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Dynamic Expansion and Contraction of cagA Copy Number in Helicobacter pylori Impact Development of Gastric Disease

Authors
 Sungil Jang  ;  Hanfu Su  ;  Faith C. Blum  ;  Sarang Bae  ;  Yun Hui Choi  ;  Aeryun Kim  ;  Youngmin A. Hong  ;  Jinmoon Kim  ;  Ji-Hye Kim  ;  Niluka Gunawardhana  ;  Yeong-Eui Jeon  ;  Yun-Jung Yoo  ;  D. Scott Merrell  ;  Linhu Ge  ;  Jeong-Heon Cha 
Citation
 MBIO, Vol.8(1) : e01779-16, 2017 
Journal Title
 MBIO 
Issue Date
2017
MeSH
Antigens, Bacterial/genetics* ; Bacterial Proteins/genetics* ; Gene Dosage* ; Gene Expression Profiling ; Helicobacter Infections/microbiology* ; Helicobacter Infections/pathology* ; Helicobacter pylori/genetics* ; Helicobacter pylori/pathogenicity ; Humans ; Korea ; Repetitive Sequences, Nucleic Acid ; Sequence Analysis, DNA ; Sequence Homology ; Stomach Diseases/microbiology* ; Stomach Diseases/pathology* ; United States
Abstract
Infection with Helicobacter pylori is a major risk factor for development of gastric disease, including gastric cancer. Patients infected with H. pylori strains 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 the cagA copy number dynamically expands and contracts in H. pylori Analysis of strain PMSS1 revealed a heterogeneous population in terms of numbers of cagA copies; strains carried from zero to four copies of cagA that were arranged as direct repeats within the chromosome. Each of the multiple copies of cagA was expressed and encoded functional CagA; strains with more cagA repeats 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 three cagA homologous areas (CHAs) within the cagA repeats. Of these, CHA-ud flanked each of the cagA copies and is likely important for the dynamic variation of cagA copy numbers. Analysis of a large panel of clinical isolates showed that 7.5% of H. pylori strains isolated in the United States harbored multiple cagA repeats, while none of the tested Korean isolates carried more than one copy of cagA Finally, H. pylori strains carrying multiple cagA copies were differentially associated with gastric disease. Thus, the dynamic expansion and contraction of cagA copy numbers may serve as a novel mechanism by which H. pylori modulates gastric disease development.IMPORTANCE Severity of H. 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 all H. pylori strains carry one or no copies of cagA This study showed that H. pylori can carry multiple tandem copies of cagA that can change dynamically. Isolates harboring more cagA copies produced more CagA, thus enhancing toxicity to host cells. Analysis of 314 H. pylori clinical strains isolated from patients in South Korea and the United States showed that 7.5% of clinical strains in the United States carried multiple cagA copies whereas none of the South Korean strains did. This study demonstrated a novel molecular mechanism by which H. pylori dynamically modulates cagA copy number, which affects CagA expression and activity and may impact downstream development of gastric disease.
Files in This Item:
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DOI
10.1128/mBio.01779-16
Appears in Collections:
2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Ji Hye(김지혜)
Kim, Jin Moon(김진문)
Yoo, Yun Jung(유윤정) ORCID logo https://orcid.org/0000-0002-0045-9597
Jang, Sungil(장성일) ORCID logo https://orcid.org/0000-0001-6144-6899
Jeon, Yeong Eui(전영의) ORCID logo https://orcid.org/0000-0001-6316-4107
Cha, Jung Heon(차정헌) ORCID logo https://orcid.org/0000-0002-9385-2653
Hong, Youngmin A.(홍영민)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/154685
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