). This helps mitigate the direct bactericidal effect of gastric acid. Furthermore, increased functional urease activity (urease B) and the production of ammonia disrupt the cellular cytoskeleton-mediated tight junctions by regulating the phosphorylation of myosin light chain (MLC) and endocytosis of the tight junction protein occluding, leading to enlarged intercellular spaces (Wroblewski et al., 2009). This allows harmful substances in the gastric fluid to penetrate further into the gastric wall tissue. Gastric mucins have physiologically relevant sol and gel properties. In the acidic environment of the stomach, mucins typically form a gel-like state that effectively captures bacteria. However, in the presence of urease activity, the pH increases, subsequently decreasing the viscosity of the mucins and enabling bacteria to move within the mucous layer (Celli et al., 2009; Celli et al., 2005). Although the primary function of urease in H. pylori is to alter pH by producing ammonia, studies have revealed the presence of urease in the lamina propria of individuals infected with H. pylori. The interaction between Urease B and CD74 activates NF-κB, leading to increased production of interleukin-8 (IL-8), a potent chemotactic factor for monocytes and neutrophils (Beswick et al., 2006). H. pylori urease and functionally active recombinant urease also stimulate the expression of inducible nitric oxide synthase in macrophages (Gobert et al., 2002), which may lead to the production of substances causing nitrosative damage.

Motility is crucial for H. pylori infection (O'Toole et al., 2000). Similarly, mutants lacking directed motility exhibit weakened virulence. H. pylori exhibits chemotaxis, mediated by a complex chemosensory system comprising multiple receptors like TlpA, TlpB, TlpC, and TlpD, detecting various chemical signals. These signals, relayed through coupling proteins to CheA kinase, alter CheY activity. Active CheY then guides the bacterium’s movement via its flagellar motor, allowing H. pylori to adeptly navigate and localize within specific gastric mucosal and glandular niches. This precise localization enables robust colonization during the acute phase of infection (Johnson and Ottemann, 2018; Williams et al., 2007). Mutations in chemotactic receptors TlpA or TlpB of H. pylori can lead to reduced or lost chemotaxis (Williams et al., 2007). In addition, mutations that lack the Cag pathogenicity island (PAI) were found in in vitro experiments to impair the ability of H. pylori to trigger gastric epithelial cells to secrete pro-inflammatory cytokines and chemokines, such as IL-8 and urease (Ferreira et al., 2016). This reduces the number of bacteria approaching gastric epithelial cells, thereby alleviating the severity of gastritis. In such cases, bacteria fail to trigger a strong immune response. The helical shape of H. pylori allows it to navigate the gastric mucus layer and facilitates penetration through epithelial cells (Constantino et al., 2016). Its spiral shape is influenced by various proteins, including Csd1/2, Csd5, Csd7, CcmA, and MurF, which directly or indirectly affect the structure and composition of peptidoglycan (PG). Particularly, the rod-shaped protein domain of CcmA and its N-terminal region are crucial for the helical shape, enabling polymerization and interaction with Csd5 and Csd7, playing a key role in maintaining cellular shape stability and regulating cell wall architecture (Sichel et al., 2022). This complex helical structure has been considered by some authors to be a virulence factor. In vitro experiments have shown that helical cells exhibit a 15% increase in propulsive force compared to straight mutants. Although the helical cell shape has little effect on swimming speed, the loss of helical shape increases the proportion of bacteria completely immobilized in mucus by 30-40%, potentially affecting the turnover rate of bacterial clearance from the mucus layer (Constantino et al., 2016; Martínez et al., 2016). Moreover, the helical shape increases the proportion of motile bacteria. Beyond cell shape, the number of flagella significantly contributes to the motility speed of H. pylori. The flagellar structure of H. pylori contributes to effective colonization on the gastric mucosa through mechanisms such as motility, adhesion capability, and penetration through the mucous layer (Gu, 2017).

