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He QC, Huang ZN, Lv CB, Wu YH, Qiu WW, Ma YB, Wu J, Zheng CY, Lin GS, Li P, Wang JB, Lin JX, Lin M, Tu RH, Zheng CH, Huang CM, Cao LL, Xie JW. Effect of Helicobacter pylori infection on survival outcomes of patients undergoing radical gastrectomy after neoadjuvant chemotherapy: a multicenter study in China. BMC Cancer 2025; 25:460. [PMID: 40082850 PMCID: PMC11907980 DOI: 10.1186/s12885-025-13840-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 02/28/2025] [Indexed: 03/16/2025] Open
Abstract
BACKGROUND Neoadjuvant chemotherapy (NAC) has been confirmed to improve the prognosis of patients with advanced gastric cancer (AGC). However, no study has investigated whether Helicobacter pylori (HP) infection affects the postoperative survival of patients who receive NAC. METHODS This retrospective cohort study included 307 patients with AGC who underwent laparoscopic radical gastrectomy after NAC at three hospitals in China between January 1, 2016, and April 31, 2020. Cox regression was used to assess prognostic factors for survival. Kaplan-Meier was used for survival analysis. RESULTS The HP + and the HP- group included 141 and 166 cases. The 3-year overall survival (OS) and disease-free survival (DFS) of the HP + group were significantly better than the HP- group (3-year OS: 75.9% vs. 60.2%, 3-year DFS: 70.2% vs. 52.3%; All P < 0.001). For the HP + group, ypTNM Stage III (HR, 4.00; 95% CI, 1.11-14.39; P = 0.034), NAC ≥ 4 cycles (HR, 0.43; 95% CI, 0.20-0.90; P = 0.026), and adjuvant chemotherapy (AC) ≥ 4 cycles (HR, 0.20; 95% CI, 0.09-0.48; P < 0.001) are independent prognostic factors for OS. In the cohort of HP + patients who received ≥ 4 cycles of NAC, the prognosis of patients who received ≥ 4 cycles of AC after surgery was better than that of patients who received < 4 cycles of AC (3-year OS: 92.5% vs 71.4%; P = 0.042). CONCLUSIONS Following NAC, HP + patients with AGC exhibit better prognosis than that of HP- counterparts. For potentially resectable HP + AGC patients, radical surgery following ≥ 4 cycles of NAC with ≥ 4 cycles of sequential AC might be recommended to improve survival.
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Affiliation(s)
- Qi-Chen He
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Rd, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Ze-Ning Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Rd, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Chen-Bin Lv
- Department of Gastrointestinal Surgery, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, China
| | - Yong-He Wu
- Department of Pathology, Zhangzhou Affiliated Hospital of Fujian Medical University, ZhangZhou, China
| | - Wen-Wu Qiu
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Rd, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Yu-Bin Ma
- Department of Gastrointestinal Surgery, Qinghai University Affiliated Hospital, Xining, China
| | - Ju Wu
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Rd, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
- Department of General Surgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Chang-Yue Zheng
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Rd, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Putian University, Putian, China
| | - Guo-Sheng Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Rd, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Ping Li
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Rd, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Jia-Bin Wang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Rd, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Jian-Xian Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Rd, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Mi Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Rd, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Ru-Hong Tu
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Rd, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Chao-Hui Zheng
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Rd, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
| | - Chang-Ming Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Rd, Fuzhou, 350001, Fujian Province, China.
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China.
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China.
| | - Long-Long Cao
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Rd, Fuzhou, 350001, Fujian Province, China.
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China.
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China.
| | - Jian-Wei Xie
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Rd, Fuzhou, 350001, Fujian Province, China.
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China.
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China.
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Sun M, Liu Y, Ni X, Tan R, Wang Y, Jiang Y, Ke D, Du H, Guo G, Liu K. Intranasal immunization with poly I:C and CpG ODN adjuvants enhances the protective efficacy against Helicobacter pylori infection in mice. Microbes Infect 2025; 27:105433. [PMID: 39461584 DOI: 10.1016/j.micinf.2024.105433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 10/17/2024] [Accepted: 10/19/2024] [Indexed: 10/29/2024]
Abstract
Helicobacter pylori (H. pylori) infection is a serious public health issue, and development of vaccines is a desirable preventive strategy for H. pylori. Toll-like receptor (TLR) ligands have shown potential as vaccine adjuvants that induce immune responses, but polyinosinic-polycytidylic acid (poly I:C), a nucleic acid-based TLR9 ligand, is less well studied in H. pylori vaccine research. Here, we evaluated the effects of poly I:C and CpG oligodeoxynucleotide (CpG ODN), a nucleic acid TLR3 ligand, as adjuvants in combination with the H. pylori recombinant proteins LpoB and UreA to protect against H. pylori infection. For analysis of specific immune responses, the levels of specific antibodies and splenic cytokines were measured in the immunized mice. Compared with CpG ODN, poly I:C could induce mucosal sIgA antibody responses and reduce H. pylori colonization. Additionally, the combination of poly I:C and CpG ODN caused greater immunoprotection and significantly reduced gastritis, exerting synergistic effects. Analysis of splenic cytokines revealed that poly I:C mainly triggered a mixed Th1/Th2/Th17 immune response, whereas the combination of CpG ODN and poly I:C induced a Th1/Th17 immune response. Our findings indicated that increased levels of mucosal sIgA antibodies and a robust splenic Th1/Th17 immune response were associated with reduced H. pylori colonization in vaccinated mice. This study identified a potential TLR ligand adjuvant for developing more effective H. pylori vaccines.
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Affiliation(s)
- Min Sun
- Biopharmaceutical Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yu Liu
- Biopharmaceutical Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiumei Ni
- Biopharmaceutical Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Runqing Tan
- Biopharmaceutical Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yi Wang
- Biopharmaceutical Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yajun Jiang
- Biopharmaceutical Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Dingxin Ke
- Biopharmaceutical Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Han Du
- Biopharmaceutical Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Gang Guo
- Biopharmaceutical Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Kaiyun Liu
- Biopharmaceutical Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China.
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Zhang H, Liu Z, Li Y, Tao Z, Shen L, Shang Y, Huang X, Liu Q. Adjuvants for Helicobacter pylori vaccines: Outer membrane vesicles provide an alternative strategy. Virulence 2024; 15:2425773. [PMID: 39501551 PMCID: PMC11583678 DOI: 10.1080/21505594.2024.2425773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 09/19/2024] [Accepted: 10/31/2024] [Indexed: 11/12/2024] Open
Abstract
Helicobacter pylori (H. pylori) is a gram-negative, spiral-shaped bacterium that colonizes the human stomach, leading to various gastric diseases. The efficacy of traditional treatments, such as bismuth-based triple and quadruple therapies, has been reduced due to increasing antibiotic resistance and drug toxicity. As a result, the development of effective vaccines was proposed to control H. pylori-induced infections; however, one of the primary challenges is the lack of potent adjuvants. Although various adjuvants, both toxic (e.g. cholera toxin and Escherichia coli heat-labile toxin) and non-toxic (e.g. aluminum and propolis), have been tested for vaccine development, no clinically favorable adjuvants have been identified due to high toxicity, weak immunostimulatory effects, inability to elicit specific immune responses, or latent side effects. Outer membrane vesicles (OMVs), mainly secreted by gram-negative bacteria, have emerged as promising candidates for H. pylori vaccine adjuvants due to their potential applications. OMVs enhance mucosal immunity and Th1 and Th17 cell responses, which have been recognized to have protective effects and guarantee safety and efficacy. The development of an effective vaccine against H. pylori infection is ongoing, with clinical trials expected in the future.
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Affiliation(s)
- Hanchi Zhang
- Department of Medical Microbiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
- The Second Clinical Medical College, Nanchang University, Nanchang, China
| | - Zhili Liu
- Department of Medical Microbiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yi Li
- Department of Medical Microbiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
- The First Clinical Medical College, Nanchang University, Nanchang, China
| | - Ziwei Tao
- Department of Medical Microbiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Lu Shen
- Department of Medical Microbiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yinpan Shang
- Department of Medical Microbiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Xiaotian Huang
- Department of Medical Microbiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Qiong Liu
- Department of Medical Microbiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
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Teng Y, Xie R, Xu J, Wang P, Chen W, Shan Z, Yan Z, Mao F, Cheng P, Peng L, Zhang J, Tian W, Yang S, Zhao Y, Chen W, Zou Q, Zhuang Y. Tubulointerstitial nephritis antigen-like 1 is a novel matricellular protein that promotes gastric bacterial colonization and gastritis in the setting of Helicobacter pylori infection. Cell Mol Immunol 2023; 20:924-940. [PMID: 37336990 PMCID: PMC10387474 DOI: 10.1038/s41423-023-01055-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 05/29/2023] [Indexed: 06/21/2023] Open
Abstract
The interaction between the gastric epithelium and immune cells plays key roles in H. pylori-associated pathology. Here, we demonstrate a procolonization and proinflammatory role of tubulointerstitial nephritis antigen-like 1 (TINAGL1), a newly discovered matricellular protein, in H. pylori infection. Increased TINAGL1 production by gastric epithelial cells (GECs) in the infected gastric mucosa was synergistically induced by H. pylori and IL-1β via the ERK-SP1 pathway in a cagA-dependent manner. Elevated human gastric TINAGL1 correlated with H. pylori colonization and the severity of gastritis, and mouse TINAGL1 derived from non-bone marrow-derived cells promoted bacterial colonization and inflammation. Importantly, H. pylori colonization and inflammation were attenuated in Tinagl1-/- and Tinagl1ΔGEC mice and were increased in mice injected with mouse TINAGL1. Mechanistically, TINAGL1 suppressed CCL21 expression and promoted CCL2 production in GECs by directly binding to integrin α5β1 to inhibit ERK and activate the NF-κB pathway, respectively, which not only led to decreased gastric influx of moDCs via CCL21-CCR7-dependent migration and, as a direct consequence, reduced the bacterial clearance capacity of the H. pylori-specific Th1 response, thereby promoting H. pylori colonization, but also resulted in increased gastric influx of Ly6Chigh monocytes via CCL2-CCR2-dependent migration. In turn, TINAGL1 induced the production of the proinflammatory protein S100A11 by Ly6Chigh monocytes, promoting H. pylori-associated gastritis. In summary, we identified a model in which TINAGL1 collectively ensures H. pylori persistence and promotes gastritis.
