H. pylori Virulence Factor vacA

Helicobacter pylori (H. pylori) is a gram-negative, spiral-shaped bacterium that infects the stomach lining, causing chronic gastritis, peptic ulcers, and increasing the risk of gastric lymphoma and carcinoma. 

It is one of the most common chronic bacterial infections worldwide, affecting up to 50% of the global population, with higher prevalence in developing countries. 

H. pylori is typically acquired in early childhood and can persist without treatment. The bacterium's ability to survive in the acidic environment of the stomach is attributed to various virulence factors. 

Its high mutation and recombination rates lead to extensive strain diversity. 

While many infected individuals remain asymptomatic, H. pylori can cause symptoms such as abdominal pain, nausea, vomiting, and dyspepsia when gastritis or peptic ulcer disease develops. 

Diagnosis involves non-invasive methods like urea breath tests and stool antigen tests, and invasive methods such as endoscopic biopsy.   Treatment generally includes a combination of proton pump inhibitors and antibiotics. 

The vacuolating cytotoxin A (VacA) is a major secreted virulence factor of H. pylori that plays a crucial role in the pathogenesis of gastric diseases. 

VacA is a pore-forming toxin that induces the formation of vacuoles in gastric epithelial cells, disrupts endosomal and lysosomal function, inhibits T-cell activation and proliferation, disrupts mitochondrial function and induces apoptosis. 

VacA interacts with and promotes the accumulation of the CagA oncoprotein, another major H. pylori virulence factor, by disrupting the autophagy pathway in host cells.  

The presence of the vacA s1 and m1 alleles is considered a marker for increased virulence and disease severity in H. pylori infections.

What is H. Pylori?  [9., 12.]

Helicobacter pylori (H. pylori) is a gram-negative, spiral-shaped bacterium that infects the stomach lining and is a common cause of chronic gastritis, peptic ulcers, gastric lymphoma, and gastric carcinoma. 

It affects up to 50% of the global population, with higher prevalence in developing countries.  It is one of the most common chronic bacterial infections worldwide.

H. pylori is typically acquired in early childhood and persists without treatment. 

It is able to survive in the harsh acidic environment of the stomach due to its unique features like flagella for motility and urease enzyme production.

Its genome exhibits high mutation and recombination rates, leading to extensive strain diversity.  [9., 15.] 

While many infected individuals remain asymptomatic, the bacteria can cause symptoms such as abdominal pain, nausea, vomiting, and dyspepsia once gastritis or peptic ulcer disease develops.   H. pylori infection causes chronic gastritis in all cases and increases the risk of peptic ulcers by 2-6 fold and gastric cancer by 2-6 fold compared to uninfected individuals.  [5., 9.] 

Transmission occurs through fecal-oral, oral-oral, and gastric-oral routes, with lower socioeconomic status being a significant risk factor.  

Diagnosis involves both non-invasive methods like urea breath tests and stool antigen tests, and invasive methods such as endoscopic biopsy. 

Treatment often includes a combination of proton pump inhibitors and antibiotics.  Antibiotic combination therapies like clarithromycin triple therapy or bismuth quadruple therapy may be used.  [5.]  

Early identification and treatment of H. pylori infections are crucial to prevent serious gastrointestinal diseases and potential malignancies.  Collaboration among healthcare professionals is essential for effective management and improved patient outcomes.

What are H. pylori Virulence Factors?  [1., 4., 7.]

H. pylori virulence factors refer to the various bacterial components and mechanisms that enable the pathogen Helicobacter pylori to successfully colonize the human stomach, evade the host's immune defenses, and cause associated diseases and complications.

