Helicobacter pylori infection, pathogenicity, and therapeutic advances: Comparison
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A primer on Helicobacter pylori virulence factors, pathogenicity, gastric conditions that are caused by infection, and treatment modalities.

This entry is adapted from the peer-reviewed paper 10.3390/pathogens13050392

  •  Helicobacter pylori 
  • virulence factor
  • outer membrane protein
  • gastric cancer
  • gastric disease

1. Introduction

Helicobacter pylori is considered an ancient microorganism, the existence of which can be traced back to before the voyages of Christopher Columbus [1]. Yet, it took until the early 1980s for the bacterium to be first identified by the Australian physicians Barry Marshall and Robin Warren. For discovering H. pylori as the principal cause of gastritis, peptic ulcer disease and mucosa-associated lymphoid-tissue (MALT) lymphoma [2][3], they were awarded the Nobel Prize in Physiology or Medicine in 2005.

Chronic H. pylori infection is a predisposing factor for a range of other health conditions including ischemic stroke, Alzheimer’s disease, multiple sclerosis, autoimmune neutropenia, vitamin B12 deficiency, diabetes mellitus, cholelithiasis, idiopathic thrombocytopenic purpura, iron-deficiency anemia, cardiovascular diseases, hepatobiliary diseases, and biofilm-related infections, although further research is needed to verify each proposed link [4][5][6][7][8][9][10][11][12][13][14][15]. It is estimated that more than half of the world’s population is infected with this microorganism, its prevalence in developing countries reaching 70–90%, compared to developed nations where it is between 20–30% [16][17]. Typically, a person becomes infected with H. pylori during childhood through either oral–fecal or oral–oral routes of transmission [18].

This Gram-negative, microaerophilic, helical bacterium is a major source of global gastric cancer mortality, so it is considered as an oncogenic pathogen (oncopathogen) and hence is classified as a class I carcinogen by the World Health Organization [19]. It is equipped with different virulence factors including flagella, lipopolysaccharide (LPS), urease, and outer membrane proteins (OMPs), which are encoded by many paralogous gene families. It owes its characteristically high motility to its 4–6 co-located flagella, which facilitate its movement and colonization of the stomach mucosa layer. The first step for H. pylori to induce inflammation and cause infection is to colonize and attach to gastric mucosa. Usually, this happens through OMPs, which play a pivotal role in adherence and pathogenicity. To date, 64 members of this family have been recognized [20][21][22]. While some OMPs are porins, others are adhesins. Each OMP has a distinct receptor, so gaining a clear understanding of them all aids diagnosis of infection and benefits clinical outcomes.

Urease production provides ammonia for bacterial protein synthesis and neutralizes gastric acid, thereby making the stomach a preferred environment for colonization. This virulence factor can damage host tissue via several mechanisms, which, together with the inflammatory immune response that this triggers, causes ulceration. Similarly, the unique structure of LPS promotes bacterial pathogenicity by facilitating attachment to gastric mucosa, thus supporting persistence of infection [23][24][25][26].

Only around 20% of H. pylori carriers develop symptoms of disease. Chronic gastritis is the condition ascribed for H. pylori carriers without any clinical symptoms. At the same time, this pathogen is a risk factor for progression to gastric problems like peptic ulcers [27][28][29]. Chronic gastritis follows colonization of the stomach by H. pylori, which resists clearance and causes mucosal inflammation and atrophy. Peptic ulcer formation, a consequence of damaged mucosa through stomach acid activity, is accelerated by the chronically acidic environment [30]. These sores can develop either into a lesion inside the stomach, known as a gastric ulcer, or inside the adjoining duodenum within the small intestine, termed a duodenal ulcer [31]. Importantly, having chronic gastritis increases a person’s risk of acquiring severe gastric conditions, notably gastric cancer that most often manifests as stomach adenocarcinoma [32].

H. pylori is the leading cause of two-thirds of all stomach cancer and three-quarters of non-cardia gastric cancer (that affects the first part of the stomach) [33]. While there is now a decreasing trend in the rate of gastric cancer worldwide, it is still the second highest cause of cancer mortality [34]. The progression of H. pylori infection to gastric cancer happens through a series of events. Primary inflammation may develop into acute gastritis and chronic gastritis. At this stage, multiple factors such as stomach pH, genetic diversity and environmental factors can gradually alter the gastric condition to cancer.

