May 28, 2024

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New Mutation Boosts Helicobacter pylori’s Virulence: Tied to Gastric Cancer

New Mutation Boosts Helicobacter pylori’s Virulence: Tied to Gastric Cancer



New Mutation Boosts Helicobacter pylori’s Virulence: Tied to Gastric Cancer.

Discovery of a “Deadly” Strain of Helicobacter pylori – Scientists Uncover a Variant that Makes H. pylori Deeper and More Toxic, Significantly Linked to Gastric Cancer | A Landmark Scientific Revelation.

Research suggests that approximately 90% of gastric cancer cases can be attributed to Helicobacter pylori infection [1].

However, what’s perplexing is that around 50% of the global population is infected with H. pylori, yet only 1-5% of infected individuals develop gastric cancer over their lifetime [2].

Given these statistics, you, like many, must be wondering: What determines whether H. pylori infection leads to gastric cancer or not?

Current research points to various factors such as genetic background, living environment, dietary habits, and lifestyle as significant influencers [2]. However, these factors alone cannot adequately explain this phenomenon. In recent years, scientists have begun investigating H. pylori itself and have found that certain genetic variations within H. pylori significantly enhance its association with gastric cancer [3,4].

These discoveries imply that some genotypes of H. pylori are more virulent, making them more capable of promoting gastric cancer. Unfortunately, previous studies, although identifying potential mutation sites, did not systematically elucidate how these mutations make H. pylori more toxic.

Recently, a research team led by Steffen Backert from the University of Erlangen-Nuremberg in Germany published a groundbreaking study in the renowned journal “Cell Host & Microbe” [5]. After analyzing the genomic data of 1043 H. pylori strains, they identified a single base substitution in the serine protease HtrA, changing the 171st amino acid from serine to leucine (171S→L), which was significantly associated with gastric cancer.

 

New Mutation Boosts Helicobacter pylori's Virulence: Tied to Gastric Cancer

 

Mechanistically, the 171L variant in H. pylori leads to more severe damage to the gastric epithelium, making it easier for H. pylori to penetrate deep into the gastric epithelium, increasing its toxin injection and pro-inflammatory abilities, and promoting DNA double-strand breaks in host gastric epithelial cells.

This marks the first time that scientists have discovered and functionally validated a bacterial mutation related to gastric cancer. Undoubtedly, this finding holds important implications for the prevention and treatment of gastric cancer, particularly in individuals infected with the 171L-type H. pylori, who may require urgent therapeutic interventions.

From a pathogenic perspective, H. pylori possesses a Type IV secretion system (T4SS) that allows them to inject the oncogenic protein cytotoxin-associated gene A (CagA) into gastric epithelial cells, initiating a series of gastric lesions.

As early as 2017, the Backert team discovered that H. pylori cannot inject CagA from the top of gastric epithelial cells but needs to traverse the epithelial cell layers, reaching the basal part of the epithelial cells for the T4SS injector to function and deliver the toxic CagA [6]. In this process, serine protease HtrA, which cleaves interconnected epithelial cells, plays a crucial role [6].

 

New Mutation Boosts Helicobacter pylori's Virulence: Tied to Gastric Cancer

HtrA plays an important role in Helicobacter pylori infection

 

 

This discovery prompted Backert to consider whether HtrA, present in all H. pylori strains, might influence the relationship between H. pylori and gastric cancer through genetic variations.

To answer this question, Backert’s team analyzed the genomes of 1043 H. pylori strains collected from individuals with gastric cancer, gastritis, asymptomatic infection, and ulcers. They identified three HtrA genetic variations closely related to gastric diseases, including the 171S/L mutation located within the protease domain, which became the focal point of their research.

 

New Mutation Boosts Helicobacter pylori's Virulence: Tied to Gastric Cancer

H. pylori type 171L HtrA leads to larger gaps between epithelial cells and more H. pylori entering the basal side

 

 

Comparing 171S-type and 171L-type HtrA, they found that 171S-type HtrA from gastritis samples mainly existed as monomers, while 171L-type HtrA from gastric cancer patients predominantly formed stable trimers, resulting in a 3-5-fold increase in protein hydrolysis activity. It’s evident that 171L-type HtrA exhibits a stronger ability to separate epithelial cells.

 

Further analysis revealed that in the presence of 171L-type HtrA, there was increased degradation of epithelial cell E-cadherin, higher injection of the CagA toxin, enhanced activation of pro-inflammatory NF-kB, release of pro-inflammatory cytokine IL-8, and an increased rate of DNA double-strand breaks and micronucleus formation. This series of responses compromises genomic integrity and raises the frequency of harmful mutations, ultimately leading to epithelial cell malignancy.

 

 

New Mutation Boosts Helicobacter pylori's Virulence: Tied to Gastric Cancer

Mechanism diagram

 

 

 

In summary, the research by Backert’s team indicates that single nucleotide polymorphisms (SNPs) in the serine protease HtrA of H. pylori are associated with gastric cancer, particularly the 171S/L SNP.

This achievement marks the first discovery and confirmation of H. pylori SNPs linked to gastric cancer, offering a new avenue for future gastric cancer prevention.

Perhaps, in future H. pylori screenings, the determination of an individual’s risk of developing gastric cancer may be significantly enhanced by assessing the 171S/L genotype of HtrA.

 

 

 

 

 

references:

[1].Moss SF. The Clinical Evidence Linking Helicobacter pylori to Gastric Cancer. Cell Mol Gastroenterol Hepatol. 2016;3(2):183-191. doi:10.1016/j.jcmgh.2016.12.001

[2].Malfertheiner P, Camargo MC, El-Omar E, et al. Helicobacter pylori infection. Nat Rev Dis Primers. 2023;9(1):19. Published 2023 Apr 20. doi:10.1038/s41572-023-00431 -8

[3].Berthenet E, Yahara K, Thorell K, et al. A GWAS on Helicobacter pylori strains points to genetic variants associated with gastric cancer risk. BMC Biol. 2018;16(1):84. Published 2018 Aug 2. doi :10.1186/s12915-018-0550-3

[4].Tuan VP, Yahara K, Dung HDQ, et al. Genome-wide association study of gastric cancer- and duodenal ulcer-derived Helicobacter pylori strains reveals discriminatory genetic variations and novel oncoprotein candidates. Microb Genom. 2021;7(11 ):000680. doi:10.1099/mgen.0.000680

[5].Sharafutdinov I, Tegtmeyer N, Linz B, et al. A single-nucleotide polymorphism in Helicobacter pylori promotes gastric cancer development. Cell Host Microbe. 2023;31(8):1345-1358.e6. doi:10.1016/ j.chom.2023.06.016

[6].Tegtmeyer N, Wessler S, Necchi V, et al. Helicobacter pylori Employs a Unique Basolateral Type IV Secretion Mechanism for CagA Delivery. Cell Host Microbe. 2017;22(4):552-560.e5. doi:10.1016 /j.chom.2017.09.005

New Mutation Boosts Helicobacter pylori’s Virulence: Tied to Gastric Cancer

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