Lipopolysaccharide (LPS) is a key component on the surface of H. pylori, facilitating the bacterium’s invasiveness, interaction with the host, and evasion of gastric mucosal defense mechanisms. The lipid A region of LPS can react with protons in gastric acid, reducing the bactericidal effect of the acid (Calam et al., 1997), thus favoring the survival of H. pylori in the gastric environment. Specifically, the core region of LPS binds to host extracellular matrix (ECM) layer adhesins (Valkonen et al., 1994), and the LeX polysaccharide structures in the O antigen are bound by host β-galactoside-binding lectin (galectin-3) (Fowler et al., 2006), which have been proven to participate in the colonization process, laying the groundwork for chronic infection. Additionally, the PAP2 protein HP0851 (HupA), a key enzyme in LPS biosynthesis, is involved in LPS modifications that increase the positive charge of lipid A, thereby enhancing resistance to cationic antimicrobial peptides (CAMP) (Gasiorowski et al., 2019), helping the bacteria evade the host’s innate immune response.

The immune response elicited by H. pylori infection is characterized by a mixed reaction involving T helper cells, cytotoxic T cells, and NK cells (Larussa et al., 2015). In the early stages of infection, a population of CD8+ T cells with a tissue-resident memory (TRM) phenotype has been identified. These cells rapidly infiltrate the gastric mucosa and recognize specific antigens, including surface proteins and lipopolysaccharides. This mechanism provides a swift and effective immune response, which is crucial for controlling the infection. As the infection persists, the presence of TRM phenotype CD8+ T cells diminishes and is gradually replaced by CD4+ T cells, a shift that signifies a transformation in the immune response during the chronic phase of the infection (Koch et al., 2023).

Alterations in epigenetic mechanisms, such as aberrations in DNA methylation and various histone modifications including acetylation, methylation, and phosphorylation, are pivotal in the pathogenesis of human cancers. They exert an impact on gene expression through the silencing of various tissue-specific genes and the methylation of imprinted genes (Pajares et al., 2021; Audia and Campbell, 2016). Additionally, the expression of microRNAs (miRNAs) is also regulated by epigenetic variations. Changes in miRNA expression in gastric epithelial cells induced by H. pylori infection are closely linked to the progression of gastric mucosal lesions and play a dual role in cancer development as tumor suppressors or oncogenes, underscoring their importance in gene regulation (Săsăran et al., 2021).

MiRNAs have been described in multiple studies as modulators of TLR signaling, influencing the release of pro-inflammatory cytokines and signaling cascade proteins by binding to the 3’-UTR regions of TLRs or acting as transcriptional regulators. During the process of H. pylori infection, particularly under the influence of CagA-positive strains, the expression of the let-7 family of miRNAs in gastric epithelial cells is inhibited (Hayashi et al., 2013). This downregulation directly leads to the suppression of TLR4 and NF-κB signaling pathways, consequently reducing the inflammatory response (Teng et al., 2013). This highlights the role of miRNAs as direct ligands affecting the activity of TLR signaling pathways. Concurrently, the expression of miRNA-146 and miRNA-155 is upregulated in gastric epithelial cells, macrophages, and T cells (Xie et al., 2014; O'Connell et al., 2007). This upregulation inhibits the NF-κB signaling pathway and the release of the pro-inflammatory cytokine IL-8, while also modulating T cell activity and the differentiation of Th1 and Th17 cells (Möhnle et al., 2015; Oertli et al., 2011). This dual regulatory function aids in balancing immune responses, facilitating persistent H. pylori infection and resistance to apoptosis. Therefore, the crosstalk between TLRs and miRNAs is crucial for ensuring an appropriate immune response to pathogens. H. pylori infection also triggers an upregulation of specific miRNAs in macrophages, notably let-7i-5p, miR-146b-5p, and miR-185-5p. These miRNAs, by suppressing CIITA, lead to a decreased expression of HLA class II molecules. This reduction impairs the macrophages’ capacity for bacterial processing and antigen presentation to Th cells, consequently attenuating the immune response against H. pylori (Codolo et al., 2019). Moreover, H. pylori infection downregulates miR-4270, promoting the expression of CD300E, which further affects MHC-II functionality and reduces immune presentation (Pagliari et al., 2017). These miRNAs, due to their role in regulating innate immunity and inflammatory responses during H. pylori infection, hold promise as biomarkers for the disease.

