- Characterization of East-Asian Helicobacter pylori encoding Western EPIYA-ABC CagA
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Kavinda Tissera , Myeong-A Kim , Jing Lai , Sacheera Angulmaduwa , Aeryun Kim , D. Scott Merrell , Ji-Hye Kim , Hanfu Su , Jeong-Heon Cha
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J. Microbiol. 2022;60(2):207-214. Published online November 10, 2021
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DOI: https://doi.org/10.1007/s12275-022-1483-7
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 Abstract
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The polymorphic bacterial oncoprotein, CagA shows geography-
dependent variation in the C-terminal Glu-Pro-Ile-
Tyr-Ala (EPIYA) motifs; East-Asian H. pylori isolates carry
the ABD type while Western isolates carry the ABC type. In
Western isolates, the EPIYA-C motif is sometimes found in
multi-copy and this genotype is associated with disease severity.
Interestingly, a small number of East-Asian H. pylori
isolates have been found to carry Western ABC-type CagA.
To gain a better understanding of these unusual isolates, the
genomes of four Korean H. pylori clinical isolates carrying
ABC-type CagA were sequenced via third generation (Pac-
Bio SMRT) sequencing technology. The obtained data were
utilized for phylogenetic analysis as well as comparison of
additional virulence factors that are known to show geographic-
dependent polymorphisms. Three of four isolates indeed
belonged to the hpEastAsia group and showed typical East-
Asian polymorphism in virulence factors such as homA/B/C,
babA/B/C, and oipA. One isolate grouped to HpAfrica and
showed typical Western polymorphism of virulence factors
such as cagA, homA/B/C, and oipA. To understand the occurrence
of the multi-copy EPIYA-C motif genotype in an East-
Asian H. pylori background, the Korean clinical isolate, K154
was analyzed; this strain belonged to hpEastAsia but encoded
CagA EPIYA-ABCCCC. Based on DNA sequence homology
within the CagA multimerization (CM) sequence that flanked
the EPIYA-C motifs, we predicted that the number of C motifs
might change via homologous recombination. To test this
hypothesis, K154 was cultured for one generation and 287
single colonies were analyzed for the number of EPIYA-C
motifs using PCR-based screening and DNA sequencing verification.
Three out of 284 (1%) single colony isolates showed
changes in the number of EPIYA-C motifs in vitro; one isolate
increased to five EPIYA-C motifs, one decreased to three
EPIYA-C motifs, and one completely deleted the EPIYA-C
motifs. The capacity for dynamic changes in the number of
EPIYA-C repeats of CagA may play a role in generating important
intraspecies diversity in East-Asian H. pylori.
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Citations
Citations to this article as recorded by  - Helicobacter pylori’s Seven-housekeeping Gene and CagA EPIYA Motif Patterns Linking to Gastrointestinal Diseases
Nattamon Narkwichearn, Phataraporn Khumphai, Sasiporn Tongman, K.-S. Cheng
BIO Web of Conferences.2025; 163: 01002. CrossRef - Virulence gene polymorphisms in Shandong Helicobacter pylori strains and their relevance to gastric cancer
Zhijing Xue, Weijia Li, Hailing Ding, Fengyan Pei, Jianzhong Zhang, Yanan Gong, Ruyue Fan, Fang Wang, Youjun Wang, Qing Chen, Yanran Li, Xinyu Yang, Yan Zheng, Guohai Su, Saeid Ghavami
PLOS ONE.2024; 19(9): e0309844. CrossRef - Amino acid deletions at positions 893 and 894 of cytotoxin-associated gene A protein affect Helicobacter pylori gastric epithelial cell interactions
Zhi-Jing Xue, Ya-Nan Gong, Li-Hua He, Lu Sun, Yuan-Hai You, Dong-Jie Fan, Mao-Jun Zhang, Xiao-Mei Yan, Jian-Zhong Zhang
World Journal of Gastroenterology.2024; 30(41): 4449. CrossRef - Characteristics of different types of Helicobacter pylori: New evidence from non-amplified white light endoscopy
Weidong Liu, Wenjie Kong, Wenjia Hui, Chun Wang, Qi Jiang, Hong Shi, Feng Gao
Frontiers in Microbiology.2023;[Epub] CrossRef
- Geographic diversity in Helicobacter pylori oipA genotype between Korean and United States isolates
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Aeryun Kim , Jing Lai , D. Scott Merrell , Ji-Hye Kim , Hanfu Su , Jeong-Heon Cha
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J. Microbiol. 2021;59(12):1125-1132. Published online October 31, 2021
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DOI: https://doi.org/10.1007/s12275-021-1450-8
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989
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Helicobacter pylori outer membrane inflammatory protein
A (OipA) was originally named for its role in inducing inflammation
in the host, as evidenced by high mucosal IL-8
levels. Expression of OipA is regulated by phase variation of
a CT dinucleotide-repeat located in the 5region of the gene.