Colonization Factors

• Urease enzyme: allows H. pylori to survive in the acidic environment of the stomach by producing ammonia to neutralize gastric acid

• Flagella and chemotaxis: enables motility and directed movement towards the gastric epithelium for colonization

Adhesins:

• BabA (Blood group antigen binding adhesin): binds to Lewis b antigens on gastric epithelial cells

• SabA (Sialic acid-binding adhesin): binds to sialyl-Lewis x antigens

• OipA (Outer inflammatory protein A): promotes inflammation and IL-8 production

• Vacuolating cytotoxin (VacA): induces vacuolation and apoptosis in gastric epithelial cells

• Cag Pathogenicity Island (cagPAI)/cagA:

• Encodes a type IV secretion system (T4SS) to inject the CagA effector protein into host cells

• CagA disrupts signaling pathways, causing cytoskeletal rearrangements and increased inflammation 

Other Factors

• IceA (Induced by contact with epithelium): upregulated upon adherence, increases mucosal injury

• DupA (Duodenal ulcer promoting gene A): associated with increased duodenal ulcer risk

• GGT (Gamma-glutamyl transpeptidase): helps H. pylori persist by metabolizing glutamine and glutathione

H. pylori Virulence Factor vacA  [10., 11.]

The vacuolating cytotoxin A (VacA) is a major virulence factor secreted by Helicobacter pylori that is involved in the pathogenesis of gastric diseases. 

VacA functions as an anion-selective pore-forming toxin that can insert into cellular membranes, including mitochondrial membranes.  It induces the formation of large cytoplasmic vacuoles resembling late endosomes/early lysosomes in gastric epithelial cells, hence its name. 

VacA also promotes the accumulation of the CagA oncoprotein, another major H. pylori virulence factor, by disrupting its autophagic degradation.

H. pylori Virulence Factor vacA Functions  [11.]

‍Vacuolation

VacA induces vacuole formation in host cells by creating anion-selective channels in endosomal and lysosomal membranes.

This results in increased chloride ion concentrations, leading to osmotic swelling and the accumulation of large vesicles inside cells.

Mitochondrial Disruption

VacA targets mitochondria, where it disrupts mitochondrial functions and contributes to the initiation of apoptosis.

It forms membrane-embedded pores in the inner mitochondrial membrane, dissipating the mitochondrial membrane potential (Δψ).  This leads to the release of cytochrome c, activation of caspases, and ultimately cell death.

Apoptosis

VacA can trigger the apoptotic cascade by both direct and indirect mechanisms.  It may form pores in the mitochondrial membrane, facilitating the release of apoptotic factors.

Additionally, VacA can upregulate pro-apoptotic proteins like Bax and VDAC1, and downregulate the anti-apoptotic protein Bcl-2, promoting cell death.

T-Cell Proliferation Inhibition

VacA inhibits T-cell proliferation, impairing the host's immune response.  Specifically, it binds to specific receptors on T-cells, such as the β2 integrin subunit (CD18), and disrupts their function.

Autophagy Induction

VacA induces autophagy in gastric epithelial cells, a process that may be linked to its pore-forming activity.

Laboratory Testing for H. pylori Virulence Factor vacA

Test Information, Sample Collection and Preparation

Laboratory testing for H. pylori virulence factors typically involves a stool sample, which is tested via polymerase chain reaction (PCR) for H. pylori virulence factors.

The stool sample may be collected at home.  While special preparation is not typically required for this assessment, other test components may require special preparation such as avoidance of certain foods, supplements or medications.

Click here to discover a laboratory test that assesses for H. pylori and virulence factors.  

Interpretation of Test Results

Optimal Levels of H. pylori Virulence Factor vacA

H. pylori infections can cause serious conditions including peptic ulcer disease and gastric cancer, and the presence of virulence factors such as the vacA virulence factor may increase the risk of developing peptic ulcer disease, gastritis, and/or gastric cancer.  

Optimal levels of H. pylori virulence factor vacA are undetectable.

Clinical Significance of Elevated H. pylori Virulence Factor vacA

A positive test result indicates the presence of H. pylori and the virulence factor vacA, which requires prompt treatment.  

Treatments for H. pylori Infection

Typical first-line eradication therapies may include medications such as clarithromycin, bismuth, amoxicillin, metronidazole, or tetracycline in combination, along with a PPI.

The presence of vacA-positive strains may indicate the need for more intensive therapies, including mitochondrial support.  [10., 11.] 

