Copyright
©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
Discovery of unique African Helicobacter pylori CagA-multimerization motif in the Dominican Republic
Takaaki Ono, Modesto Cruz, Hiroyuki Nagashima, Phawinee Subsomwong, Junko Akada, Takashi Matsumoto, Tomohisa Uchida, Rumiko Suzuki, Celso Hosking, José A Jiménez Abreu, Yoshio Yamaoka
Takaaki Ono, Phawinee Subsomwong, Junko Akada, Takashi Matsumoto, Rumiko Suzuki, Yoshio Yamaoka, Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu 879-5593, Japan
Takaaki Ono, Criminal Investigation Laboratory, Oita Prefectural Police Headquarters, Oita 870-1117, Japan
Modesto Cruz, Celso Hosking, Institute of Microbiology and Parasitology, IMPA, Faculty of Science, Autonomous University of Santo Domingo, Santo Domingo 10103, Dominican Republic
Modesto Cruz, Department of Biomedical Research, National Institute of Medicine and Diagnostic Imaging, Santo Domingo 10107, Dominican Republic
Hiroyuki Nagashima, Department of Gastroenterology, Hokkaido Cancer Center, Sapporo 003-0804, Japan
Tomohisa Uchida, Department of Molecular Pathology, Oita University Faculty of Medicine, Yufu 879-5593, Japan
José A Jiménez Abreu, Dominican-Japanese Digestive Disease Center, Dr Luis E. Aybar Health and Hygiene City, Santo Domingo 10302, Dominican Republic
Yoshio Yamaoka, Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, TX 77030, United States
Author contributions: Suzuki R, Cruz M and Yamaoka Y conceived and designed the experiments; Ono T, Nagashima H, Subsomwong P and Uchida T performed the experiments; Ono T, Akada J, Matsumoto T, Suzuki R and Yamaoka Y analyzed the data; Cruz M, Hosking C and Jiménez Abreu JA contributed to obtaining the samples; Ono T and Yamaoka Y wrote the manuscript; Yamaoka Y and Cruz M revised the manuscript and added important content.
Supported by The Grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, No. 16H05191, No. 221S0002, No. 16H06279, No. 18KK0266 and No. 19H03473; and (partly) the National Fund for Innovation and Development of Science and Technology from the Ministry of Higher Education Science and Technology of the Dominican Republic, No. 2012-2013-2A1-65 and No. 2015-3A1-182 (MC).
Institutional review board statement: The protocol was reviewed and approved by the Ethics Committees of Dr Luis E. Aybar Health and Hygiene City, the Institute of Microbiology and Parasitology, IMPA, Faculty of Sciences, Autonomous University of Santo Domingo, UASD and The National Council of Bioethics in Health, CONABIOS, in the Dominican Republic and Oita University, Faculty of Medicine, Japan.
Institutional animal care and use committee statement: This study did not contain animal experiments.
Conflict-of-interest statement: No conflicts of interest exist.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
http://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Yoshio Yamaoka, MD, PhD, Doctor, Professor, Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu 879-5593, Japan. yyamaoka@oita-u.ac.jp
Received: August 1, 2020
Peer-review started: August 1, 2020
First decision: September 30, 2020
Revised: October 10, 2020
Accepted: November 12, 2020
Article in press: November 12, 2020
Published online: December 7, 2020
BACKGROUND
Helicobacter pylori (H. pylori) colonizes the human stomach and is a major cause of peptic ulcer disease and gastric cancer. However, although the prevalence of H. pylori is high in Africa, the incidence of gastric cancer is low, and this phenomenon is called to be African enigma. The CagA protein produced by H. pylori is the most studied virulence factor. The carcinogenic potential of CagA is associated with the Glu-Pro-Ile-Tyr-Ala (EPIYA) patterns and CagA-multimerization (CM) motifs.
AIM
To better understand the EPIYA patterns and CM motifs of the cagA gene.
METHODS
Gastric mucosal biopsy specimens were obtained from 258 patients with dyspepsia living in the Dominican Republic, from which 120 H. pylori strains were cultured. After the bacterial DNA extraction, the EPIYA pattern and CM motif genotypes were determined using a polymerase chain reaction-based sequencing. The population structure of the Dominican Republic strains was analyzed using multilocus sequence typing (MLST). Peptic ulcer disease and gastric cancer were identified via endoscopy, and gastric cancer was confirmed by histopathology. Histological scores of the gastric mucosa were evaluated using the updated Sydney system.
RESULTS
All CagA-positive strains carried the Western-type CagA according to the identified EPIYA patterns. Twenty-seven kinds of CM motifs were observed. Although the typical Western CM motif (FPLKRHDKVDDLSKVG) was observed most frequently, the typical East Asian CM motif (FPLRRSAAVNDLSKVG) was not observed. However, “FPLRRSAKVEDLSKVG”, similar to the typical East Asian CM motif, was found in 21 strains. Since this type was significantly more frequent in strains classified as hpAfrica1 using MLST analysis (P = 0.034), we termed it Africa1-CM (Af1-CM). A few hpEurope strains carried the Af1-CM motif, but they had a significantly higher ancestral Africa1 component than that of those without the Af1-CM motif (P = 0.030). In 30 cagA-positive strains, the "GKDKGPE" motif was observed immediately upstream of the EPIYA motif in the EPIYA-A segment, and there was a significant association between strains with the hpAfrica1 population and those containing the “GKDKGPE” motif (P = 0.018). In contrast, there was no significant association between the CM motif patterns and histological scores and clinical outcomes.
CONCLUSION
We found the unique African CM motif in Western-type CagA and termed it Africa1-CM. The less toxicity of this motif could be one reason to explain the African enigma.
Core Tip: We found the unique African (hpAfrica1-type) CagA-multimerization (CM) motif in Western-type CagA in the Dominican Republic and termed it Africa1-CM (Af1-CM). In addition, a few hpEurope strains carrying the Af1-CM motif had a significantly higher ancestral Africa1 component than those without the Af1-CM motif. This result suggests that the ancestors of these hpEurope strains having the Af1-CM motif underwent genetic recombination with the hpAfrica1 strains in the past. In contrast, there was no significant association between the CM motif patterns and histological scores and clinical outcomes.