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Affiliation(s)
- Yongsheng Teng
- Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
- The 940th Hospital of Joint Logistics Support Force of PLA, Lanzhou, China
| | - Rui Xie
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, Guizhou, China
| | - Jingyu Xu
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, Guizhou, China
| | - Pan Wang
- Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
- The 940th Hospital of Joint Logistics Support Force of PLA, Lanzhou, China
| | - Wanyan Chen
- Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Zhiguo Shan
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Zongbao Yan
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Fangyuan Mao
- Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Ping Cheng
- Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Liusheng Peng
- Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Jinyu Zhang
- Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Wenqing Tian
- Department of Gastroenterology, Chongqing University Cancer Hospital, Chongqing, China
| | - Shiming Yang
- Department of Gastroenterology, XinQiao Hospital, Third Military Medical University, Chongqing, China
| | - Yongliang Zhao
- Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Weisan Chen
- La Trobe Institute of Molecular Science, La Trobe University, Bundoora, VIC, Australia
| | - Quanming Zou
- Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China.
| | - Yuan Zhuang
- Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
- National Engineering Research Center of Immunological Products, Third Military Medical University, Chongqing, China.
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Liu S, Deng Z, Zhu J, Ma Z, Tuo B, Li T, Liu X. Gastric immune homeostasis imbalance: An important factor in the development of gastric mucosal diseases. Biomed Pharmacother 2023; 161:114338. [PMID: 36905807 DOI: 10.1016/j.biopha.2023.114338] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 01/18/2023] [Accepted: 01/27/2023] [Indexed: 03/11/2023] Open
Abstract
The gastric mucosal immune system is a unique immune organ independent of systemic immunity that not only maintains nutrient absorption but also plays a role in resisting the external environment. Gastric mucosal immune disorder leads to a series of gastric mucosal diseases, including autoimmune gastritis (AIG)-related diseases, Helicobacter pylori (H. pylori)-induced diseases, and various types of gastric cancer (GC). Therefore, understanding the role of gastric mucosal immune homeostasis in gastric mucosal protection and the relationship between mucosal immunity and gastric mucosal diseases is very important. This review focuses on the protective effect of gastric mucosal immune homeostasis on the gastric mucosa, as well as multiple gastric mucosal diseases caused by gastric immune disorders. We hope to offer new prospects for the prevention and treatment of gastric mucosal diseases.
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Affiliation(s)
- Shuhui Liu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Zilin Deng
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Jiaxing Zhu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Zhiyuan Ma
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Biguang Tuo
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Taolang Li
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
| | - Xuemei Liu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China.
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Tas SK, Kirkik D, Altunkanat D, Uzunoglu AS, Uzunoglu MS, Celik BA, Ilgar E. Immune Response and Therapeutic Vaccination against Helicobacter pylori. BRAZILIAN ARCHIVES OF BIOLOGY AND TECHNOLOGY 2023; 66. [DOI: 10.1590/1678-4324-2023230123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/01/2023]
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Sukri A, Hanafiah A, Kosai NR. The Roles of Immune Cells in Gastric Cancer: Anti-Cancer or Pro-Cancer? Cancers (Basel) 2022; 14:cancers14163922. [PMID: 36010915 PMCID: PMC9406374 DOI: 10.3390/cancers14163922] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 08/05/2022] [Accepted: 08/07/2022] [Indexed: 12/03/2022] Open
Abstract
Simple Summary Gastric cancer is still one of the leading causes of death caused by cancer in developing countries. The emerging role of immunotherapy in cancer treatment has led to more research to elucidate the roles of essential immune cells in gastric cancer prognosis. We reviewed the roles of immune cells including T cells, B cells, dendritic cells, macrophages and natural killer cells in gastric cancer. Although the studies conducted on the roles of immune cells in gastric cancer pathogenesis produced conflicting results, understanding the roles of immune cells in gastric cancer will help us to harness them for application in immunotherapy for better prognosis and management of gastric cancer patients. Abstract Despite the fact that the incidence of gastric cancer has declined over the last decade, it is still the world’s leading cause of cancer-related death. The diagnosis of early gastric cancer is difficult, as symptoms of this cancer only manifest at a late stage of cancer progression. Thus, the prognosis of gastric cancer is poor, and the current treatment for improving patients’ outcomes involves the application of surgery and chemotherapy. Immunotherapy is one of the most recent therapies for gastric cancer, whereby the immune system of the host is programmed to combat cancer cells, and the therapy differs based upon the patient’s immune system. However, an understanding of the role of immune cells, namely the cell-mediated immune response and the humoral immune response, is pertinent for applications of immunotherapy. The roles of immune cells in the prognosis of gastric cancer have yielded conflicting results. This review discusses the roles of immune cells in gastric cancer pathogenesis, specifically, T cells, B cells, macrophages, natural killer cells, and dendritic cells, as well as the evidence presented thus far. Understanding how cancer cells interact with immune cells is of paramount importance in designing treatment options for gastric cancer immunotherapy.
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Affiliation(s)
- Asif Sukri
- Integrative Pharmacogenomics Institute (iPROMISE), Universiti Teknologi MARA (UiTM), Bandar Puncak Alam, Shah Alam 43200, Malaysia
| | - Alfizah Hanafiah
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia
- Correspondence:
| | - Nik Ritza Kosai
- Department of Surgery, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia
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Jang S, Hansen LM, Su H, Solnick JV, Cha JH. Host immune response mediates changes in cagA copy number and virulence potential of Helicobacter pylori. Gut Microbes 2022; 14:2044721. [PMID: 35289715 PMCID: PMC8928821 DOI: 10.1080/19490976.2022.2044721] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 02/15/2022] [Indexed: 02/04/2023] Open
Abstract
Helicobacter pylori is the major risk factor for gastric cancer. H. pylori harboring the type IV secretion system (T4SS) and its effector CagA encoded on the cag pathogenicity Island (cagPAI) increases the risk. H. pylori PMSS1 has a multi-cagA genotype, modulating cagA copy number dynamically from zero to four copies. To examine the effect of the immune response on cagA copy number change, we utilized a mouse model with different immune status. PMSS1 recovered from Rag1-/- mice, lacking functional T or B cells, retained more cagA copies. PMSS1 recovered from Il10-/- mice, showing intense inflammation, had fewer cagA copies compared to those recovered from wild-type mice. Moreover, cagA copy number of PMSS1 recovered from wild-type and Il10-/- mice was positively correlated with the capacity to induce IL-8 secretion at four weeks of infection. Since recombination in cagY influences T4SS function, including CagA translocation and IL-8 induction, we constructed a multiple linear regression model to predict H. pylori-induced IL-8 expression based on cagA copy number and cagY recombination status; H. pylori induces more IL-8 secretion when the strain has more cagA copies and intact cagY. This study shows that H. pylori PMSS1 in mice with less intense immune response possess higher cagA copy number than those infected in mice with more intense immune response and thus the multi-cagA genotype, along with cagY recombination, functions as an immune-sensitive regulator of H. pylori virulence.
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Affiliation(s)
- Sungil Jang
- Department of Oral Biology, Oral Science Research Center, Department of Applied Life Science, The Graduate School, BK21 Four Project, Yonsei University College of Dentistry, Seoul, Republic of Korea
- Department of Oral Biochemistry, School of Dentistry, Jeonbuk National University, Jeonju, Republic of Korea
| | - Lori M. Hansen
- Center for Immunology and Infectious Diseases; Departments of Medicine and of Microbiology and Immunology, School of Medicine; University of California Davis, Davis, CA, USA
| | - Hanfu Su
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, China
| | - Jay V. Solnick
- Center for Immunology and Infectious Diseases; Departments of Medicine and of Microbiology and Immunology, School of Medicine; University of California Davis, Davis, CA, USA
| | - Jeong-Heon Cha
- Department of Oral Biology, Oral Science Research Center, Department of Applied Life Science, The Graduate School, BK21 Four Project, Yonsei University College of Dentistry, Seoul, Republic of Korea
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, China
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9
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Mohammadzadeh R, Soleimanpour S, Pishdadian A, Farsiani H. Designing and development of epitope-based vaccines against Helicobacter pylori. Crit Rev Microbiol 2021; 48:489-512. [PMID: 34559599 DOI: 10.1080/1040841x.2021.1979934] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Helicobacter pylori infection is the principal cause of serious diseases (e.g. gastric cancer and peptic ulcers). Antibiotic therapy is an inadequate strategy in H. pylori eradication because of which vaccination is an inevitable approach. Despite the presence of countless vaccine candidates, current vaccines in clinical trials have performed with poor efficacy which makes vaccination extremely challenging. Remarkable advancements in immunology and pathogenic biology have provided an appropriate opportunity to develop various epitope-based vaccines. The fusion of proper antigens involved in different aspects of H. pylori colonization and pathogenesis as well as peptide linkers and built-in adjuvants results in producing epitope-based vaccines with excellent therapeutic efficacy and negligible adverse effects. Difficulties of the in vitro culture of H. pylori, high genetic variation, and unfavourable immune responses against feeble epitopes in the complete antigen are major drawbacks of current vaccine strategies that epitope-based vaccines may overcome. Besides decreasing the biohazard risk, designing precise formulations, saving time and cost, and induction of maximum immunity with minimum adverse effects are the advantages of epitope-based vaccines. The present article is a comprehensive review of strategies for designing and developing epitope-based vaccines to provide insights into the innovative vaccination against H. pylori.
