title: Dynamic Expansion and Contraction ofcagACopy Number inHelicobacter pyloriImpact Development of Gastric Disease.
abstract: Infection withHelicobacter pyloriis a major risk factor for development of gastric disease, including gastric cancer. Patients infected withH. pyloristrains that express CagA are at even greater risk of gastric carcinoma. Given the importance of CagA, this report describes a new molecular mechanism by which thecagAcopy number dynamically expands and contracts inH. pyloriAnalysis of strain PMSS1 revealed a heterogeneous population in terms of numbers ofcagAcopies; strains carried from zero to four copies ofcagAthat were arranged as direct repeats within the chromosome. Each of the multiple copies ofcagAwas expressed and encoded functional CagA; strains with morecagArepeats exhibited higher levels of CagA expression and increased levels of delivery and phosphorylation of CagA within host cells. This concomitantly resulted in more virulent phenotypes as measured by cell elongation and interleukin-8 (IL-8) induction. Sequence analysis of the repeat region revealed threecagAhomologous areas (CHAs) within thecagArepeats. Of these, CHA-ud flanked each of thecagAcopies and is likely important for the dynamic variation ofcagAcopy numbers. Analysis of a large panel of clinical isolates showed that 7.5% ofH. pyloristrains isolated in the United States harbored multiplecagArepeats, while none of the tested Korean isolates carried more than one copy ofcagAFinally,H. pyloristrains carrying multiplecagAcopies were differentially associated with gastric disease. Thus, the dynamic expansion and contraction ofcagAcopy numbers may serve as a novel mechanism by whichH. pylorimodulates gastric disease development.IMPORTANCESeverity ofH. pylori-associated disease is directly associated with carriage of the CagA toxin. Though the sequences of the CagA protein can differ across strains, previous analyses showed that virtually allH. pyloristrains carry one or no copies ofcagAThis study showed thatH. pylorican carry multiple tandem copies ofcagAthat can change dynamically. Isolates harboring morecagAcopies produced more CagA, thus enhancing toxicity to host cells. Analysis of 314H. pyloriclinical strains isolated from patients in South Korea and the United States showed that 7.5% of clinical strains in the United States carried multiplecagAcopies whereas none of the South Korean strains did. This study demonstrated a novel molecular mechanism by whichH. pyloridynamically modulatescagAcopy number, which affects CagA expression and activity and may impact downstream development of gastric disease.
authors.affiliation: Department of Oral Biology, Oral Science Research Center, Department of Applied Life Science, The Graduate School, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, Republic of Korea.
authors.forename: Sungil
authors.identifier: 0000-0001-6144-6899
authors.initials: S
authors.lastname: Jang
authors.affiliation: Department of Oral Biology, Oral Science Research Center, Department of Applied Life Science, The Graduate School, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, Republic of Korea.
authors.forename: Hanfu
authors.initials: H
authors.lastname: Su
authors.affiliation: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
authors.forename: Faith C
authors.initials: FC
authors.lastname: Blum
authors.affiliation: Department of Oral Biology, Oral Science Research Center, Department of Applied Life Science, The Graduate School, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, Republic of Korea.
authors.forename: Sarang
authors.initials: S
authors.lastname: Bae
authors.affiliation: Department of Oral Biology, Oral Science Research Center, Department of Applied Life Science, The Graduate School, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, Republic of Korea.
authors.forename: Yun Hui
authors.initials: YH
authors.lastname: Choi
authors.affiliation: Department of Oral Biology, Oral Science Research Center, Department of Applied Life Science, The Graduate School, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, Republic of Korea.
authors.forename: Aeryun
authors.initials: A
authors.lastname: Kim
authors.affiliation: Department of Oral Biology, Oral Science Research Center, Department of Applied Life Science, The Graduate School, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, Republic of Korea.
authors.forename: Youngmin A
authors.initials: YA
authors.lastname: Hong
authors.affiliation: Department of Oral Biology, Oral Science Research Center, Department of Applied Life Science, The Graduate School, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, Republic of Korea.
authors.forename: Jinmoon
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Dental Hygiene, Jeonju Kijeon College, Jeonju, Republic of Korea.
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Oral Biology, Oral Science Research Center, Department of Applied Life Science, The Graduate School, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, Republic of Korea.
authors.forename: Niluka
authors.initials: N
authors.lastname: Gunawardhana
authors.affiliation: Department of Oral Biology, Oral Science Research Center, Department of Applied Life Science, The Graduate School, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, Republic of Korea.
authors.forename: Yeong-Eui
authors.initials: YE
authors.lastname: Jeon
authors.affiliation: Department of Oral Biology, Oral Science Research Center, Department of Applied Life Science, The Graduate School, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, Republic of Korea.
authors.forename: Yun-Jung
authors.initials: YJ
authors.lastname: Yoo
authors.affiliation: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
authors.forename: D Scott
authors.initials: DS
authors.lastname: Merrell
authors.affiliation: Microbiology & Molecular Biology, Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Stomatology Hospital of Guangzhou Medical University, China gelinhu@yeah.net jcha@yuhs.ac.
authors.forename: Linhu
authors.initials: L
authors.lastname: Ge
authors.affiliation: Department of Oral Biology, Oral Science Research Center, Department of Applied Life Science, The Graduate School, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, Republic of Korea gelinhu@yeah.net jcha@yuhs.ac.|Microbiology & Molecular Biology, Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Stomatology Hospital of Guangzhou Medical University, China.
authors.forename: Jeong-Heon
authors.initials: JH
authors.lastname: Cha
mesh_terms: D000942:Antigens, Bacterial / Q000235:genetics*; D001426:Bacterial Proteins / Q000235:genetics*; D018628:Gene Dosage; D020869:Gene Expression Profiling; D016481:Helicobacter Infections / Q000382:microbiology* / Q000473:pathology*; D016480:Helicobacter pylori / Q000235:genetics* / Q000472:pathogenicity; D006801:Humans; D007723:Korea; D012091:Repetitive Sequences, Nucleic Acid; D017422:Sequence Analysis, DNA; D017385:Sequence Homology; D013272:Stomach Diseases / Q000382:microbiology* / Q000473:pathology*; D014481:United States
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C080866:cagA protein, Helicobacter pylori