Editing Helicobacter pylori (section)

===CagA===
'''CagA''' (cytotoxin-associated antigen A) is a major [[virulence factor]] for ''H.&nbsp;pylori'', an [[oncoprotein]] that is encoded by the ''cagA'' gene. Bacterial strains with the ''cagA'' gene are associated with the ability to cause ulcers, MALT lymphomas, and gastric cancer.<ref name="Wallden">{{cite journal |vauthors=Wallden K, Rivera-Calzada A, Waksman G |title=Type IV secretion systems: versatility and diversity in function |journal=Cell Microbiol |volume=12 |issue=9 |pages=1203–12 |date=September 2010 |pmid=20642798 |pmc=3070162 |doi=10.1111/j.1462-5822.2010.01499.x |url=}}</ref><ref name="pmid11283049">{{cite journal | vauthors = Broutet N, Marais A, Lamouliatte H, de Mascarel A, Samoyeau R, Salamon R, Mégraud F | title = cagA Status and eradication treatment outcome of anti-Helicobacter pylori triple therapies in patients with nonulcer dyspepsia | journal = Journal of Clinical Microbiology | volume = 39 | issue = 4 | pages = 1319–22 | date = April 2001 | pmid = 11283049 | pmc = 87932 | doi = 10.1128/JCM.39.4.1319-1322.2001 }}</ref> The ''cagA'' gene codes for a relatively long (1186-[[amino acid]]) protein. The ''cag'' [[pathogenicity island]] (PAI) has about 30 genes, part of which code for a complex [[type IV secretion system]] (T4SS or TFSS). The low [[GC-content]] of the ''cag'' PAI relative to the rest of the ''Helicobacter'' genome suggests the island was acquired by [[horizontal gene transfer|horizontal transfer]] from another bacterial species.<ref name="Tomb 1997"/> The [[serine protease]] [[Peptidase Do|HtrA]] also plays a major role in the pathogenesis of ''H.&nbsp;pylori''. The HtrA protein enables the bacterium to transmigrate across the host cells' epithelium, and is also needed for the translocation of CagA.<ref name="Zawilak-Pawlik2019">{{cite journal | vauthors = Zawilak-Pawlik A, Zarzecka U, Żyła-Uklejewicz D, Lach J, Strapagiel D, Tegtmeyer N, Böhm M, Backert S, Skorko-Glonek J | title = Establishment of serine protease htrA mutants in Helicobacter pylori is associated with secA mutations | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 11794 | date = August 2019 | pmid = 31409845 | pmc = 6692382 | doi = 10.1038/s41598-019-48030-6 | bibcode = 2019NatSR...911794Z }}</ref>

The virulence of ''H.&nbsp;pylori'' may be increased by genes of the ''cag'' pathogenicity island; about 50–70% of ''H.&nbsp;pylori'' strains in Western countries carry it.<ref name="Peek 2006">{{cite journal | vauthors = Peek RM, Crabtree JE | title = Helicobacter infection and gastric neoplasia | journal = The Journal of Pathology | volume = 208 | issue = 2 | pages = 233–48 | date = January 2006 | pmid = 16362989 | doi = 10.1002/path.1868 | s2cid = 31718278 | doi-access = free }}</ref> Western people infected with strains carrying the ''cag'' PAI have a stronger inflammatory response in the stomach and are at a greater risk of developing peptic ulcers or stomach cancer than those infected with strains lacking the island.<ref name="Kusters2006"/> Following attachment of ''H.&nbsp;pylori'' to stomach epithelial cells, the type IV secretion system expressed by the ''cag'' PAI "injects" the [[inflammation]]-inducing agent, peptidoglycan, from their own [[cell wall]]s into the epithelial cells. The injected peptidoglycan is recognized by the cytoplasmic [[pattern recognition receptor]] (immune sensor) Nod1, which then stimulates expression of [[cytokines]] that promote inflammation.<ref>{{cite journal | vauthors = Viala J, Chaput C, Boneca IG, Cardona A, Girardin SE, Moran AP, Athman R, Mémet S, Huerre MR, Coyle AJ, DiStefano PS, Sansonetti PJ, Labigne A, Bertin J, Philpott DJ, Ferrero RL | title = Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island | journal = Nature Immunology | volume = 5 | issue = 11 | pages = 1166–74 | date = November 2004 | pmid = 15489856 | doi = 10.1038/ni1131 | s2cid = 2898805 }}</ref>

The type-IV [[secretion]] apparatus also injects the ''cag'' PAI-encoded protein CagA into the stomach's epithelial cells, where it disrupts the [[cytoskeleton]], adherence to adjacent cells, intracellular signaling, [[Epithelial polarity|cell polarity]], and other cellular activities.<ref name="Backert 2008">{{cite journal | vauthors = Backert S, Selbach M | title = Role of type IV secretion in Helicobacter pylori pathogenesis | journal = Cellular Microbiology | volume = 10 | issue = 8 | pages = 1573–81 | date = August 2008 | pmid = 18410539 | doi = 10.1111/j.1462-5822.2008.01156.x | s2cid = 37626 | doi-access = free }}</ref> Once inside the cell, the CagA protein is [[Phosphorylation|phosphorylated]] on [[Protein kinase#Tyrosine-specific protein kinases|tyrosine residues]] by a host cell membrane-associated [[tyrosine kinase]] (TK). CagA then allosterically activates [[protein tyrosine phosphatase]]/[[protooncogene]] [[Shp2]].<ref name="Hatakeyama">{{cite journal | vauthors = Hatakeyama M | title = Oncogenic mechanisms of the Helicobacter pylori CagA protein | journal = Nature Reviews. Cancer | volume = 4 | issue = 9 | pages = 688–94 | date = September 2004 | pmid = 15343275 | doi = 10.1038/nrc1433 | s2cid = 1218835 }}</ref>
These proteins are directly toxic to cells lining the stomach and signal strongly to the immune system that an invasion is under way. As a result of the bacterial presence, neutrophils and macrophages set up residence in the tissue to fight the bacteria assault.<ref>{{cite journal | doi=10.1007/s12156-008-0068-y | title=The role of Helicobacter pylori in the pathogenesis of gastric malignancies | date=2008 | journal=Oncology Reviews | volume=2 | issue=3 | pages=131–140 | vauthors = Kim W, Moss SF }}</ref> Pathogenic strains of ''H.&nbsp;pylori'' have been shown to activate the [[epidermal growth factor receptor]] (EGFR), a [[membrane protein]] with a TK [[protein domain|domain]]. Activation of the EGFR by ''H.&nbsp;pylori'' is associated with altered [[signal transduction]] and [[gene expression]] in host epithelial cells that may contribute to pathogenesis. A [[C-terminus|C-terminal]] region of the CagA protein (amino acids 873–1002) has also been suggested to be able to regulate host cell [[Transcription (genetics)|gene transcription]], independent of protein tyrosine phosphorylation.<ref name="pmid11283049"/> A great deal of diversity exists between strains of ''H.&nbsp;pylori'', and the strain that infects a person can predict the outcome.