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Affiliation(s)
- Roghayeh Mohammadzadeh
- Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Saman Soleimanpour
- Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Reference Tuberculosis Laboratory, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abbas Pishdadian
- Department of Immunology, School of Medicine, Zabol University of Medical Sciences, Zabol, Iran
| | - Hadi Farsiani
- Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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10
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Aydın EM, Demir TD, Seymen N, Said SS, Oktem-Okullu S, Tiftikci A, Cicek B, Tokat F, Tozun N, Ince U, Sezerman U, Sayi-Yazgan A. The crosstalk between H. pylori virulence factors and the PD1:PD-L1 immune checkpoint inhibitors in progression to gastric cancer. Immunol Lett 2021; 239:1-11. [PMID: 34363898 DOI: 10.1016/j.imlet.2021.06.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 06/14/2021] [Accepted: 06/16/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND The progression to gastric cancer has been linked to chronic infection with Helicobacter pylori (H. pylori). Immune checkpoint inhibitors (programmed cell death -1, PD-1; programmed cell death -ligand 1, PD-L1) have a role in cancer immune escape. The relationship between H. pylori virulence factors with PD-1, PD-L1 T helper 1 (Th1), T helper 17 (Th17), and regulatory T cell (Treg) response genes, has not been thoroughly investigated in the development of gastric cancer. Therefore, we evaluated how H. pylori virulence factors influence the expression levels of immune-related genes in the development of gastric immunopathology. METHODS A total of 92 gastric tissues of normal controls and patients with gastritis, gastric ulcer, and gastric cancer were examined for the expression of immune-checkpoint inhibitor genes (PD-1 PD-L1), Th1 (interferon- γ, IFN-γ), Th17 (interleukin- 17, IL-17, Retinoic-acid-receptor- related orphan nuclear receptor gamma t, RORγ-t), and Treg (Forkhead box P3, FOXP3) response genes with quantitative real-time PCR (qRT-PCR). Furthermore, correlation of H. pylori virulence factors' (cytotoxin-associated gene A, cagA; vacuolating cytotoxin gene A, vacA (s1,s2,m1,m2); blood group antigen-binding adhesin gene A, babA, duodenal ulcer promoting gene A, dupA; the putative neuraminyllactose-binding hemagglutinin homolog, hpaA; neutrophil-activating protein A napA; outer inflammatory protein A, oipA; urease A, ureA; and urease B, ureB) genotypes with a degree of inflammation and density of H. pylori were investigated. Next, the relationship between H. pylori virulence factors and immune-checkpoint inhibitor genes, and T-cell response genes was evaluated. Eventually, a decision tree model was developed to determine the clinical outcome of patients using expression data. RESULTS The intensity of PD-1 and PD-L1 mRNA expression was increased significantly in gastric tissue of patients with gastric ulcer (PD-1: 2.3 fold, p=0.01; PD-L1: 2.1 fold, p=0.004), and gastric cancer (PD-1: 2 fold, p= 0.04; PD-L1: 1.8 fold, p=0.05) compared with control subjects. Also, PD-1: PD-L1 expression was significantly higher in patients with gastritis, who were infected with a marked density of H. pylori compared with its mildly infected counterparts. Furthermore, a novel negative correlation was found between PD-1 (r= -0.43) and PD-L1 (r= -0.42) with FOXP3 in patients with gastritis. CagA-positive H. pylori strain's negative association with PD-L1 expression (r=-0.34) was detected in patients with gastritis. Interestingly, PD-1 mRNA expression correlated positively with vacA s2/m2, in gastritis (r=0.43) and ulcer (r=0.43) patients. Furthermore, PD-1: PDL1 expression negatively correlated with vacA m1/m2 (r=-0.43 for PD-1; r=-0.38 for PD-L1) in gastritis patients. Moreover, an inverse correlation of PDL1 was present with vacA m1 (r=0.52) and vacA s1/m1 (r=0.46) versus vacA m2 (r=-0.44) and vacA m1 (r=0.52) and vacA s1/m2 (r=-0.14) in ulcer patients, respectively. Also, a correlation of vacA m2 (r=-0.47) and vacA s1/s2 (r= 0.45) with PD-1 was detected in ulcer patients. In addition, a novel negative correlation between FOXP3 mRNA levels and napA was shown in patients with gastritis and ulcer (r=-0.59). Finally, a computer-based model that was developed showed that knowing the expression levels of PD-L1, RORγ-t, and vacA s1/m2 would be useful to detect the clinical outcome of a patient. CONCLUSION Our results suggested that PD-1:PD-L1 immune checkpoint inhibitors were increased in gastric pre-cancerous lesions that progress to gastric cancer. Herein, we report the relationship between H. pylori virulence factors and expression of host immune checkpoint inhibitors for diagnostic prediction of gastric malignancies using computer-based models.
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Affiliation(s)
- Elif Merve Aydın
- Department of Molecular Biology and Genetics, Istanbul Technical University, Maslak, Istanbul, 34469, Turkey
| | - Tevriz Dilan Demir
- Department of Molecular Biology and Genetics, Istanbul Technical University, Maslak, Istanbul, 34469, Turkey
| | - Nogayhan Seymen
- Department of Biostatistics and Medical Informatics, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Atasehir, Istanbul, 34684, Turkey
| | - Sawsan Sudqi Said
- Department of Molecular Biology and Genetics, Istanbul Technical University, Maslak, Istanbul, 34469, Turkey
| | - Sinem Oktem-Okullu
- Department of Medical Microbiology, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Atasehir, Istanbul, 34684, Turkey
| | - Arzu Tiftikci
- Department of Internal Medicine, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Atasehir, Istanbul, 34457, Turkey
| | - Bahattin Cicek
- Department of Internal Medicine, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Atasehir, Istanbul, 34457, Turkey
| | - Fatma Tokat
- Department of Pathology, School of Medicine, Acibadem Mehmet Ali Aydinlar University, 34752, Istanbul, Turkey
| | - Nurdan Tozun
- Department of Internal Medicine, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Atasehir, Istanbul, 34457, Turkey
| | - Umit Ince
- Department of Pathology, School of Medicine, Acibadem Mehmet Ali Aydinlar University, 34752, Istanbul, Turkey
| | - Ugur Sezerman
- Department of Biostatistics and Medical Informatics, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Atasehir, Istanbul, 34684, Turkey
| | - Ayca Sayi-Yazgan
- Department of Molecular Biology and Genetics, Istanbul Technical University, Maslak, Istanbul, 34469, Turkey.
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11
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Mao FY, Lv YP, Hao CJ, Teng YS, Liu YG, Cheng P, Yang SM, Chen W, Liu T, Zou QM, Xie R, Xu JY, Zhuang Y. Helicobacter pylori-Induced Rev-erbα Fosters Gastric Bacteria Colonization by Impairing Host Innate and Adaptive Defense. Cell Mol Gastroenterol Hepatol 2021; 12:395-425. [PMID: 33676046 PMCID: PMC8255816 DOI: 10.1016/j.jcmgh.2021.02.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 02/25/2021] [Accepted: 02/25/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Rev-erbα represents a powerful transcriptional repressor involved in immunity. However, the regulation, function, and clinical relevance of Rev-erbα in Helicobacter pylori infection are presently unknown. METHODS Rev-erbα was examined in gastric samples from H pylori-infected patients and mice. Gastric epithelial cells (GECs) were isolated and infected with H pylori for Rev-erbα regulation assays. Gastric tissues from Rev-erbα-/- and wild-type (littermate control) mice or these mice adoptively transferred with CD4+ T cells from IFN-γ-/- and wild-type mice, bone marrow chimera mice and mice with in vivo pharmacological activation or inhibition of Rev-erbα were examined for bacteria colonization. GECs, CD45+CD11c-Ly6G-CD11b+CD68- myeloid cells and CD4+ T cells were isolated, stimulated and/or cultured for Rev-erbα function assays. RESULTS Rev-erbα was increased in gastric mucosa of H pylori-infected patients and mice. H pylori induced GECs to express Rev-erbα via the phosphorylated cagA that activated ERK signaling pathway to mediate NF-κB directly binding to Rev-erbα promoter, which resulted in increased bacteria colonization within gastric mucosa. Mechanistically, Rev-erbα in GECs not only directly suppressed Reg3b and β-defensin-1 expression, which resulted in impaired bactericidal effects against H pylori of these antibacterial proteins in vitro and in vivo; but also directly inhibited chemokine CCL21 expression, which led to decreased gastric influx of CD45+CD11c-Ly6G-CD11b+CD68- myeloid cells by CCL21-CCR7-dependent migration and, as a direct consequence, reduced bacterial clearing capacity of H pylori-specific Th1 cell response. CONCLUSIONS Overall, this study identifies a model involving Rev-erbα, which collectively ensures gastric bacterial persistence by suppressing host gene expression required for local innate and adaptive defense against H pylori.
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Affiliation(s)
- Fang-Yuan Mao
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Yi-Pin Lv
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Chuan-Jie Hao
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Yong-Sheng Teng
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Yu-Gang Liu
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Ping Cheng
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Shi-Ming Yang
- Department of Gastroenterology, XinQiao Hospital, Third Military Medical University, Chongqing, China
| | - Weisan Chen
- La Trobe Institute of Molecular Science, La Trobe University, Bundoora, Australia
| | - Tao Liu
- Department of Pharmacology, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Quan-Ming Zou
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
| | - Rui Xie
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jing-Yu Xu
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Yuan Zhuang
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China,Department of Gastroenterology, the Affiliated Hospital of Southwest Medical University, Luzhou, China,Correspondence Address correspondence to: Yuan Zhuang, National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, No.30 Gaotanyan Street, Chongqing 400038, China.fax: (86)023-68752315.
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12
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O'Brien VP, Koehne AL, Dubrulle J, Rodriguez AE, Leverich CK, Kong VP, Campbell JS, Pierce RH, Goldenring JR, Choi E, Salama NR. Sustained Helicobacter pylori infection accelerates gastric dysplasia in a mouse model. Life Sci Alliance 2021; 4:e202000967. [PMID: 33310760 PMCID: PMC7768197 DOI: 10.26508/lsa.202000967] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 11/23/2020] [Accepted: 11/24/2020] [Indexed: 12/12/2022] Open
Abstract
More than 80% of gastric cancer is attributable to stomach infection with Helicobacter pylori (Hp). Gastric preneoplastic progression involves sequential tissue changes, including loss of parietal cells, metaplasia and dysplasia. In transgenic mice, active KRAS expression recapitulates these tissue changes in the absence of Hp infection. This model provides an experimental system to investigate additional roles of Hp in preneoplastic progression, beyond its known role in initiating inflammation. Tissue histology, gene expression, the immune cell repertoire, and metaplasia and dysplasia marker expression were assessed in KRAS+ mice +/-Hp infection. Hp+/KRAS+ mice had severe T-cell infiltration and altered macrophage polarization; a different trajectory of metaplasia; more dysplastic glands; and greater proliferation of metaplastic and dysplastic glands. Eradication of Hp with antibiotics, even after onset of metaplasia, prevented or reversed these tissue phenotypes. These results suggest that gastric preneoplastic progression differs between Hp+ and Hp- cases, and that sustained Hp infection can promote the later stages of gastric preneoplastic progression.
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Affiliation(s)
- Valerie P O'Brien
- Fred Hutchinson Cancer Research Center, Human Biology Division, Seattle, WA, USA
| | - Amanda L Koehne
- Fred Hutchinson Cancer Research Center, Comparative Medicine Shared Resource, Seattle, WA, USA
- Fred Hutchinson Cancer Research Center, Experimental Histopathology Shared Resource, Seattle, WA, USA
| | - Julien Dubrulle
- Fred Hutchinson Cancer Research Center, Genomics and Bioinformatics Shared Resource, Seattle, WA, USA
| | - Armando E Rodriguez
- Fred Hutchinson Cancer Research Center, Human Biology Division, Seattle, WA, USA
| | - Christina K Leverich
- Fred Hutchinson Cancer Research Center, Human Biology Division, Seattle, WA, USA
| | - V Paul Kong
- Fred Hutchinson Cancer Research Center, Experimental Histopathology Shared Resource, Seattle, WA, USA
| | - Jean S Campbell
- Fred Hutchinson Cancer Research Center, Program in Immunology, Seattle, WA, USA
| | - Robert H Pierce
- Fred Hutchinson Cancer Research Center, Program in Immunology, Seattle, WA, USA
| | - James R Goldenring
- Department of Surgery, Epithelial Biology Center, Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
- Nashville Veterans Affairs Medical Center, Nashville, TN, USA
| | - Eunyoung Choi
- Department of Surgery, Epithelial Biology Center, Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Nina R Salama
- Fred Hutchinson Cancer Research Center, Human Biology Division, Seattle, WA, USA
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13
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Banga Ndzouboukou JL, Lei Q, Ullah N, Zhang Y, Hao L, Fan X. Helicobacter pylori adhesins: HpaA a potential antigen in experimental vaccines for H. pylori. Helicobacter 2021; 26:e12758. [PMID: 33259676 DOI: 10.1111/hel.12758] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 08/14/2020] [Accepted: 09/01/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Helicobacter pylori is a gram-negative bacterium involved in many gastric pathologies such as ulcers and cancers. Although the treatment for this infection has existed for several years, the development of a vaccine is nevertheless necessary to reduce the severe forms of the disease. For more than three decades, many advances have been made particularly in the understanding of virulence factors as well as the pathogenesis of gastric diseases caused by H. pylori. Among these key virulence factors, specific antigens have been identified: Urease, Vacuolating cytotoxin A (VacA), Cytotoxin-associated gene A (CagA), Blood group antigen-binding adhesin (BabA), H. pylori adhesin A (HpaA), and others. OBJECTIVES This review will focus on H. pylori adhesins, in particular, on HpaA and on the current knowledge of H. pylori vaccines. METHODS All of the information included in this review was retrieved from published studies on H. pylori adhesins in H. pylori infections. RESULTS These proteins, used in their native or recombinant forms, induce protection against H. pylori in experimental animal models. CONCLUSION H. pylori adhesins are known to be promising candidate vaccines against H. pylori. Future research should be carried out on adhesins, in particular, on HpaA.
