Dynamic Expansion and Contraction of <italic toggle="yes">cagA</italic> Copy Number in <italic toggle="yes">Helicobacter pylori</italic> Impact Development of Gastric Disease

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 molecul...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/3b40edfbea66457ea16dcf830c88fbb0
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:3b40edfbea66457ea16dcf830c88fbb0
record_format	dspace
spelling	oai:doaj.org-article:3b40edfbea66457ea16dcf830c88fbb02021-11-15T15:51:07ZDynamic Expansion and Contraction of <italic toggle="yes">cagA</italic> Copy Number in <italic toggle="yes">Helicobacter pylori</italic> Impact Development of Gastric Disease10.1128/mBio.01779-162150-7511https://doaj.org/article/3b40edfbea66457ea16dcf830c88fbb02017-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01779-16https://doaj.org/toc/2150-7511ABSTRACT 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.Sungil JangHanfu SuFaith C. BlumSarang BaeYun Hui ChoiAeryun KimYoungmin A. HongJinmoon KimJi-Hye KimNiluka GunawardhanaYeong-Eui JeonYun-Jung YooD. Scott MerrellLinhu GeJeong-Heon ChaAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 8, Iss 1 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 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 Dynamic Expansion and Contraction of <italic toggle="yes">cagA</italic> Copy Number in <italic toggle="yes">Helicobacter pylori</italic> Impact Development of Gastric Disease
description	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.
format	article
author	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
author_facet	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
author_sort	Sungil Jang
title	Dynamic Expansion and Contraction of <italic toggle="yes">cagA</italic> Copy Number in <italic toggle="yes">Helicobacter pylori</italic> Impact Development of Gastric Disease
title_short	Dynamic Expansion and Contraction of <italic toggle="yes">cagA</italic> Copy Number in <italic toggle="yes">Helicobacter pylori</italic> Impact Development of Gastric Disease
title_full	Dynamic Expansion and Contraction of <italic toggle="yes">cagA</italic> Copy Number in <italic toggle="yes">Helicobacter pylori</italic> Impact Development of Gastric Disease
title_fullStr	Dynamic Expansion and Contraction of <italic toggle="yes">cagA</italic> Copy Number in <italic toggle="yes">Helicobacter pylori</italic> Impact Development of Gastric Disease
title_full_unstemmed	Dynamic Expansion and Contraction of <italic toggle="yes">cagA</italic> Copy Number in <italic toggle="yes">Helicobacter pylori</italic> Impact Development of Gastric Disease
title_sort	dynamic expansion and contraction of <italic toggle="yes">caga</italic> copy number in <italic toggle="yes">helicobacter pylori</italic> impact development of gastric disease
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/3b40edfbea66457ea16dcf830c88fbb0
work_keys_str_mv	AT sungiljang dynamicexpansionandcontractionofitalictoggleyescagaitaliccopynumberinitalictoggleyeshelicobacterpyloriitalicimpactdevelopmentofgastricdisease AT hanfusu dynamicexpansionandcontractionofitalictoggleyescagaitaliccopynumberinitalictoggleyeshelicobacterpyloriitalicimpactdevelopmentofgastricdisease AT faithcblum dynamicexpansionandcontractionofitalictoggleyescagaitaliccopynumberinitalictoggleyeshelicobacterpyloriitalicimpactdevelopmentofgastricdisease AT sarangbae dynamicexpansionandcontractionofitalictoggleyescagaitaliccopynumberinitalictoggleyeshelicobacterpyloriitalicimpactdevelopmentofgastricdisease AT yunhuichoi dynamicexpansionandcontractionofitalictoggleyescagaitaliccopynumberinitalictoggleyeshelicobacterpyloriitalicimpactdevelopmentofgastricdisease AT aeryunkim dynamicexpansionandcontractionofitalictoggleyescagaitaliccopynumberinitalictoggleyeshelicobacterpyloriitalicimpactdevelopmentofgastricdisease AT youngminahong dynamicexpansionandcontractionofitalictoggleyescagaitaliccopynumberinitalictoggleyeshelicobacterpyloriitalicimpactdevelopmentofgastricdisease AT jinmoonkim dynamicexpansionandcontractionofitalictoggleyescagaitaliccopynumberinitalictoggleyeshelicobacterpyloriitalicimpactdevelopmentofgastricdisease AT jihyekim dynamicexpansionandcontractionofitalictoggleyescagaitaliccopynumberinitalictoggleyeshelicobacterpyloriitalicimpactdevelopmentofgastricdisease AT nilukagunawardhana dynamicexpansionandcontractionofitalictoggleyescagaitaliccopynumberinitalictoggleyeshelicobacterpyloriitalicimpactdevelopmentofgastricdisease AT yeongeuijeon dynamicexpansionandcontractionofitalictoggleyescagaitaliccopynumberinitalictoggleyeshelicobacterpyloriitalicimpactdevelopmentofgastricdisease AT yunjungyoo dynamicexpansionandcontractionofitalictoggleyescagaitaliccopynumberinitalictoggleyeshelicobacterpyloriitalicimpactdevelopmentofgastricdisease AT dscottmerrell dynamicexpansionandcontractionofitalictoggleyescagaitaliccopynumberinitalictoggleyeshelicobacterpyloriitalicimpactdevelopmentofgastricdisease AT linhuge dynamicexpansionandcontractionofitalictoggleyescagaitaliccopynumberinitalictoggleyeshelicobacterpyloriitalicimpactdevelopmentofgastricdisease AT jeongheoncha dynamicexpansionandcontractionofitalictoggleyescagaitaliccopynumberinitalictoggleyeshelicobacterpyloriitalicimpactdevelopmentofgastricdisease
_version_	1718427391383044096

Dynamic Expansion and Contraction of <italic toggle="yes">cagA</italic> Copy Number in <italic toggle="yes">Helicobacter pylori</italic> Impact Development of Gastric Disease

Ejemplares similares