Pathogenesis of Helicobacter pylori Infection
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Pathogenesis of Helicobacter pylori Infection
The gastrointestinal tract represents an important barrier between human hosts and microbial populations. One potential consequence of host-microbial interactions is the development of mucosal inflammation. A paradigm for such chronic host-microbial relationships is carriage of Helicobacter pylori, Gram-negative bacteria that colonize the stomachs of humans and primates. H. pylori colonization induces chronic gastritis in essentially all hosts, a process that increases the risk of developing peptic ulceration, distal gastric adenocarcinoma, and gastric mucosal lymphoproliferative disease. However, only a small percentage of persons carrying H. pylori develop clinical sequelae; enhanced risk may be related to differences in expression of specific bacterial products, to variations in the host inflammatory response to the bacteria, or to specific interactions between host and microbe (Ref.1).

The whole genome of H. pylori consists of several putative virulence factors, including VacA (Vacuolating cytotoxin A), IceA, OipA, HrgA, LPS (Lipopolysaccharide), and NAP (Neutrophil Activating Protein). The CagPAI (Cag Pathogenicity Island), a complex of Cag genes (CagE, CagG, CagH, CagI, CagL, and CagM) coding 40-kb protein is a major virulence factor of H. pylori. This lesion codes for the Type IV secretion machinery system forming a cylinder-like structure connected to epithelial cells. Many virulence gene products or other interactive proteins are transferred into the host cells via this system (Ref.2). The single layer of epithelial cells that lines the gastric mucosa is the initial site of interaction between the host and H. pylori. During infection, the bacterium enters the gastric lumen where the urease allows survival in the acidic environment by producing ammonia molecules that buffer cytosolic and periplasmic pH as well as the surface layer around the bacterium. The flagella propel the helicoidal bacterium into the mucus layer and allow it to reach the apical domain of gastric epithelial cells, to which it sticks using specialized adhesins. H. pylori then inject the CagA protein into the host cells by Type IV secretion system and release other toxic factors such as VacA and HP-NAP (H. pylori NAP). VacA induces alterations of tight junctions and the formation of large vacuoles. The HP-NAP crosses the epithelial lining and recruits neutrophils and monocytes, which extravasate and cause tissue damage by releasing ROIs (Reactive Oxygen Intermediates). Injected Cag proteins cause alteration of the cytoskeleton, pedestal formation and signal the nucleus to release proinflammatory lymphokines, which amplify the inflammatory reaction with recruitment of lymphocytes and further induce the release of ROIs. The combined toxic activity of VacA and of ROIs leads to tissue damage that is enhanced by loosening of the protective mucus layer and acid permeation. VacA also inserts into mitochondrial membranes and induce CytoC (Cytochrome-C) release, and activate the Caspase3-dependent cell-death signaling cascade (Ref.3). Another mechanism by which H. pylori can stimulate apoptosis is by inducing expression of the cell-surface receptor Fas and FasL (Fas Ligand). The pathogen can also bind to class MHC-II (Major Histocompatibility Complex-II) molecules on the surface of gastric epithelial cells, inducing their apoptosis. H. pylori urease and porins may contribute to extravasation and chemotaxis of neutrophils. The gastric epithelium of H. pylori-infected person has enhanced levels of IL-1Beta (Interleukin-1Beta), IL-2, IL-6, IL-8, IL-12 and TNF-Alpha (Tumor Necrosis Factor-Alpha). Among these, IL-8, a potent neutrophil-activating chemokine expressed by gastric epithelial cells, apparently has a central role. H. pylori strains carrying the Cag-PAI induce a far stronger IL-8 response than Cag-negative strains, and this response depends on activation of NF-KappaB (Nuclear Factor-kappaB) and the early-response transcription factor Activating Protein-1 (Ref.4). Macrophages that participate in IL-8 production produce proinflammatory cytokines involved in the activation of the recruited cells, in particular T Helper cells (TH0, TH1, and TH2). In turn, TH1-type cytokines such as Ifn-Gamma (Interferon-Gamma) induce the expression of MHC-II and accessory molecules B7-1 and B7-2 by epithelial cells, making them competent for antigen presentation. The cytotoxin VacA and Fas-mediated apoptosis induced by TNF-Alpha leads to disruption of the epithelial barrier, facilitating translocation of bacterial antigens and leading to further activation of macrophages. Cytokines produced by macrophages can also alter the secretion of mucus, contributing to H. pylori-mediated disruption of the mucous layer. TNF-Alpha, IL-1Beta, Ifn-Gamma and PLA2 (Phospholipase-A2) increases gastrin release, causes alterations in mucus glycoproteins and stimulate parietal and enterochromaffin cells and acid secretion. TNF-Alpha also induces a decrease in the number of antral D cells, leading to decreased somatostatin production and indirectly enhancing acid production (Ref.5).

H. pylori infection in humans represents a serious public health concern. The WHO (World Health Organization) classifies this bacterium as a Type 1 carcinogen. The clinical course of H. pylori infection is highly variable and is influenced by both microbial and host factors. The pattern and distribution of gastritis correlate strongly with the risk of clinical sequelae, namely duodenal or gastric ulcers, mucosal atrophy, gastric carcinoma, or gastric lymphoma. Patients with antral-predominant gastritis, the most common form of H. pylori gastritis, are predisposed to duodenal ulcers, whereas patients with corpus-predominant gastritis and multifocal atrophy are more likely to have gastric ulcers, gastric atrophy, intestinal metaplasia, and ultimately gastric carcinoma. In addition, several non-gastrointestinal tract diseases associated with H. pylori infection include diabetes mellitus, thyroiditis, heart diseases, rheumatoid arthritis, dermatological disorders, hepatic encephalopathy, childhood anemia and several more (Ref.6). H. pylori are also associated with stomach cancer and a rare type of lymphocytic tumor of the stomach called MALT (Mucosa-Associated Lymphoid Tissue) lymphoma. Genetic variability in host factors such as gender, blood group antigens, human lymphocyte antigen type, and the age of the host when the infection was acquired play a primary role in determining different clinical outcomes. Environmental factors may also play a role in the outcome of the infection. Socioeconomic class, which affects living conditions and sanitation, may increase the risk of exposure to the bacterium. Tobacco smoking increases the risk of duodenal ulceration for patients infected with H. pylori. Accurate tests for the detection of H. pylori infection include blood antibody tests, UBT (Urea Breath Test), stool antigen tests and endoscopic biopsies. The UBT is a safe, easy, and accurate test for the presence of H. pylori in the stomach. The breath test relies on the ability of H. pylori to break down urea into carbon dioxide which is eliminated from the body in the breath. Endoscopy is also an accurate test for diagnosing H. pylori as well as the inflammation and ulcers that it causes (Ref.1).