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Affiliation(s)
- Jo-Lewis Banga Ndzouboukou
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qing Lei
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Nadeem Ullah
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yandi Zhang
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ling Hao
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xionglin Fan
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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14
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Dysregulated Immune Responses by ASK1 Deficiency Alter Epithelial Progenitor Cell Fate and Accelerate Metaplasia Development during H. pylori Infection. Microorganisms 2020; 8:microorganisms8121995. [PMID: 33542169 PMCID: PMC7765114 DOI: 10.3390/microorganisms8121995] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/11/2020] [Accepted: 12/11/2020] [Indexed: 02/06/2023] Open
Abstract
The mechanism of H. pylori-induced atrophy and metaplasia has not been fully understood. Here, we demonstrate the novel role of Apoptosis signal-regulating kinase 1 (ASK1) and downstream MAPKs as a regulator of host immune responses and epithelial maintenance against H. pylori infection. ASK1 gene deficiency resulted in enhanced inflammation with numerous inflammatory cells including Gr-1+CD11b+ myeloid-derived suppressor cells (MDSCs) recruited into the infected stomach. Increase of IL-1β release from apoptotic macrophages and enhancement of TH1-polarized immune responses caused STAT1 and NF-κB activation in epithelial cells in ASK1 knockout mice. Dysregulated immune and epithelial activation in ASK1 knockout mice led to dramatic expansion of gastric progenitor cells and massive metaplasia development. Bone marrow transplantation experiments revealed that ASK1 in inflammatory cells is critical for inducing immune disorder and metaplastic changes in epithelium, while ASK1 in epithelial cells regulates cell proliferation in stem/progenitor zone without changes in inflammation and differentiation. These results suggest that H. pylori-induced immune cells may regulate epithelial homeostasis and cell fate as an inflammatory niche via ASK1 signaling.
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15
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Soudi H, Falsafi T, Gharavi S, Mahboubi M. The Role of Helicobacter pylori Proinflammatory Outer Membrane Protein and Propolis in Immunomodulation on U937 Macrophage Cell Model. Galen Med J 2020; 9:e1687. [PMID: 34466568 PMCID: PMC8343919 DOI: 10.31661/gmj.v9i0.1687] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Revised: 12/22/2019] [Accepted: 01/24/2020] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Regarding the important role of proinflammatory outer membrane protein (OipA) in the pathogenesis of Helicobacter pylori infection and immunomodulatory activity of propolis, we aimed to evaluate the immunogenicity effect of a purified recombinant OipA protein and propolis in the induction of two cytokines, interferon-gamma (IFN-γ) and interleukin-4 (IL-4), in a macrophage cell model. MATERIALS AND METHODS The recombinant protein used in the present study corresponding to the oipA expressing a 34-35 kDa protein. OipA protein was purified by Ni-NTA affinity chromatography. The purified OipA protein (2.5- 40 μg /mL) and the propolis ethanolic extract (5-40 μg/mL) were incubated with phorbol 12-myristate 13-acetate-treated human myelomonocytic cell line U937 cells. IL-4 and IFN-γ levels were measured after 48 hours of incubation using enzyme-linked immunosorbent assay. RESULTS The amounts of IL-4 and IFN-γ were significantly increased. The optimum concentration of OipA for the secretion of IL-4 was 5 μg/ml (P<0.0001). At higher concentrations, the amount of IL-4 diminished until suppression at 40 μg/mL. The optimum concentration of propolis, resulting in the most significant increased secretion of both IL-4 and IFN-γ was 40 μg/mL (P=0.0001 and P=0.0004). CONCLUSION We found that an OipA concentration of 10 μg/mL was more effective for IFN-γ production; however, it was not effective for the high production of IL-4. Therefore, it is postulated that the OipA could mainly induce a Th1 response through the production of IFN-γ. We also observed propolis's capability to induce IFN-γ production; however, the effective concentration for this was the same as for IL-4. Therefore, as an adjuvant, proper concentration of propolis is required for OipA to give the optimum response.
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Affiliation(s)
- Hengameh Soudi
- Microbiology Department, Faculty of Biological Sciences, Alzahra University, Tehran, Iran
| | - Tahereh Falsafi
- Microbiology Department, Faculty of Biological Sciences, Alzahra University, Tehran, Iran
| | - Sara Gharavi
- Biotechnology Department, Faculty of Biological Sciences, Alzahra University, Tehran, Iran
| | - Mohaddeseh Mahboubi
- Medicinal Plants Research Department, Research and Development, Tabib-Daru Pharmaceutical Company, Kashan, Iran
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16
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Xie J, Wen J, Chen C, Luo M, Hu B, Wu D, Ye J, Lin Y, Ning L, Ning Y, Li Y. Notch 1 Is Involved in CD4 + T Cell Differentiation Into Th1 Subtype During Helicobacter pylori Infection. Front Cell Infect Microbiol 2020; 10:575271. [PMID: 33224898 PMCID: PMC7667190 DOI: 10.3389/fcimb.2020.575271] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 09/24/2020] [Indexed: 12/14/2022] Open
Abstract
Helicobacter pylori infection induces CD4+ T differentiation cells into IFN-γ-producing Th1 cells. However, the details of mechanism underlying this process remain unclear. Notch signal pathway has been reported to regulate the differentiation of CD4+ T cells into Th1 subtype in many Th1-mediated inflammatory disorders but not yet in H. pylori infection. In the present study, the mRNA expression pattern of CD4+ T cells in H. pylori-infected patients differed from that of healthy control using Human Signal Transduction Pathway Finder RT2 Profiler PCR Array, and this alteration was associated with Notch signal pathway, as analyzed by Bioinformation. Quantitative real-time PCR showed that the mRNA expression of Notch1 and its target gene Hes-1 in CD4+ T cells of H. pylori-infected individuals increased compared with the healthy controls. In addition, the mRNA expression of Th1 master transcription factor T-bet and Th1 signature cytokine IFN-γ was both upregulated in H. pylori-infected individuals and positively correlated with Notch1 expression. The increased protein level of Notch1 and IFN-γ were also observed in H. pylori-infected individuals confirmed by flow cytometry and ELISA. In vitro, inhibition of Notch signaling decreased the mRNA expression of Notch1, Hes-1, T-bet, and IFN-γ, and reduced the protein levels of Notch1 and IFN-γ and the secretion of IFN-γ in CD4+ T cells stimulated by H. pylori. Collectively, this is the first evidence that Notch1 is upregulated and involved in the differentiation of Th1 cells during H. pylori infection, which will facilitate exploiting Notch1 as a therapeutic target for the control of H. pylori infection.
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Affiliation(s)
- Jinling Xie
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China.,Affiliated Xinhui People's Hospital, Southern Medical University, Jiangmen, China
| | - Junjie Wen
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Chuxi Chen
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Meiqun Luo
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Bingxin Hu
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Danlin Wu
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Jianbin Ye
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Yanqing Lin
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Lijun Ning
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Yunshan Ning
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Yan Li
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
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17
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Clearance of Brucella with formulation rCagA, TN-OMPs & LPS in mice. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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18
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MohabatiMobarez A, Salmanian AH, Hosseini AZ, Esmaeili D. Clearance of Helicobacter pylori with formulation rCagA and LPS in a mouse model. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100588] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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19
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Gastric cancer: genome damaged by bugs. Oncogene 2020; 39:3427-3442. [PMID: 32123313 PMCID: PMC7176583 DOI: 10.1038/s41388-020-1241-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 02/18/2020] [Accepted: 02/20/2020] [Indexed: 12/20/2022]
Abstract
Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. The role of the microorganisms in gastric tumorigenesis attracts much attention in recent years. These microorganisms include bacteria, virus, and fungi. Among them, Helicobacter pylori (H. pylori) infection is by far the most important risk factor for GC development, with special reference to the early-onset cases. H. pylori targets multiple cellular components by utilizing various virulence factors to modulate the host proliferation, apoptosis, migration, and inflammatory response. Epstein–Barr virus (EBV) serves as another major risk factor in gastric carcinogenesis. The virus protein, EBER noncoding RNA, and EBV miRNAs contribute to the tumorigenesis by modulating host genome methylation and gene expression. In this review, we summarized the related reports about the colonized microorganism in the stomach and discussed their specific roles in gastric tumorigenesis. Meanwhile, we highlighted the therapeutic significance of eradicating the microorganisms in GC treatment.
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20
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Paydarnia N, Mansoori B, Esmaeili D, Kazemi T, Aghapour M, Hajiasgharzadeh K, Alizadeh N, Baradaran B. Helicobacter pylori Recombinant CagA Regulates Th1/Th2 Balance in a BALB/c Murine Model. Adv Pharm Bull 2020; 10:264-270. [PMID: 32373495 PMCID: PMC7191242 DOI: 10.34172/apb.2020.031] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 08/17/2019] [Accepted: 09/30/2019] [Indexed: 12/12/2022] Open
Abstract
Purpose:Helicobacter pylori is recognized as one of the prevalent causes of human gastricinfection. In the present study, the role of mixed immunization with H. pylori lipopolysaccharide(LPS) and recombinant cytotoxin-associated gene A (rCagA) as a stimulator of host immuneresponses was determined. Methods: BALB/c mice were immunized with different formulations by the systemic administrationat 14-day intervals. The effects of the formulations plus CpG adjuvants were assessed before andpost-immunization in separated studies. Moreover, the expression of Th1/Th2 cytokines wasquantified in sera of immunized mice using reverse transcription polymerase chain reaction (RTPCR)test and the protein levels confirmed with enzyme linked immunosorbent assay (ELISA).Finally, the specific antibody levels in sera were studied by ELISA and the tendency of cellularresponse was examined by IgG1/IgG2a ratio. Results: Data of Western blotting verified the presence of constructed protein. Analysisof lymphocyte proliferation showed that CpG-conjugated rCagA increases lymphocytesproliferation compared to the control group. Also, it was shown that formulations containing LPSand rCagA promote a Th1 response indicated by interferon-gamma expression and induced Th1/Th2 balance. Additionally, the specific IgG1, total IgG and IgG2a levels elevated in response toall treatments. Ultimately, the IgG2a/IgG1 ratio in the mice immunized with rCagA-containingformulations increased. Conclusion: These results indicated that rCagA protein carried with CpG adjuvant not onlymaintained its antigenicity throughout the experiment but also induced robust Th1-biasedimmune responses. Therefore, it holds promise for the production of an efficient vaccine against H. pylori infection.
