Posts Tagged ‘Helicobacter pylori’

Helicobacter pylori and stomach lesions

Friday, July 18th, 2014

Helicobacter pylori Helicobacter pylori infection promotes stomach ulcers and cancer. How H. pylori initially interacts with and irritates gastric tissue is not well understood.

A new article describes how H. pylori rapidly identifies and colonizes sites of minor injuries in the stomach, almost immediately interferes with healing at those injury sites, and so promotes sustained gastric damage.

Smoking, alcohol, excessive salt intake, and non-steroidal anti-inflammatory drugs cause damage to the tissue lining the stomach, and are associated with stomach ulcers. Scientists asked whether H. pylori can sense and respond to such damage and so contribute to disease development.

The researchers induced small stomach lesions in mice and observed that H. pylori bacteria can rapidly detect the injury site and navigate toward it. Within minutes, accumulation of bacteria interferes with repair of the tissue damage.

To examine how the bacteria accomplish this, the researchers also studied mice with larger stomach lesions (ulcers) that were subsequently infected with H. pylori. They found that H. pylori preferentially colonizes stomach tissue at injured ulcer sites, and there impairs healing of the damaged tissue. Selective colonization requires both bacterial motility and chemotaxis (the ability to change direction of movement in response to environmental cues), and higher levels of bacterial accumulation cause slower healing. However, when extremely high levels of immotile or chemotaxis-deficient bacteria are added to damaged tissue, they can also slow healing.

While the signals that attract H. pylori (but not benign stomach bacteria) toward injured tissue are not yet known, the researchers hope that their ability to rapidly measure H. pylori accumulation at the injured site now provides an experimental set-up to determine the factor(s) involved.


Motility and Chemotaxis Mediate the Preferential Colonization of Gastric Injury Sites by Helicobacter pylori. (2014) PLoS Pathog 10(7): e1004275. doi:10.1371/journal.ppat.1004275


Plasmid DNA Transfer in Helicobacter pylori

Friday, September 28th, 2012

Helicobacter pylori Helicobacter pylori is a highly motile, microaerophilic, Gram-negative bacterium, resident in the gastric mucus layer of about 50% of the human population. Infection with H. pylori is a major cause of gastroduodenal disease, including chronic active gastritis, peptic ulcer disease, mucosa-associated lymphoid tissue lymphoma and gastric carcinoma. A remarkable feature of H. pylori is its panmictic population structure, reflected by an extreme genetic heterogeneity, possibly resulting from frequent recombination events after import of small pieces of foreign DNA from other H. pylori strains during persistent or transient mixed infections. Such an efficient DNA exchange has been attributed to the natural transformation competence of H. pylori.


Multiple Pathways of Plasmid DNA Transfer in Helicobacter pylori. (2012) PLoS ONE 7(9): e45623. doi:10.1371/journal.pone.0045623
Many Helicobacter pylori (Hp) strains carry cryptic plasmids of different size and gene content, the function of which is not well understood. A subgroup of these plasmids (e.g. pHel4, pHel12), contain a mobilisation region, but no cognate type IV secretion system (T4SS) for conjugative transfer. Instead, certain H. pylori strains (e.g. strain P12 carrying plasmid pHel12) can harbour up to four T4SSs in their genome (cag-T4SS, comB, tfs3, tfs4). Here, we show that such indigenous plasmids can be efficiently transferred between H. pylori strains, even in the presence of extracellular DNaseI eliminating natural transformation. Knockout of a plasmid-encoded mobA relaxase gene significantly reduced plasmid DNA transfer in the presence of DNaseI, suggesting a DNA conjugation or mobilisation process. To identify the T4SS involved in this conjugative DNA transfer, each individual T4SS was consecutively deleted from the bacterial chromosome. Using a marker-free counterselectable gene deletion procedure (rpsL counterselection method), a P12 mutant strain was finally obtained with no single T4SS (P12ΔT4SS). Mating experiments using these mutants identified the comB T4SS in the recipient strain as the major mediator of plasmid DNA transfer between H. pylori strains, both in a DNaseI-sensitive (natural transformation) as well as a DNaseI-resistant manner (conjugative transfer). However, transfer of a pHel12::cat plasmid from a P12ΔT4SS donor strain into a P12ΔT4SS recipient strain provided evidence for the existence of a third, T4SS-independent mechanism of DNA transfer. This novel type of plasmid DNA transfer, designated as alternate DNaseI-Resistant (ADR) mechanism, is observed at a rather low frequency under in vitro conditions. Taken together, our study describes for the first time the existence of three distinct pathways of plasmid DNA transfer between H. pylori underscoring the importance of horizontal gene transfer for this species.

Helicobacter pylori infection – what’s new?

Wednesday, May 16th, 2012

Helicobacter pylori Helicobacter pylori is a spiral-shaped, flagellated, microaerophilic Gram-negative bacillus discovered at the beginning of the 1980s that causes gastritis, peptic ulcers and stomach cancer in humans. So what’s new?


Helicobacter pylori infection: what’s new. Current Opinion in Infectious Diseases, 25(3): 337–344
Helicobacter pylori colonizes the human stomach causing gastritis and severe diseases including gastric cancer. One of the most dangerous H. pylori factors, CagA, has been investigated in relation to gastric cancer: recently this relationship was strongly reinforced by the finding that CagA interacts with the tumor suppressor apoptosis-stimulating protein of p53-2 (ASPP2), promoting p53 degradation. Treg have been proposed to be involved in H. pylori infection and gastric disease: recent findings suggest that Treg-induced tolerance, rather than immunity to H. pylori, may result in less severe disease. The eradication rates achieved with the standard triple therapy dropped below 80%, mainly due to antibiotic resistance, while no vaccines are currently licensed; new treatments/regimens were subjected to clinical trials, in some cases strongly increasing the eradication rates.

