title: Attenuated CagA oncoprotein in Helicobacter pylori from Amerindians in Peruvian Amazon.
abstract: Population genetic analyses of bacterial genes whose products interact with host tissues can give new understanding of infection and disease processes. Here we show that strains of the genetically diverse gastric pathogen Helicobacter pylori from Amerindians from the remote Peruvian Amazon contain novel alleles of cagA, a major virulence gene, and reveal distinctive properties of their encoded CagA proteins. CagA is injected into the gastric epithelium where it hijacks pleiotropic signaling pathways, helps Hp exploit its special gastric mucosal niche, and affects the risk that infection will result in overt gastroduodenal diseases including gastric cancer. The Amerindian CagA proteins contain unusual but functional tyrosine phosphorylation motifs and attenuated CRPIA motifs, which affect gastric epithelial proliferation, inflammation, and bacterial pathogenesis. Amerindian CagA proteins induced less production of IL-8 and cancer-associated Mucin 2 than did those of prototype Western or East Asian strains and behaved as dominant negative inhibitors of action of prototype CagA during mixed infection of Mongolian gerbils. We suggest that Amerindian cagA is of relatively low virulence, that this may have been selected in ancestral strains during infection of the people who migrated from Asia into the Americas many thousands of years ago, and that such attenuated CagA proteins could be useful therapeutically.
authors.affiliation: Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Suzuki
authors.forename: Kotaro
authors.initials: K
authors.lastname: Kiga
authors.forename: Dangeruta
authors.initials: D
authors.lastname: Kersulyte
authors.forename: Jaime
authors.initials: J
authors.lastname: Cok
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Hooper
authors.forename: Hitomi
authors.initials: H
authors.lastname: Mimuro
authors.forename: Takahito
authors.initials: T
authors.lastname: Sanada
authors.forename: Shiho
authors.initials: S
authors.lastname: Suzuki
authors.forename: Masaaki
authors.initials: M
authors.lastname: Oyama
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kozuka-Hata
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kamiya
authors.forename: Quan-Ming
authors.initials: QM
authors.lastname: Zou
authors.forename: Robert H
authors.initials: RH
authors.lastname: Gilman
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Berg
authors.forename: Chihiro
authors.initials: C
authors.lastname: Sasakawa
mesh_terms: D000483:Alleles; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D019143:Evolution, Molecular; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism / Q000382:microbiology; D005849:Gerbillinae; D016481:Helicobacter Infections / Q000235:genetics / Q000378:metabolism*; D016480:Helicobacter pylori / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D006801:Humans; D007199:Indians, South American; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D055262:Mucin-2 / Q000235:genetics / Q000378:metabolism; D010568:Peru; D010766:Phosphorylation; D015398:Signal Transduction / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000382:microbiology; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C508606:CXCL8 protein, human; D016209:Interleukin-8; D055262:Mucin-2; D037521:Virulence Factors; C080866:cagA protein, Helicobacter pylori