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Affiliation(s)
- Nafiseh Paydarnia
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Tabriz University of Medical Sciences, International Branch (Aras), Tabriz, Iran
| | - Behzad Mansoori
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Davoud Esmaeili
- Department of Medical Microbiology, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Tohid Kazemi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahyar Aghapour
- Department of Pathobiology, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | | | - Nazila Alizadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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21
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Meyer TF, Morey P. A Future for a Vaccine Against the Cancer-Inducing Bacterium Helicobacter pylori? MUCOSAL VACCINES 2020:579-596. [DOI: 10.1016/b978-0-12-811924-2.00033-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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22
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Longet S, Abautret-Daly A, Davitt CJH, McEntee CP, Aversa V, Rosa M, Coulter IS, Holmgren J, Raghavan S, Lavelle EC. An oral alpha-galactosylceramide adjuvanted Helicobacter pylori vaccine induces protective IL-1R- and IL-17R-dependent Th1 responses. NPJ Vaccines 2019; 4:45. [PMID: 31666991 PMCID: PMC6814776 DOI: 10.1038/s41541-019-0139-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 10/01/2019] [Indexed: 12/12/2022] Open
Abstract
Helicobacter pylori causes chronic gastric infection that can lead to peptic ulcers and is an identified risk factor for gastric cancer development. Although much effort has been put into the development of a Helicobacter pylori vaccine over the last three decades, none has yet reached clinical application. Specific challenges pertaining to effective H. pylori vaccine development include the lack of proven vaccine-effective antigens and safe mucosal adjuvants to enhance local immune responses as well as the lack of accepted correlates of protection. Herein, we demonstrate that prophylactic intragastric immunisation with a whole-cell killed H. pylori antigen administered together with the non-toxic oral adjuvant α-galactosylceramide (α-GalCer) induced effective immune protection against H. pylori infection in mice, which was of similar magnitude as when using the “gold standard” cholera toxin as adjuvant. We further describe that this α-GalCer-adjuvanted vaccine formulation elicited strong intestinal and systemic Th1 responses as well as significant antigen-specific mucosal and systemic antibody responses. Finally, we report that the protective intestinal Th1 responses induced by α-GalCer are dependent on CD1d, IL-1R as well as IL-17R signalling. In summary, our results show that α-GalCer is a promising adjuvant for inclusion in an oral vaccine against H. pylori infection. Infection by Helicobacter pylori is highly prevalent in humans and can lead to chronic inflammation and gastric cancer, but to date no effective vaccine has been approved for clinical use owing to the lack of appropriate antigens and of safe mucosal adjuvants that can produce protective and durable immunity to the bacterium. Sukanya Raghavan, Ed Lavelle and colleagues now show that prophylactic intragastric administration of an inactivated whole-cell H. pylori preparation, together with the oral adjuvant α-galactosylceramide, reduced H. pylori infection in mice by eliciting a protective mucosal and systemic TH1 response. The immunisation triggered antigen-specific antibodies and interferon-γ that prevented effective colonisation of H. pylori after challenge in a process dependent on the CD1d, IL-1 receptor and IL-17 receptor pathways. The reported enhanced immune response to this orally adjuvanted vaccine formulation paves the way for further studies of its safety and efficacy.
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Affiliation(s)
- Stephanie Longet
- 1Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, D02 R590 Ireland
| | - Aine Abautret-Daly
- 1Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, D02 R590 Ireland
| | - Christopher J H Davitt
- 1Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, D02 R590 Ireland
| | - Craig P McEntee
- 1Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, D02 R590 Ireland
| | - Vincenzo Aversa
- 2Sublimity Therapeutics Limited, Dublin City University, Alpha Innovation Campus, Old Finglas Road, Dublin, D11 KXN4 Ireland
| | - Monica Rosa
- 2Sublimity Therapeutics Limited, Dublin City University, Alpha Innovation Campus, Old Finglas Road, Dublin, D11 KXN4 Ireland
| | - Ivan S Coulter
- 2Sublimity Therapeutics Limited, Dublin City University, Alpha Innovation Campus, Old Finglas Road, Dublin, D11 KXN4 Ireland
| | - Jan Holmgren
- 3University of Gothenburg Vaccine Research Institute, Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Box 435, 405 30 Gothenburg, Sweden
| | - Sukanya Raghavan
- 3University of Gothenburg Vaccine Research Institute, Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Box 435, 405 30 Gothenburg, Sweden
| | - Ed C Lavelle
- 1Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, D02 R590 Ireland.,4Centre for Research on Adaptive Nanostructures and Nanodevices & Advanced Materials Bio-Engineering Research Centre, Trinity College Dublin, Dublin 2, D02 PN40 Ireland
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23
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Abstract
Helicobacter pylori is a Gram-negative bacterium that infects the gastric epithelia of its human host. Everyone who is colonized with these pathogenic bacteria can develop gastric inflammation, termed gastritis. Additionally, a small proportion of colonized people develop more adverse outcomes, including gastric ulcer disease, gastric adenocarcinoma, or gastric mucosa-associated lymphoid tissue lymphoma. The development of these adverse outcomes is dependent on the establishment of a chronic inflammatory response. The development and control of this chronic inflammatory response are significantly impacted by CD4+ T helper cell activity. Noteworthy, T helper 17 (Th17) cells, a proinflammatory subset of CD4+ T cells, produce several proinflammatory cytokines that activate innate immune cell antimicrobial activity, drive a pathogenic immune response, regulate B cell responses, and participate in wound healing. Therefore, this review was written to take an intricate look at the involvement of Th17 cells and their affiliated cytokines (interleukin-17A [IL-17A], IL-17F, IL-21, IL-22, and IL-26) in regulating the immune response to H. pylori colonization and carcinogenesis.
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24
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Xue RY, Guo MF, Guo L, Liu C, Li S, Luo J, Nie L, Ji L, Ma CJ, Chen DQ, Sun S, Jin Z, Zou QM, Li HB. Synthetic Lipopeptide Enhances Protective Immunity Against Helicobacter pylori Infection. Front Immunol 2019; 10:1372. [PMID: 31258538 PMCID: PMC6587705 DOI: 10.3389/fimmu.2019.01372] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 05/30/2019] [Indexed: 12/15/2022] Open
Abstract
Over fifty percent of the people around the world is infected with Helicobacter pylori (H. pylori), which is the main cause of gastric diseases such as chronic gastritis and stomach cancer. H. pylori adhesin A (HpaA), which is a surface-located lipoprotein, is essential for bacterial colonization in the gastric mucosa. HpaA had been proposed to be a promising vaccine candidate against H. pylori infection. However, the effect of non-lipidated recombinant HpaA (rHpaA) to stimulate immune response was not very ideal, and the protective effect against H. pylori infection was also limited. Here, we hypothesized that low immunogenicity of rHpaA may attribute to lacking the immunostimulatory properties endowed by the lipid moiety. In this study, two novel lipopeptides, LP1 and LP2, which mimic the terminal structure of the native HpaA (nHpaA), were synthesized and TLR2 activation activity was confirmed in vitro. To investigate whether two novel lipopeptides could improve the protective effect of rHpaA against the infection of H. pylori, groups of mice were immunized either intramuscularly or intranasally with rHpaA together with LP1 or LP2. Compared with rHpaA alone, the bacterial colonization of the mice immunized with rHpaA plus LP2 via intranasal route was significantly decreased and the expression levels of serum IgG2a, IFN-γ, and IL-17 cytokines in spleen lymphocyte culture supernatant increased obviously, indicating that the enhanced protection of LP2 may be associated with elevated specific Th1 and Th17 responses. In conclusion, LP2 has been shown to improve the protective effect of rHpaA against H. pylori infection, which may be closely related to its ability in activating TLR2 by mimicking the terminal structure of nHpaA.
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Affiliation(s)
- Ruo-Yi Xue
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Center of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Mu-Fei Guo
- Chongqing Nankai Secondary School, Chongqing, China
| | - Ling Guo
- Chongqing Technical Center for Drug Evaluation and Certification, Chongqing, China
| | - Chang Liu
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Center of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Sun Li
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Center of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Jiao Luo
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Center of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Li Nie
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Center of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Lu Ji
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Center of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Cong-Jia Ma
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Center of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Da-Qun Chen
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Center of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Si Sun
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Center of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Zhe Jin
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Center of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Quan-Ming Zou
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Center of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Hai-Bo Li
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Center of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
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25
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Morey P, Meyer TF. The Sweeping Role of Cholesterol Depletion in the Persistence of Helicobacter pylori Infections. Curr Top Microbiol Immunol 2019; 421:209-227. [PMID: 31123891 DOI: 10.1007/978-3-030-15138-6_9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The ability of Helicobacter pylori to persist lifelong in the human gastric mucosa is a striking phenomenon. It is even more surprising since infection is typically associated with a vivid inflammatory response. Recent studies revealed the mechanism by which this pathogen inhibits the epithelial responses to IFN-γ and other central inflammatory cytokines in order to abolish an effective antimicrobial defense. The mechanism is based on the modification and depletion of cholesterol by the pathogen's cholesterol-α-glucosyltransferase. It abrogates the assembly of numerous cytokine receptors due to the reduction of lipid rafts. Particularly, the receptors for IFN-γ, IL-22, and IL-6 then fail to assemble properly and to activate JAK/STAT signaling. Consequently, cholesterol depletion prevents the release of antimicrobial peptides, including the highly effective β-defensin-3. Intriguingly, the inhibition is spatially restricted to heavily infected cells, while the surrounding epithelium continues to respond normally to cytokine stimulation, thus providing a platform of the intense inflammation typically observed in H. pylori infections. It appears that pathogen and host establish a homeostatic balance between tightly colonized and rather inflamed sites. This homeostasis is influenced by the levels of available cholesterol, which potentially exacerbate H. pylori-induced inflammation. The observed blockage of epithelial effector mechanisms by H. pylori constitutes a convincing explanation for the previous failures of T-cell-based vaccination against H. pylori, since infected epithelial cells remain inert upon stimulation by effector cytokines. Moreover, the mechanism provides a rationale for the carcinogenic action of this pathogen in that persistent infection and chronic inflammation represent a pro-carcinogenic environment. Thus, cholesterol-α-glucosyltransferase has been revealed as a central pathogenesis determinant of H. pylori.