However, little is known about OipA geographic diversity
across isolates. To address this gap, we conducted a large-scale
molecular epidemiologic analysis using H. pylori clinical isolates
obtained from two geographically distinct populations:
Korea and the United States (US). Most Korean isolates (98.7%)
possessed two copies of oipA located at two specific loci (A
and B) while all US isolates contained only one copy of oipA
at locus A. Furthermore, most Korean oipA (94.8%) possessed
three or less CT repeats while most US oipA (96.6%) contained
five or more CT repeats. Among the two copies, all Korean
H. pylori possessed at least one oipA ‘on’ phase variant while
the single copy of oipA in US isolates showed 56.2% ‘on’ and
43.8% ‘off.’ Thus, host differences seem to have driven geographic
diversification of H. pylori across these populations
such that OipA expression in US isolates is still regulated by
phase variation with 5 or more CT repeats, while Korean isolates
always express OipA; duplication of the oipA combined
with a reduction of CT repeats to three or less ensures continued
expression. En masse, these findings suggest that diversity
in the oipA gene copy number, CT repeats, and phase
variation among H. pylori from different populations may
confer a benefit in adaptation to particular host populations.
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Citations
Citations to this article as recorded by -
Helicobacter pylori
geographic variation: a window into global differences in gastric cancer incidence
Chiamaka D. Okoye, Georgia C. Caso, Timothy L. Cover, Federico Rey
Microbiology and Molecular Biology Reviews.2026;[Epub] CrossRef -
Pathogenicity and virulence of
Helicobacter pylori
: A paradigm of chronic infection
Marguerite Clyne, Tadhg Ó Cróinín
Virulence.2025;[Epub] CrossRef - Genetic diversity of the oipA gene among Helicobacter pylori isolates and clinical outcome in Vietnam
Thi Hong Nhung Thai, Hong Phong Nguyen, Thi Hai Yen Nguyen, Thi Be Hai Nguyen, Thai Hoa Nguyen, Thi Mai Ngan Nguyen, Thi Minh Thi Ha
Infection, Genetics and Evolution.2023; 112: 105438. CrossRef - Characterization of East-Asian Helicobacter pylori encoding Western EPIYA-ABC CagA
Kavinda Tissera, Myeong-A Kim, Jing Lai, Sacheera Angulmaduwa, Aeryun Kim, D. Scott Merrell, Ji-Hye Kim, Hanfu Su, Jeong-Heon Cha
Journal of Microbiology.2022; 60(2): 207. CrossRef
- Role of bacterial γ-glutamyltranspeptidase as a novel virulence factor in bone-resorbing pathogenesis
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Jinmoon Kim , Sungil Jang , Aeryun Kim , Hanfu Su , Niluka Gunawardhana , Yeong-Eui Jeon , Eun Jung Bak , Ji-Hye Kim , Jeong-Heon Cha
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J. Microbiol. 2016;54(5):396-402. Published online April 20, 2016
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DOI: https://doi.org/10.1007/s12275-016-6137-1
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Mammalian γ-glutamyltranspeptidase (GGT) has been identified
as a bone-resorbing factor. Since GGT of Bacillus subtilis
exhibits similarity in their primary structure and enzymatic
characteristics with mammalian GGTs, the bone-resorbing
activity of bacterial GGT was examined in this study. Osteoclastogenesis
was performed in a co-culture system of mouse
calvaria-derived osteoblasts and bone marrow cells. A conditioned
medium from GGT-overproducing B. subtilis culture
showed significantly higher activity of osteoclast formation
than a conditioned medium from wild-type B. subtilis culture.
