Category Archives: Helicobacter pylori infection

Vacuolating cytotoxin (Part 3)

An increase in paracellular permeability of epithelial monolayers also results from treatment with VacA, which may provide a strategy for the bacterium to release nutrients from the host. Phenotypically, VacA induces formation of numerous cytoplasmic vacuoles in host cells. These vacuoles exhibit an acidic microenvironment and express specific markers of late endosomes and lysosomes, the development of which are coordinated by the small GTPase Rab7 and, to a lesser extent, Rab5.

Vacuolating cytotoxin (Part 2)

plasma membraneOther putative VacA receptors include receptor-like protein tyrosine phosphatase-alpha and -beta , but their functional role in vivo is unknown. Together, this evidence suggests an in vivo role for VacA during pathogenesis. birth control pills

There are multiple lines of in vitro evidence showing that VacA modulates host cell signal transduction and function. VacA is associated with the bacterial outer membrane and its secretion allows monomers of the toxin to assemble into hexa-mers or heptamers in a process requiring acid activation.

Vacuolating cytotoxin (Part 1)

Vacuolating cytoxin (VacA) activity is produced by approximately 50% of H pylori isolates, but the vacA gene is encoded in the genome of all H pylori strains . Activity of the protein toxin is dependent on allelic variations in the gene, in which vacA alleles posses either signal region s1 or s2, and midregion ml or m2 (in all possible combinations), and where sl/ml represents the most active toxin . Clinical studies have associated higher VacA activity with more severe disease.

H pylori-induced NF-kB activation (Part 2)

The signalling pathways can vary based on the TLR or Nod activated, and on the adaptor molecules expressed in a particular cell type, leading to distinct gene expression effects. H pylori flagellin is 1000-fold less potent at activating gastric epithelial cell TLR-5 than is flagellin of Salmonella typhimurium . in addition, blockade of TLR-4 using a monoclonal antibody did not prevent H pylori-induced IL-8 secretion from gastric epithelial cells. However, the absence of cytotoxin-associated gene (cag) E abolishes the ability of H pylori to induce NF-kB activity and IL-8 secretion from epithelial cells, but not from monocytes.

H pylori-induced NF-kB activation (Part 1)

Bacterial adhesionBacterial adhesion to multiple host cell receptors, either secreted in the mucous or attached to the plasma membrane, in either healthy or inflamed gastric tissues, likely serves to mediate the chronic colonization observed following H pylori infection. H pylori infection induces secretion of IL-8 from human gastric epithelial cells , a process requiring NF-kB activation.

The proximal aspect of this pathway begins with functional tumour necrosis factor receptor-associated factor-2 and factor-6 adapter proteins, which are necessary to activate NF-KB-inducing kinase.

Adhesion to host epithelial cells

Bacterial adhesion to host cells is often a critical step for microbial infections as a prerequisite to colonization, internalization or the delivery of toxins. In vivo studies to delineate tissue tropism of H pylori have shown that the organism binds specifically to gastric epithelial cells and in areas of gastric metaplasia, with multiple, redundant bacterial adhesins likely participating in adhesion.

Several laboratories have delineated bacterial adhesins and their respective host cell receptors (Table 1). Although adhesin-receptor binding at the host cell surface probably initiates host cell signalling casacades, the precise events triggered by such binding are not characterized.

Modulation of host cell signalling by bacterial pathogens

bacterial pathogensCurrent evidence suggests that bacterial pathogens establish infection and cause disease by modulating host cell signal transduction responses. Indeed, disrupting the ability of pathogens to modulate host signalling cascades can alter the sequelae of infection. For example, treating mice with Gram-positive lipoprotein leads to cytokine production and induces shock; effects that are ameliorated by cotreatment with a monoclonal antibody directed against the host cell lipoprotein receptor, Toll-like receptor (TLR)-2 . Also, humans suffering from traveller’s diarrhea treated with a calmodulin kinase inhibitor experience a decreased severity and duration of the disease.

Complications associated with H pylori infection (Part 2)

Clearly, studies should be performed on populations at risk. However, the declining prevalence of H pylori infection in the Western world suggests changing patterns of transmission. Therefore, studies should be performed on children in both low- and high-risk geographical areas, and with diverse socioeconomic and ethnic backgrounds. In Canada, studies need to be undertaken to identify populations at risk and to determine whether the high prevalence rates of H pylori infection are associated with high complication rates.

Complications associated with H pylori infection (Part 1)

gastric cancerInterestingly, the average annual age-adjusted incidence of hospitalizations for treaty-status Aboriginals aged zero to nine years and 10 to 19 years was not different from other age-matched Manitobans (1.15 versus 1.19 and 18.7 versus 19.5, respectively). However, it is possible that fewer patients received medical attention and that different diagnostic and therapeutic medical practices were followed, leading to a potential underestimation of the severity of the disease in the Wasagamack community.

Changing prevalence of H pylori infection (Part 2)

Children referred to the gastroenterology department of the Hospital for Sick Children, Toronto, Ontario, for upper GI symptoms in the early 1990s were found to have H pylori infection rates of 26% to 43% (Table 2); whereas elsewhere, infection rates appear to be decreasing, with lower infection rates of approximately 5% recently observed in Canadian children referred to tertiary care institutions in the ongoing PSI-PHI study (unpublished data).

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