Regarding miRNA-155, an LNA-modified antisense inhibitor, MRG-106, is currently in phase II clinical trials for patients with cutaneous T-cell lymphoma and mycosis fungoides. This miRNA has been recognized for its role in inflammation, and its inhibition could enhance the differentiation of brown adipocytes (Kornmueller et al., 2022). There is also evidence that miRNA mimics of miR-146 may be promising for anti-inflammatory therapy in further preclinical studies (Comer et al., 2014), while Mesenchymal Stem Cells (MSC) -derived exosomes transduced with miR-146a/miR-155 have shown potential immunomodulatory effects in experimental models (Tavasolian et al., 2020). Although no specific therapeutic applications in clinical trials have been found for let-7i-5p, miR-146b-5p, and miR-185-5p, these miRNAs have been identified as targets for mitigating the adverse effects of macrophage antigen presentation (Deng et al., 2022), suggesting they may play a role in modulating inflammatory responses. Furthermore, let-7i-5p is considered to be involved in various signaling pathways related to cell morphology and migration, and some miRNA-based drugs, such as anti-Let-7f, have been tested in experimental models of central nervous system injury (Tavasolian et al., 2020).

Antibiotics serve as the primary modality for treating H. pylori infections. Unfortunately, this bacterium has demonstrated resistance to multiple antibiotics, a phenomenon largely attributable to genetic mutations. These mutations not only confer resistance but may also enhance the virulence of the bacteria (Lin et al., 2023). For instance, mutations in the 23S rRNA gene of H. pylori can impede the binding of clarithromycin to the ribosomal subunit, leading to resistance to this drug (Albasha et al., 2021). Generally, antibiotics inhibit bacterial growth by interfering with DNA gyrase or topoisomerase activities. In H. pylori, mutations in the gyrA and gyrB genes could alter the structure or function of DNA gyrase and topoisomerase, resulting in resistance to antibiotics such as levofloxacin (Fauzia et al., 2023). Since the 1990s, studies have confirmed that oral vaccines can provide protection before and after H. pylori infection (Czinn et al., 1993), and the development of effective vaccines is viewed as a promising strategy to prevent gastric cancer. Vaccine antigen research has focused on H. pylori virulence factors, such as urease, cytotoxin-associated gene A (CagA), vacuolating cytotoxin A (VacA), neutrophil-activating protein (NAP), and heat shock proteins (HSPs) (Tshibangu-Kabamba and Yamaoka, 2021; Corthésy-Theulaz et al., 1995). Administration via various routes including sublingual, intranasal, and gastric mucosal delivery simultaneously stimulates both mucosal and systemic immune responses (Sjökvist Ottsjö et al., 2017). However, the capability of these vaccines to directly neutralize all virulence factors of H. pylori, including CagA and VacA proteins, remains an ongoing research topic. The efficacy of H. pylori vaccines largely depends on their ability to elicit effective immune responses to combat the bacteria. T.H. Ermak et al. demonstrated in murine models that the protective effect induced by urease vaccines primarily relies on MHC class II-restricted cell-mediated immune mechanisms. Furthermore, even in B-cell knockout mice, the vaccine provided protection comparable to that in normal mice, underscoring the significance of cell-mediated immunity in the immunogenic response induced by urease vaccines (Ermak et al., 1998).

Inducing potent cellular immunity, particularly Th1 and Th17 responses, is crucial for the eradication of H. pylori. Kao and others demonstrated that vaccination against H. pylori could successfully stimulate a Th17 immune response in mice lacking antibodies or Th2 responses, inversely correlated with H. pylori colonization (Kao et al., 2010). The vaccine-induced Th17 cell response, associated with the gastric aggregation of neutrophils, plays a central role in the clearance of H. pylori (DeLyria et al., 2009). Another study pointed out that the immune protection induced by specific Th epitopes in BALB/c mice relies on the production of IFN-γ by CD4+ T cells (Li et al., 2015), which appears to depend on the antigen’s characteristics and its interaction with the immune system. Additionally, dendritic cells play a pivotal role in vaccine-induced immune protection through the expression of protease-activated receptor 2 (PAR2) (Velin et al., 2011), which is crucial for balancing tissue damage and immune response.