Recombinant GGT (rGGT) of wild-type B. subtilis and an
enzymatic activity-defected rGGT of B. subtilis 2288 mutant
were expressed in Escherichia coli and purified using His tag.
Both purified rGGTs induced similar levels of osteoclastogenesis,
suggesting that B. subtilis GGT possesses virulent boneresorbing
activity and its activity is probably independent of
its enzymatic activity. Furthermore, a recombinant protein of
B. subtilis GGT heavy subunit (Bs rGGT/H) showed strong
activity of osteoclastogenesis while the light subunit failed to
show strong activity, suggesting that the bone-resorbing activity
is mainly located at the heavy subunit. More importantly,
the GGT enzymatic activity may not be required for this virulence
activity since the light subunit contains the catalytic
pocket. In addition, B. subtilis rGGT stimulated mRNA expressions
of receptor activator of nuclear factor kappa-B ligand
(RANKL) and cyclooxygenase-2 (COX-2), while an
osteoprotegerin inhibited the osteoclast formation induced by Bs rGGT/H. This is the first demonstration that bacterial
GGT itself is sufficient to act as a bone-resorbing virulence
factor via RANKL-dependent pathway. Therefore, it can be
hypothesized that GGT of periodontopathic bacteria may play
an important role as a virulence factor in bone destruction.
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Citations
Citations to this article as recorded by - Bacterial Gamma-Glutamyl Transpeptidase, an Emerging Biocatalyst: Insights Into Structure–Function Relationship and Its Biotechnological Applications
Meenu Saini, Amuliya Kashyap, Shruti Bindal, Kuldeep Saini, Rani Gupta
Frontiers in Microbiology.2021;[Epub] CrossRef - Quantitative analysis of γ-glutamylpeptides by liquid chromatography-mass spectrometry and application for γ-glutamyltransferase assays
Sho Kobayashi, Yoshinori Tokairin, Takeru Miyakoshi, Takuya Saito, Keita Nagaoka, Yoshitaka Ikeda, Junichi Fujii, Hiroyuki Konno
Analytical Biochemistry.2019; 578: 13. CrossRef - Isolation of γ-Glutamyl-Transferase Rich-Bacteria from Mouse Gut by a Near-Infrared Fluorescent Probe with Large Stokes Shift
Tao Liu, Qiu-Long Yan, Lei Feng, Xiao-Chi Ma, Xiang-Ge Tian, Zhen-Long Yu, Jing Ning, Xiao-Kui Huo, Cheng-Peng Sun, Chao Wang, Jing-Nan Cui
Analytical Chemistry.2018; 90(16): 9921. CrossRef - Heterologous expression and enzymatic characterization of γ-glutamyltranspeptidase from Bacillus amyloliquefaciens
Jung-Min Lee, Jaejung Lee, Gyeong-Hwa Nam, Byung-Sam Son, Myoung-Uoon Jang, So-Won Lee, Byung-Serk Hurh, Tae-Jip Kim
Journal of Microbiology.2017; 55(2): 147. CrossRef - Scientific Opinion on the update of the list of QPS‐recommended biological agents intentionally added to food or feed as notified to EFSA†
Antonia Ricci, Ana Allende, Declan Bolton, Marianne Chemaly, Robert Davies, Rosina Girones, Lieve Herman, Konstantinos Koutsoumanis, Roland Lindqvist, Birgit Nørrung, Lucy Robertson, Giuseppe Ru, Moez Sanaa, Marion Simmons, Panagiotis Skandamis, Emma Snar
EFSA Journal.2017;[Epub] CrossRef
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