Helicobacter pylori VacA toxin

Wednesday, April 11th, 2012

Helicobacter pylori VacA toxin from the cancer-inducing bacterium Helicobacter pylori is currently classified as a pore-forming toxin but is also considered a multifunctional toxin, apparently causing many pleiotropic cell effects. However, an increasing body of evidence suggests that VacA could be the prototype of a new class of monofunctional A-B toxins in which the A subunit exhibits pore-forming instead of enzymatic activity. Thus, VacA may use a peculiar mechanism of action, allowing it to intoxicate the human stomach. By combining the action of a cell-binding domain, a specific intracellular trafficking pathway and a novel mitochondrion-targeting sequence, the VacA pore-forming domain is selectively delivered to the inner mitochondrial membrane to efficiently kill target epithelial cells by apoptosis.

Intoxication strategy of Helicobacter pylori VacA toxin. Trends Microbiol. 23 Feb 2012

How does Helicobacter pylori cause stomach cancer?

Friday, September 23rd, 2011

Stomach ulcers are caused by chronic infection with the bacterium Helicobacter pylori, which is also the leading risk factor for stomach cancer. One reason for the cancer risk could be that the pathogen creates breaks in the DNA molecules of infected cells:


Carcinogenic bacterial pathogen Helicobacter pylori triggers DNA double-strand breaks and a DNA damage response in its host cells. PNAS USA 108: 14944–14949 (2011)
The bacterial pathogen Helicobacter pylori chronically infects the human gastric mucosa and is the leading risk factor for the development of gastric cancer. The molecular mechanisms of H. pylori-associated gastric carcinogenesis remain ill defined. In this study, we examined the possibility that H. pylori directly compromises the genomic integrity of its host cells. We provide evidence that the infection introduces DNA double-strand breaks (DSBs) in primary and transformed murine and human epithelial and mesenchymal cells. The induction of DSBs depends on the direct contact of live bacteria with mammalian cells. The infection-associated DNA damage is evident upon separation of nuclear DNA by pulse field gel electrophoresis and by high-magnification microscopy of metaphase chromosomes. Bacterial adhesion (e.g., via blood group antigen-binding adhesin) is required to induce DSBs; in contrast, the H. pylori virulence factors vacuolating cytotoxin A, γ-glutamyl transpeptidase, and the cytotoxin-associated gene (Cag) pathogenicity island are dispensable for DSB induction. The DNA discontinuities trigger a damage-signaling and repair response involving the sequential ataxia telangiectasia mutated (ATM)-dependent recruitment of repair factors—p53-binding protein (53BP1) and mediator of DNA damage checkpoint protein 1 (MDC1)—and histone H2A variant X (H2AX) phosphorylation. Although most breaks are repaired efficiently upon termination of the infection, we observe that prolonged active infection leads to saturation of cellular repair capabilities. In summary, we conclude that DNA damage followed by potentially imprecise repair is consistent with the carcinogenic properties of H. pylori and with its mutagenic properties in vitro and in vivo and may contribute to the genetic instability and frequent chromosomal aberrations that are a hallmark of gastric cancer.

Innate immunity against Helicobacter pylori

Monday, June 7th, 2010

The spiral, microaerophilic, Gram-negative bacterium Helicobacter pylori (H. pylori) induces chronic gastritis and is a well known risk factor for peptic ulcer and gastric cancer. Although H. pylori infection can persist for decades, only a fraction of colonized individuals ever develop clinical diseases. Clinical outcome is influenced by a balance between H. pylori virulence factors and the host immune response. However, the mechanisms by which bacterial and/or host factors cause disease remain unclear. Identification of immune response genes that regulate the H. pylori-host interactions will not only have diagnostic and therapeutic implications, but may also provide insights into other inflammation related cancer.

Olfactomedin 4 down-regulates innate immunity against Helicobacter pylori infection. PNAS USA June 1 2010. doi: 10.1073/pnas.100126910
Olfactomedin 4 (OLFM4) is a glycoprotein that has been found to be up-regulated in inflammatory bowel diseases and Helicobacter pylori infected patients. However, its role in biological processes such as inflammation or other immune response is not known. In this study, we generated OLFM4 KO mice to investigate potential role(s) of OLFM4 in gastric mucosal responses to H. pylori infection. H. pylori colonization in the gastric mucosa of OLFM4 KO mice was significantly lower compared with WT littermates. The reduced bacterial load was associated with enhanced infiltration of inflammatory cells in gastric mucosa. Production and expression of proinflammatory cytokines/chemokines such as IL-1β, IL-5, IL-12 p70, and MIP-1α was increased in OLFM4 KO mice compared with infected controls. Furthermore, we found that OLFM4 is a target gene of NF-κB pathway and has a negative feedback effect on NF-κB activation induced by H. pylori infection through a direct association with nucleotide oligomerization domain-1 (NOD1) and -2 (NOD2). Together these observations indicate that OLFM4 exerts considerable influence on the host defense against H. pylori infection acting through NOD1 and NOD2 mediated NF-κB activation and subsequent cytokines and chemokines production, which in turn inhibit host immune response and contribute to persistence of H. pylori colonization.