In addition to traditional mucosal adjuvants such as Cholera Toxin and Escherichia coli heat-labile enterotoxin (Bowman and Clements, 2001), to address the issues of enzymatic degradation and extreme pH encountered in oral H. pylori vaccines, researchers have explored a variety of vaccine designs, including optimization of antigen and adjuvant technologies. For instance, the CWAE multivalent subunit vaccine, containing selected B and Th cell epitopes and the UreB subunit, can induce a mixed CD4+ T cell response and high antibody levels (Guo et al., 2017). D,L-lactide-co-glycolic acid (PLGA) and nanoparticles (NPs) as vaccine carriers enhance the stability and immunogenicity of vaccines (Waeckerle-Men and Groettrup, 2005), offering significant advantages in improving stability, extending circulation time, and enhancing safety and efficacy (Mitchell et al., 2021). In one study, an acid-resistant HP55/PLGA nanoparticle oral vaccine system elicited high levels of specific antibodies and memory T cell responses in mice, significantly reducing bacterial load and achieving 43% complete protection (Tan et al., 2017), confirming the significant potential of encapsulating vaccine antigens to enhance oral vaccine effectiveness.

Although these experimental outcomes have demonstrated positive responses in vitro, clinical trials have largely yielded disappointing results. A Phase I/II clinical trial (NCT00736476) assessed the efficacy of a vaccine composed of vacuolating cytotoxin A (VacA), cytotoxin-associated antigen (CagA), and neutrophil-activating protein (NAP) for preventing infection with cagA-positive strains post-intramuscular immunization. Findings at 12 weeks post-infection revealed a 68% clearance rate in the vaccinated group compared to a 60% rate in the placebo group (Malfertheiner et al., 2018), which does not conclusively prove the vaccine’s effectiveness due to natural immune responses elicited by H. pylori. In another Phase III trial (NCT02302170), a prophylactic vaccine containing urease and Escherichia coli heat-labile enterotoxin B fusion protein was shown to reduce H. pylori infection rates in children aged 6-15 years. The vaccine’s efficacy was 71.8% (95% CI 48.2-85.6) within the first year. However, participants had to fast for at least two hours and ingest sodium bicarbonate two minutes before vaccination. The study also suggested that the vaccine’s long-term efficacy might diminish, possibly necessitating regular revaccination (Zeng et al., 2015). Most candidate vaccines, despite demonstrating promising immunoprotective effects in animal studies, have shown limited efficacy in human clinical trials. This discrepancy is largely attributed to the high genetic diversity of H. pylori, especially in terms of antigenic variability of its virulence factors (Kabamba et al., 2018). This variability leads to low conservation of some antigens across different strains, enabling these antigens to more easily evade recognition by the host immune system. Consequently, they can only provide partial protection and exhibit poor immunogenicity. This characteristic poses significant challenges in the development of effective vaccines against H. pylori.

H. pylori is a significant gastric pathogen directly linked to various gastric diseases, such as peptic ulcers and gastric cancer. In China, the prevalence of H. pylori infection is notably high, posing a significant health challenge to the general population. Consequently, elucidating H. pylori ‘s pathogenic mechanisms and finding effective treatments have become focal points in medical research. Notably, how H. pylori evades the host immune system has emerged as a research hotspot in recent years. Despite an immune response capable of clearing most pathogens, H. pylori has evolved a suite of mechanisms to circumvent both innate and adaptive immune responses, enabling the bacterium to persistently infect and colonize the host. Numerous studies have revealed H. pylori ‘s critical role in escaping the host immune system, particularly in ex vivo preclinical models. H. pylori virulence factors can bind to host macrophage surface receptors, alter macrophage polarization states, disrupt phagocytic function, and induce differentiation of T cells into immunosuppressive regulatory T (Treg) cells. In this process, multiple potential therapeutic targets against H. pylori have been identified. Moreover, the development of vaccines targeting H. pylori infection has demonstrated potential application prospects. In summary, a thorough understanding of the interactions between H. pylori and the host immune system is crucial for developing targeted treatments and vaccines. Future research will focus on elucidating the intricate mechanisms of interaction between H. pylori and the host immune system, as well as conducting extensive experiments to evaluate the clinical efficacy of targeted therapeutics and H. pylori vaccines.

JF: Conceptualization, Data curation, Writing – original draft. JZ: Supervision, Validation, Visualization, Writing – review & editing. HX: Supervision, Validation, Visualization, Writing – review & editing.