Most patients are unaware of their condition during the early stages and so treatment is not started until symptoms are more advanced. Hence, developing earlier and more accurate screening methods to enable prevention and eradication of H. pylori at the community level, as well as better treatment strategies to combat existing infection in patients, are warranted [35]. An array of contributing factors, such as genetic susceptibility, diet, environmental variables, smoking and physical activity, are involved in progression to severe stomach conditions [36]. When considering these relationships as potential prognostic markers a number of challenges such as limited time of survival and geographical regionality of occurrence should be considered.

The protective host immune response to H. pylori helps to lessen the threat that colonization poses. However, this noted pathogen has evolved a unique strategy to overcome host defenses. Long-term infection is a consequence of remodeling of the host-pathogen interface as well as immune evasion due to expression of multiple virulence factors [37]. Hence, through modulating host immunity and inducing immune tolerance, H. pylori hinders therapeutic approaches and effective vaccine design.

In order to eradicate H. pylori, antibiotics are suggested for gastric disorders. These are often used in combination with proton pump inhibitors as a standard intervention [38]. However, a challenge to effective therapy is the capacity of H. pylori to form biofilm. Under the protection of the impervious matrix of extracellular polymeric substances (EPS), bacteria are refractory to antibiotic penetration, thus greatly reducing the efficacy of this treatment approach [39]. There is strong evidence for a direct correlation between biofilm formation and antibiotic resistance, influenced by factors such as OMPs, other virulence factors, extracellular matrix, efflux pumps and metabolic changes [40]. Therefore, susceptibility to antibiotics such as amoxicillin, clarithromycin, levofloxacin, and metronidazole by bacteria protected by biofilm is reduced substantially [41]. It should also be noted that eradicating this microorganism may provoke extra-gastric diseases, in particular iron deficiency, idiopathic thrombocytopenic purpura, chronic idiopathic urticaria and anemia. Further studies are required to confirm this correlation [42].

With the rise of antibiotic-resistant strains of H. pylori, there is a growing emphasis on exploring alternative treatments to antibiotics. Consequently, the development of an H. pylori vaccine has been extensively researched. Two types of vaccine, whole-cell bacterium and a recombinant preparation, which combines protective antigens with immune adjuvants, are considered the main approaches [43]. While development of the former was abandoned for various reasons, including complexity of vaccine production, the latter has progressed extensively. Different immune adjuvants, including the virulence factors BabA, SabA, OipA, CagA, and VacA, have provided vaccines with higher protective effects [44]. Four highly conserved OMPs were discovered that offer considerable potential as vaccine candidates. These proteins, namely HopV, HopW, HopX, and HopY, show no signs of phase variation, indicating stable expression during chronic infection and thereby their suitability as immunogens [44][45].

Yet, despite almost 40 years of research and development, no H. pylori vaccine is commercially available, with most clinical trials concluding after phase I. In addition to genetic diversity, biofilm characteristics, and the risk of exacerbating gastric diseases and autoimmunity due to an aberrant immune response, other reasons may partly account for this. For example, intracellular features of H. pylori enable it to effectively ‘hide’ inside gastric epithelial cells and gastric lamina propria, thus contributing to persistent infection [46]. Another concern is that many preclinical studies have been performed in mice, which are not natural hosts of H. pylori. Hence, any vaccine efficacy observed in mouse models may not translate accurately to humans [47]. Enhancing investment and prioritizing research into the design of an efficacious H. pylori vaccine are public health imperatives considering the widespread prevalence and significant disease burden associated with this bacterium.

Regarding other therapeutic approaches directly against H. pylori, several targets are suggested for treatment. These include shikimate pathways (involved in ubiquinone and aromatic acid synthesis), flavodoxin (electron carrier protein), coenzyme A, succinylase pathway, and urease inhibitory compounds. By developing reagents that interfere with these targets, researchers aim to disrupt essential bacterial functions and reduce colonization by H. pylori, leading to its control or even eradication from within the host [48].

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