With the increase in antibiotic resistance demonstrated by H. pylori, especially in the setting of virulence factor-positive strains, scientists are exploring alternative methods of treating H. pylori including botanical therapies.  

Some botanical compounds that have shown promise in treating H. pylori include:  [6.] 

Terpenoids:

• Monoterpenoids: compounds like limonene and β-pinene promote mucus secretion, reduce oxidative stress and inflammation, and inhibit NF-κB expression.

• Limonene can be found in the peels and essential oils of oranges, lemons, limes, grapefruits, and mandarins as well as dill, caraway, mint and parsley.

• Beta-pinene is a component of pine resin and is also found in various plants and herbs. Common sources include basil, parsley, rosemary, sage, as well as pine trees, fir trees, and other coniferous trees.

• Sesquiterpenoids: found in cedarwood essential oil, they inhibit urease activity and H. pylori growth.

• Triterpenoids: glycyrrhizic acid, found in Glycyrrhiza glabra or licorice, shows rapid anti-H. pylori properties.

• Tetraterpenoids: Carotenoids like β-carotene and astaxanthin demonstrate antioxidant properties and reduce oxidative stress-mediated inflammation.

• Beta-carotene is found in carrots, sweet potatoes, pumpkin, butternut squash, spinach, kale, collard greens, swiss chard, red and yellow peppers; mangoes, cantaloupe, apricot, papaya, peaches; cilantro, and parsley.  

• Astaxanthin is found in seafood, some algae, and in supplement form.

Polyphenols:

• Flavonoids: compounds like kaempferol and myricetin inhibit H. pylori growth, reduce urease activity, and exert anti-inflammatory effects.

• Kaempferol can be found in many foods and essential oils including leafy greens, cruciferous vegetables such as broccoli, brussels sprouts and cabbage; herbs including dill, chives and tarragon; berries, capers and beans.  

• Myricetin can be found in berries, especially cranberries; grapes, pomegranates, onions, kale, spinach, parsley, thyme, and walnuts.  

• Tannoids: these compounds damage the bacterial membrane and reduce nitric oxide levels, exerting anti-inflammatory effects.

Alkaloids:

• Berberine and Coptisine: these alkaloids inhibit urease activity and disrupt bacterial cell membranes, enhancing the effects of antibiotics.

• Curcumin: curcumin, derived from turmeric, has shown efficacy in reducing H. pylori colonization, modulating immune responses, and improving symptoms of dyspepsia.

Related Biomarkers for H. pylori Virulence Factor vacA

In addition to the vacA virulence factor, several other biomarkers have been identified and studied in the context of H. pylori infection and associated gastric diseases.

CagA Virulence Factor and its Role in Gastric Cancer  [1., 4.]

The cytotoxin-associated gene A (CagA) is a major virulence factor of H. pylori that has been extensively studied for its role in gastric cancer development. 

The presence of CagA has been strongly associated with an increased risk of gastric cancer.  

BabA Virulence Factor and its Role in Gastric Cancer  [1.]

In Western countries, infection with BabA-producing strains is associated with an increased risk of peptic ulcer disease.

A recent study indicated that BabA-positive H. pylori strains have a higher adherence to epithelial cells and are often found in pediatric ulcerogenic H. pylori strains.

BabA-positive H. pylori strains can be classified as "specialists," which bind only blood group O-specific glycans, or "generalists," which bind glycans of blood groups O, A, and B.

The ability of these strains to bind specifically to blood group O glycans explains why individuals with blood group O are at a higher risk for developing duodenal ulcers.

Serological Biomarkers (Anti-H. pylori Antibodies)

In addition to bacterial virulence factors, serological biomarkers such as anti-H. pylori antibodies can also be used for the diagnosis and monitoring of H. pylori infection. 

These antibodies are produced by the host's immune system in response to the bacterial antigens and can be detected in serum or plasma samples.

Order H. pylori and Virulence Factor Testing

Click here to compare testing options and order tests for H. pylori.