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Affiliation(s)
- Pau Morey
- Instituto Universitario de Investigación en Ciencias de la Salud (IUNICS), Universidad de las Islas Baleares, Palma de Mallorca, Spain.
| | - Thomas F Meyer
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany.
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Downregulation of Interleukin- (IL-) 17 through Enhanced Indoleamine 2,3-Dioxygenase (IDO) Induction by Curcumin: A Potential Mechanism of Tolerance towards Helicobacter pylori. J Immunol Res 2018; 2018:3739593. [PMID: 30402507 PMCID: PMC6196794 DOI: 10.1155/2018/3739593] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Accepted: 08/27/2018] [Indexed: 12/11/2022] Open
Abstract
The anti-inflammatory and antimicrobial properties of curcumin suggest its use as an anti-Helicobacter pylori (H. pylori) agent, but mechanisms underlying its helpful activity are still not clear. Indoleamine 2,3-dioxygenase (IDO) promotes the effector T cell apoptosis by catalyzing the rate-limiting first step in tryptophan catabolism, and its high expression in H. pylori-infected human gastric mucosa attenuates Th1 and Th17 immune response. The aim of this study was to investigate the role of curcumin in modulating the expression of IL-17 and IDO in H. pylori-infected human gastric mucosa. In an organ culture chamber, gastric biopsies from 35 patients were treated with and without 200 μM curcumin. In H. pylori-infected patients (n = 21), IL-17 was significantly lower, both in gastric biopsies (p = 0.0003) and culture supernatant (p = 0.0001) while IDO significantly increased (p < 0.00001) in curcumin-treated sample compared with untreated samples. In a subgroup of H. pylori-infected patients (n = 15), samples treated with curcumin in addition to IDO inhibitor 1-methyl-L-tryptophan (1-MT) showed a higher expression of IL-17 compared with untreated samples and curcumin-treated alone (p < 0.00001). Curcumin downregulates IL-17 production through the induction of IDO in H. pylori-infected human gastric mucosa, suggesting its role in dampening H. pylori-induced immune-mediated inflammatory changes.
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27
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Lin LCW, Chattopadhyay S, Lin JC, Hu CMJ. Advances and Opportunities in Nanoparticle- and Nanomaterial-Based Vaccines against Bacterial Infections. Adv Healthc Mater 2018; 7:e1701395. [PMID: 29508547 DOI: 10.1002/adhm.201701395] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 01/22/2018] [Indexed: 02/06/2023]
Abstract
As the dawn of the postantibiotic era we approach, antibacterial vaccines are becoming increasingly important for managing bacterial infection and reducing the need for antibiotics. Despite the success of vaccination, vaccines remain unavailable for many pressing microbial diseases, including tuberculosis, chlamydia, and staphylococcus infections. Amid continuing research efforts in antibacterial vaccine development, the advancement of nanomaterial engineering has brought forth new opportunities in vaccine designs. With increasing knowledge in antibacterial immunity and immunologic adjuvants, innovative nanoparticles are designed to elicit the appropriate immune responses for effective antimicrobial defense. Rationally designed nanoparticles are demonstrated to overcome delivery barriers to shape the adaptive immunity. This article reviews the advances in nanoparticle- and nanomaterial-based antibacterial vaccines and summarizes the development of nanoparticulate adjuvants for immune potentiation against microbial pathogens. In addition, challenges and progress in ongoing antibacterial vaccine development are discussed to highlight the opportunities for future vaccine designs.
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Affiliation(s)
- Leon Chien-Wei Lin
- Institute of Biomedical Sciences; Academia Sinica; 128, Sec. 2, Academia Road Nangang District Taipei 11529 Taiwan
| | - Saborni Chattopadhyay
- Institute of Biomedical Sciences; Academia Sinica; 128, Sec. 2, Academia Road Nangang District Taipei 11529 Taiwan
| | - Jung-Chen Lin
- Institute of Biomedical Sciences; Academia Sinica; 128, Sec. 2, Academia Road Nangang District Taipei 11529 Taiwan
| | - Che-Ming Jack Hu
- Institute of Biomedical Sciences; Academia Sinica; 128, Sec. 2, Academia Road Nangang District Taipei 11529 Taiwan
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28
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Tr1 responses are elevated in asymptomatic H. pylori-infected individuals and are functionally impaired in H. pylori-gastric cancer patients. Exp Cell Res 2018; 367:251-256. [DOI: 10.1016/j.yexcr.2018.04.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Revised: 03/30/2018] [Accepted: 04/03/2018] [Indexed: 01/01/2023]
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29
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Ning Y, Ye J, Wen J, Wu D, Chen Z, Lin Y, Hu B, Luo M, Luo J, Ning L, Li Y. Identification of Two Lpp20 CD4 + T Cell Epitopes in Helicobacter pylori-Infected Subjects. Front Microbiol 2018; 9:884. [PMID: 29875738 PMCID: PMC5974113 DOI: 10.3389/fmicb.2018.00884] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 04/17/2018] [Indexed: 12/22/2022] Open
Abstract
Antigen-specific CD4+ T cells play an essential role in effective immunity against Helicobacter pylori (H. pylori) infection. Lpp20, a conserved lipoprotein of H. pylori, has been investigated as one of major protective antigens for vaccination strategies. Our previous study identified two H-2d-restricted CD4+ T cell epitopes within Lpp20 and an epitope vaccine based on these epitopes was constructed, which protected mice in prophylactic and therapeutic vaccination against H. pylori infection. Immunodominant CD4+ T cell response is an important feature of antiviral, antibacterial, and antitumor cellular immunity. However, while many immunodominant HLA-restricted CD4+ T cell epitopes of H. pylori protective antigens have been identified, immunodominant HLA-restricted Lpp20 CD4+ T cell epitope has not been elucidated. In this study, a systematic method was used to comprehensively evaluate the immunodominant Lpp20-specific CD4+ T cell response in H. pylori-infected patients. Using in vitro recombinant Lpp20 (rLpp20)-specific expanded T cell lines from H. pylori-infected subjects and 27 18mer overlapping synthetic peptides spanned the whole Lpp20 protein, we have shown that L55-72 and L79-96 harbored dominant epitopes for CD4+ T cell responses. Then the core sequence within these two 18mer dominant epitopes was screened by various extended or truncated 13mer peptides. The immunodominant epitope was mapped to L57-69 and L83-95. Various Epstein-Barr virus (EBV) transformed B lymphoblastoid cell lines (B-LCLs) with different HLA alleles were used as antigen presenting cell (APC) to present peptides to CD4+ T cells. The restriction molecules were determined by HLA class-antibody blocking. L57-69 was restricted by DRB1-1501 and L83-95 by DRB1-1602. The epitopes were recognized on autologous dendritic cells (DCs) loaded with rLpp20 but also those pulsed with whole cell lysates of H. pylori (HP-WCL), suggesting that these epitopes are naturally processed and presented by APC. CD4+ T cells were isolated from H. pylori-infected patients and stimulated with L57-69 and L83-95. These two epitopes were able to stimulate CD4+ T cell proliferation. This study may be of value for the future development of potential H. pylori vaccine.
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Affiliation(s)
- Yunshan Ning
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Jianbin Ye
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Junjie Wen
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Danlin Wu
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Zhongbiao Chen
- Affiliated Foshan Hospital of Southern Medical University, Foshan, China
| | - Yanqing Lin
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Bingxin Hu
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Meiqun Luo
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Jun Luo
- School of Public Health, Southern Medical University, Guangzhou, China
| | - Lijun Ning
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Yan Li
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
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30
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ADP-ribosylating enterotoxins as vaccine adjuvants. Curr Opin Pharmacol 2018; 41:42-51. [PMID: 29702466 DOI: 10.1016/j.coph.2018.03.015] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 03/30/2018] [Indexed: 01/18/2023]
Abstract
Most infections are caused by pathogens that access the body at mucosal sites. Hence, development of mucosal vaccines to prevent local infection or invasion of pathogens appears highly warranted, especially since only mucosal immunization will stimulate strong local IgA responses and tissue resident memory CD4 and CD8 T cells. The most significant obstacle to developing such vaccines is the lack of approved adjuvants that can effectively and safely enhance relevant mucosal and systemic immune responses. The most potent mucosal adjuvants known today are the adenosine diphosphate (ADP)-ribosylating bacterial enterotoxins cholera toxin (CT) and Escherichia coli heat-labile toxins (LTs). Unfortunately, these molecules are also very toxic, which precludes their clinical use. However, much effort has been devoted to developing derivatives of these enterotoxins with low or no toxicity and retained adjuvant activity. Although it is fair to say that we know more about how these toxins affect the immune system than ever before, we still lack a detailed understanding of how and why these toxins are effective adjuvants. In the present review, we provide a state-of-the-art overview of the mechanism of action of the holotoxins and the strategies used for improving the toxin-based adjuvants.
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31
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Hu J, Chen L, Yang W, Li B, Sun H, Wei S, He Y, Zhao Z, Yang S, Zou Q, Chen W, Guo H, Wu C. Systematic identification of immunodominant CD4+ T cell responses to HpaA in Helicobacter pylori infected individuals. Oncotarget 2018; 7:54380-54391. [PMID: 27509059 PMCID: PMC5342349 DOI: 10.18632/oncotarget.11092] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Accepted: 06/29/2016] [Indexed: 12/20/2022] Open
Abstract
In mice, antigen-specific CD4+ T cell response is indispensible for the protective immunity against Helicobacter pylori (H. pylori). It has been demonstrated that neuraminyllactose-binding hemagglutinin (HpaA) immunization protected mice from H. pylori infection in a CD4+ T cell dependent manner. However, much remains unclear concerning the human CD4+ T cell responses to HpaA. We conducted a systematic study here to explore the immunodominant, HpaA-specific CD4+ T cell responses in H. pylori infected individuals. We found that HpaA-specific CD4+ T cell responses varied remarkably in their magnitude and had broad epitope-specificity. Importantly, the main responses focused on two regions: HpaA76-105 and HpaA130-159. The HLA-DRB1*0901 restricted HpaA142-159 specific CD4+ T cell response was the most immunodominant response at a population level. The immunodominant epitope HpaA142-159 was naturally presented and highly conserved. We also demonstrated that it was not the broad peptide specificity, but the strength of HpaA specific CD4+ T cell responses associated with gastric diseases potentially caused by H. pylori infection. Such investigation will aid development of novel vaccines against H. pylori infection.
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Affiliation(s)
- Jian Hu
- Department of Gastroenterology, The Second Affiliated Hospital, Third Military Medical University, Chongqing, PR China.,Department of Intensive Care Unit, Chengdu Military General Hospital, Chengdu, PR China
| | - Li Chen
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, PR China.,Department of Blood Transfusion, The Second Affiliated Hospital, Third Military Medical University, Chongqing, PR China
| | - Wuchen Yang
- Department of Gastroenterology, The Second Affiliated Hospital, Third Military Medical University, Chongqing, PR China.,Department of Hematology, The Second Affiliated Hospital, Third Military Medical University, Chongqing, PR China
| | - Bin Li
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, PR China
| | - Heqiang Sun
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, PR China
| | - Shanshan Wei
- Department of Gastroenterology, The Second Affiliated Hospital, Third Military Medical University, Chongqing, PR China
| | - Yafei He
- Department of Gastroenterology, The Second Affiliated Hospital, Third Military Medical University, Chongqing, PR China
| | - Zhuo Zhao
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, PR China
| | - Shiming Yang
- Department of Gastroenterology, The Second Affiliated Hospital, Third Military Medical University, Chongqing, PR China
| | - Quanming Zou
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, PR China
| | - Weisan Chen
- T Cell Laboratory, La Trobe Institute for Molecular Science, School of Molecular Science, La Trobe University, Bundoora, Victoria, Australia
| | - Hong Guo
- Department of Gastroenterology, The Second Affiliated Hospital, Third Military Medical University, Chongqing, PR China
| | - Chao Wu
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, PR China
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Nguyen PM, Putoczki TL. Could the inhibition of IL-17 or IL-18 be a potential therapeutic opportunity for gastric cancer? Cytokine 2018; 118:8-18. [PMID: 29396054 DOI: 10.1016/j.cyto.2018.01.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Revised: 01/08/2018] [Accepted: 01/08/2018] [Indexed: 02/07/2023]
Abstract
Chronic inflammation is recognized as a key tumor-promoting factor in a number of epithelial cancers, including gastric cancer (GC). The production of pro-inflammatory cytokines in the tumor microenvironment by both the innate and the adaptive immune response can activate signaling pathways that are associated with increased cell survival and proliferation of cancer cells. Among the cytokines that have most commonly been linked to inflammation-associated cancers, are the Th17 cell-associated cytokines IL-17A, IL-23, IL-22, and the IL-1 family members IL-1β and IL-18. However, whether their contribution to inflammation-associated cancers is universal, or specific to individual types of cancers, remains to be elucidated. This review will explore our current understanding of the known roles of these cytokines in gastritis and discuss how their therapeutic inhibition may be useful for GC.
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Affiliation(s)
- Paul M Nguyen
- Walter and Eliza Hall Institute of Medical Research, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Victoria 3052, Australia
| | - Tracy L Putoczki
- Walter and Eliza Hall Institute of Medical Research, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Victoria 3052, Australia.
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Jafarzadeh A, Larussa T, Nemati M, Jalapour S. T cell subsets play an important role in the determination of the clinical outcome of Helicobacter pylori infection. Microb Pathog 2018; 116:227-236. [PMID: 29407232 DOI: 10.1016/j.micpath.2018.01.040] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 01/20/2018] [Accepted: 01/26/2018] [Indexed: 12/12/2022]
Abstract
Helicobacter pylori (H. pylori) is one of the most prevalent human pathogen and a persistent infection with this bacterium causes common pathologies, such as gastritis or peptic ulcers, and also less common but more serious pathologies, such as gastric cancer or gastric mucosa-associated lymphoid tissue (MALT) lymphoma. The clinical outcome of gastrointestinal infection sustained by H. pylori is determined by the reciprocal interactions between virulence factors of the bacterium and host factors, including immune response genes. Although H. pylori induces a strong immune response, the bacterium is not eliminated. The eradication failure could be attributed to the bacterial capability to regulate helper T (Th) cell-related responses. H. pylori specific CD4+ T cells play a fundamental role in regulating host immunity and immunopathologic events. It has been documented that Th1, Th2, Th9, Th17, Th22 and T regulatory (Treg) cells, separately or in coordination with each other, can affect the outcome of the infection sustained by of H. pylori. Some studies indicated that both Th1 and Th17 cells may be protective or pathogenic, whereas Treg and Th2 cells perform anti-inflammatory impacts during H. pylori infection. This review gathers recent information regarding the association of the CD4+ T cells-mediated immunological responses and the clinical consequence of H. pylori infection.
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Affiliation(s)
- Abdollah Jafarzadeh
- Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
| | - Tiziana Larussa
- Department of Health Science, University of Catanzaro "Magna Graecia", 88100 Catanzaro, Italy
| | - Maryam Nemati
- Department of Laboratory Sciences, School of Para-Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Shila Jalapour
- Molecular Medicine Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
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Nishizuka SS, Tamura G, Nakatochi M, Fukushima N, Ohmori Y, Sumida C, Iwaya T, Takahashi T, Koeda K. Helicobacter pylori infection is associated with favorable outcome in advanced gastric cancer patients treated with S-1 adjuvant chemotherapy. J Surg Oncol 2018; 117:947-956. [PMID: 29355977 DOI: 10.1002/jso.24977] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 12/11/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND OBJECTIVES Limited information exists regarding beneficial effects of Helicobacter pylori. To examine the effect in advanced gastric cancer, we compared survival for patients treated with surgery-only or adjuvant chemotherapy on the basis of H. pylori infection status. METHODS A cohort of 491 patients who underwent R0 resection for locally advanced gastric cancer between 2000 and 2009 at 12 institutions in northern Japan was included. H. pylori infection status, was assessed from paraffin-embedded formalin-fixed samples. Overall survival (OS) and disease-free survival (DFS) in surgery-only (Surgery) and adjuvant chemotherapy (S-1) groups were analyzed. A propensity score matching was employed to correct for confounding factors by indication. RESULTS H. pylori infection was positive in 175 patients and negative in 316 patients. H. pylori-positive patients showed significantly better survival than H. pylori-negative patients in both OS (hazard ratio [HR] 0.593, 95% confidence interval [CI] 0.417-0.843; P = 0.003]) and DFS (HR 0.679, 95%CI 0.492-0.937; P = 0.018). Propensity score matching further confirmed that S-1 was virtually only effective when tumors were H. pylori-positive. CONCLUSIONS The favorable outcome of H. pylori-positive patients implies that the host immune system is modulated by H. pylori enhancing the chemotherapeutic efficacy.
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Affiliation(s)
- Satoshi S Nishizuka
- Molecular Therapeutics Laboratory, Iwate Medical University School of Medicine, Morioka, Japan.,Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan.,Division of Biomedical Research & Development, Institute of Biomedical Sciences, Iwate Medical University, Morioka, Japan.,Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia
| | - Gen Tamura
- Department of Laboratory Medicine, Yamagata Prefectural Central Hospital, Yamagata, Japan
| | - Masahiro Nakatochi
- Statistical Analysis Section, Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan
| | - Norimasa Fukushima
- Department of Surgery, Yamagata Prefectural Central Hospital, Yamagata, Japan
| | - Yukimi Ohmori
- Molecular Therapeutics Laboratory, Iwate Medical University School of Medicine, Morioka, Japan
| | - Chihiro Sumida
- Molecular Therapeutics Laboratory, Iwate Medical University School of Medicine, Morioka, Japan
| | - Takeshi Iwaya
- Molecular Therapeutics Laboratory, Iwate Medical University School of Medicine, Morioka, Japan.,Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan
| | - Takashi Takahashi
- Division of Molecular Carcinogenesis, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Keisuke Koeda
- Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan
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Barrozo RM, Hansen LM, Lam AM, Skoog EC, Martin ME, Cai LP, Lin Y, Latoscha A, Suerbaum S, Canfield DR, Solnick JV. CagY Is an Immune-Sensitive Regulator of the Helicobacter pylori Type IV Secretion System. Gastroenterology 2016; 151:1164-1175.e3. [PMID: 27569724 PMCID: PMC5124400 DOI: 10.1053/j.gastro.2016.08.014] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 08/08/2016] [Accepted: 08/17/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Peptic ulcer disease and gastric cancer are caused most often by Helicobacter pylori strains that harbor the cag pathogenicity island, which encodes a type IV secretion system (T4SS) that injects the CagA oncoprotein into host cells. cagY is an essential gene in the T4SS and has an unusual DNA repeat structure that predicts in-frame insertions and deletions. These cagY recombination events typically lead to a reduction in T4SS function in mouse and primate models. We examined the role of the immune response in cagY-dependent modulation of T4SS function. METHODS H pylori T4SS function was assessed by measuring CagA translocation and the capacity to induce interleukin (IL)8 in gastric epithelial cells. cagY recombination was determined by changes in polymerase chain reaction restriction fragment-length polymorphisms. T4SS function and cagY in H pylori from C57BL/6 mice were compared with strains recovered from Rag1-/- mice, T- and B-cell-deficient mice, mice with deletion of the interferon gamma receptor (IFNGR) or IL10, and Rag1-/- mice that received adoptive transfer of control or Ifng-/- CD4+ T cells. To assess relevance to human beings, T4SS function and cagY recombination were assessed in strains obtained sequentially from a patient after 7.4 years of infection. RESULTS H pylori infection of T-cell-deficient and Ifngr1-/- mice, and transfer of CD4+ T cells to Rag1-/- mice, showed that cagY-mediated loss of T4SS function requires a T-helper 1-mediated immune response. Loss of T4SS function and cagY recombination were more pronounced in Il10-/- mice, and in control mice infected with H pylori that expressed a more inflammatory form of cagY. Complementation analysis of H pylori strains isolated from a patient over time showed changes in T4SS function that were dependent on recombination in cagY. CONCLUSIONS Analysis of H pylori strains from mice and from a chronically infected patient showed that CagY functions as an immune-sensitive regulator of T4SS function. We propose that this is a bacterial adaptation to maximize persistent infection and transmission to a new host under conditions of a robust inflammatory response.
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Affiliation(s)
- Roberto M Barrozo
- Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California
| | - Lori M Hansen
- Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California
| | - Anna M Lam
- Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California
| | - Emma C Skoog
- Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California
| | - Miriam E Martin
- Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California
| | - Lucy P Cai
- Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California
| | - Yong Lin
- Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California
| | - Andreas Latoscha
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany
| | - Sebastian Suerbaum
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany; Deutsches Zentrum für Infektionsforschung, German Center for Infection Research, Hannover-Braunschweig Partner Site, Hannover, Germany
| | - Don R Canfield
- California National Primate Research Center, University of California, Davis School of Medicine, Davis, California
| | - Jay V Solnick
- Center for Comparative Medicine, University of California, Davis School of Medicine, Davis, California; California National Primate Research Center, University of California, Davis School of Medicine, Davis, California; Department of Medicine, University of California, Davis School of Medicine, Davis, California; Department of Microbiology and Immunology, University of California, Davis School of Medicine, Davis, California.
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Anti-Helicobacter pylori activity of crude N-acetylneuraminic acid isolated from glycomacropeptide of whey. Lab Anim Res 2016; 32:99-104. [PMID: 27382378 PMCID: PMC4931043 DOI: 10.5625/lar.2016.32.2.99] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Revised: 06/01/2016] [Accepted: 06/06/2016] [Indexed: 12/15/2022] Open
Abstract
Helicobacter pylori colonizes the gastric mucosa of about half of the world's population, causing chronic gastritis and gastric cancer. An increasing emergence of antibiotic-resistant H. pylori arouses demand on alternative non-antibiotic-based therapies. In this study, we freshly prepared crude N-acetylneuraminic acid obtained from glycomacropeptide (G-NANA) of whey through a neuraminidase-mediated reaction and evaluated its antibacterial ability against H. pylori and H. felis. Overnight cultures of the H. pylori were diluted with fresh media and different concentrations (1-150 mg/mL) of crude G-NANA were added directly to the culture tube. Bacterial growth was evaluated by measuring the optical density of the culture medium and the number of viable bacteria was determined by a direct count of the colony forming units (CFU) on agar plates. For the in vivo study, mice were orally infected with 100 µL (5×10(8) cfu/mL) of H. felis four times at a day's interval, accompanied by a daily administration of crude G-NANA or vehicle. A day after the last infection, the mice were daily administered the crude G-NANA (0, 75, and 300 mg/mL) for 10 days and euthanized. Their stomachs were collected and bacterial colonization was determined by quantitative real-time PCR. Crude G-NANA inhibited H. pylori's growth and reduced the number of viable bacteria in a dose-dependent manner. Furthermore, crude G-NANA inhibited bacterial colonization in the mice. These results showed that crude G-NANA has antibacterial activity against Helicobacter and demonstrated its therapeutic potential for the prevention of chronic gastritis and gastric carcinogenesis induced by Helicobacter infection in humans.
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The Immunomodulator VacA Promotes Immune Tolerance and Persistent Helicobacter pylori Infection through Its Activities on T-Cells and Antigen-Presenting Cells. Toxins (Basel) 2016; 8:toxins8060187. [PMID: 27322319 PMCID: PMC4926153 DOI: 10.3390/toxins8060187] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 06/07/2016] [Accepted: 06/08/2016] [Indexed: 12/22/2022] Open
Abstract
VacA is a pore-forming toxin that has long been known to induce vacuolization in gastric epithelial cells and to be linked to gastric disorders caused by H. pylori infection. Its role as a major colonization and persistence determinant of H. pylori is less well-understood. The purpose of this review is to discuss the various target cell types of VacA and its mechanism of action; specifically, we focus on the evidence showing that VacA targets myeloid cells and T-cells to directly and indirectly prevent H. pylori-specific T-cell responses and immune control of the infection. In particular, the ability of VacA-proficient H. pylori to skew T-cell responses towards regulatory T-cells and the effects of Tregs on H. pylori chronicity are highlighted. The by-stander effects of VacA-driven immunomodulation on extragastric diseases are discussed as well.
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38
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Solnick JV, Eaton KA, Peek RM. Animal Models of Helicobacter pylori Infection. HELICOBACTER PYLORI RESEARCH 2016:273-297. [DOI: 10.1007/978-4-431-55936-8_11] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Raghavan S, Quiding-Järbrink M. Vaccination Against Helicobacter pylori Infection. HELICOBACTER PYLORI RESEARCH 2016:575-601. [DOI: 10.1007/978-4-431-55936-8_25] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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40
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Helicobacter pylori and T Helper Cells: Mechanisms of Immune Escape and Tolerance. J Immunol Res 2015. [PMID: 26525279 DOI: 10.1155/7015/981328] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Helicobacter pylori colonizes the gastric mucosa of at least half of the human population, causing a worldwide infection that appears in early childhood and if not treated, it can persist for life. The presence of symptoms and their severity depend on bacterial components, host susceptibility, and environmental factors, which allow H. pylori to switch between commensalism and pathogenicity. H. pylori-driven interactions with the host immune system underlie the persistence of the infection in humans, since the bacterium is able to interfere with the activity of innate and adaptive immune cells, reducing the inflammatory response in its favour. Gastritis due to H. pylori results from a complex interaction between several T cell subsets. In particular, H. pylori is known to induce a T helper (Th)1/Th17 cell response-driven gastritis, whose impaired modulation caused by the bacterium is thought to sustain the ongoing inflammatory condition and the unsuccessful clearing of the infection. In this review we discuss the current findings underlying the mechanisms implemented by H. pylori to alter the T helper lymphocyte proliferation, thus facilitating the development of chronic infections and allowing the survival of the bacterium in the human host.
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Helicobacter pylori and T Helper Cells: Mechanisms of Immune Escape and Tolerance. J Immunol Res 2015; 2015:981328. [PMID: 26525279 PMCID: PMC4615206 DOI: 10.1155/2015/981328] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 01/29/2015] [Indexed: 12/18/2022] Open
Abstract
Helicobacter pylori colonizes the gastric mucosa of at least half of the human population, causing a worldwide infection that appears in early childhood and if not treated, it can persist for life. The presence of symptoms and their severity depend on bacterial components, host susceptibility, and environmental factors, which allow H. pylori to switch between commensalism and pathogenicity. H. pylori-driven interactions with the host immune system underlie the persistence of the infection in humans, since the bacterium is able to interfere with the activity of innate and adaptive immune cells, reducing the inflammatory response in its favour. Gastritis due to H. pylori results from a complex interaction between several T cell subsets. In particular, H. pylori is known to induce a T helper (Th)1/Th17 cell response-driven gastritis, whose impaired modulation caused by the bacterium is thought to sustain the ongoing inflammatory condition and the unsuccessful clearing of the infection. In this review we discuss the current findings underlying the mechanisms implemented by H. pylori to alter the T helper lymphocyte proliferation, thus facilitating the development of chronic infections and allowing the survival of the bacterium in the human host.
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42
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Immunodominant epitope-specific Th1 but not Th17 responses mediate protection against Helicobacter pylori infection following UreB vaccination of BALB/c mice. Sci Rep 2015; 5:14793. [PMID: 26434384 PMCID: PMC4593181 DOI: 10.1038/srep14793] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Accepted: 09/09/2015] [Indexed: 12/13/2022] Open
Abstract
Helicobacter pylori (H. pylori) infects more than half of the world’s population, causing chronic gastritis, peptic ulcers and gastric cancer. Urease B subunit (UreB), a conserved protein of H. pylori, is capable of inducing specific CD4+ T-cell responses and provides protection against this infection. Previous studies have confirmed the effectiveness of rUreB subunit vaccines in generating CD4+ T-cell-mediated protection, but less is known regarding the roles of different subtypes of T-cell immunity, such as Th1, Th2 and Th17, particularly the immunodominant epitopes inducing specific CD4+ T-cell responses, in vaccine-mediated protection. In this study, we demonstrated that the vaccination of BALB/c mice with rUreB resulted in significant antigen-specific Th1 and Th17 immune responses. Importantly, two novel Th epitopes, UreB317–329 and UreB409–421, which are recognized by a major population of CD4+ T cells, were identified in immunized mice. Our results demonstrated that two novel epitopes can simultaneously induce Th1 and Th17 immune responses; however, only the epitope vaccine-induced CD4+ T-cells secreting IFN-γ mediated the protection against H. pylori; cells secreting IL-17A did not. Taken together, our results suggest that two novel immunodominant epitopes can induce Th1 and Th17 immune responses, but only the induced Th1 lymphocytes mediate protection against H. pylori.
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Zhuang Y, Cheng P, Liu XF, Peng LS, Li BS, Wang TT, Chen N, Li WH, Shi Y, Chen W, Pang KC, Zeng M, Mao XH, Yang SM, Guo H, Guo G, Liu T, Zuo QF, Yang HJ, Yang LY, Mao FY, Lv YP, Zou QM. A pro-inflammatory role for Th22 cells in Helicobacter pylori-associated gastritis. Gut 2015; 64:1368-78. [PMID: 25134787 PMCID: PMC4552937 DOI: 10.1136/gutjnl-2014-307020] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Revised: 07/17/2014] [Accepted: 08/02/2014] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Helper T (Th) cell responses are critical for the pathogenesis of Helicobacter pylori-induced gastritis. Th22 cells represent a newly discovered Th cell subset, but their relevance to H. pylori-induced gastritis is unknown. DESIGN Flow cytometry, real-time PCR and ELISA analyses were performed to examine cell, protein and transcript levels in gastric samples from patients and mice infected with H. pylori. Gastric tissues from interleukin (IL)-22-deficient and wild-type (control) mice were also examined. Tissue inflammation was determined for pro-inflammatory cell infiltration and pro-inflammatory protein production. Gastric epithelial cells and myeloid-derived suppressor cells (MDSC) were isolated, stimulated and/or cultured for Th22 cell function assays. RESULTS Th22 cells accumulated in gastric mucosa of both patients and mice infected with H. pylori. Th22 cell polarisation was promoted via the production of IL-23 by dendritic cells (DC) during H. pylori infection, and resulted in increased inflammation within the gastric mucosa. This inflammation was characterised by the CXCR2-dependent influx of MDSCs, whose migration was induced via the IL-22-dependent production of CXCL2 by gastric epithelial cells. Under the influence of IL-22, MDSCs, in turn, produced pro-inflammatory proteins, such as S100A8 and S100A9, and suppressed Th1 cell responses, thereby contributing to the development of H. pylori-associated gastritis. CONCLUSIONS This study, therefore, identifies a novel regulatory network involving H. pylori, DCs, Th22 cells, gastric epithelial cells and MDSCs, which collectively exert a pro-inflammatory effect within the gastric microenvironment. Efforts to inhibit this Th22-dependent pathway may therefore prove a valuable strategy in the therapy of H. pylori-associated gastritis.
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Affiliation(s)
- Yuan Zhuang
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Ping Cheng
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Xiao-fei Liu
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
- Department of Laboratory Medicine, General Hospital of Ji'nan Military Region of PLA, Ji'nan, Shandong, China
| | - Liu-sheng Peng
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Bo-sheng Li
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Ting-ting Wang
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Na Chen
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Wen-hua Li
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Yun Shi
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Weisan Chen
- School of Molecular Science, La Trobe University, Bundoora, Victoria, Australia
| | - Ken C Pang
- Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia
| | - Ming Zeng
- National Institutes for Food and Drug Control, Beijing, China
| | - Xu-hu Mao
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Shi-ming Yang
- Department of Gastroenterology, XinQiao Hospital, Third Military Medical University, Chongqing, China
| | - Hong Guo
- Department of Gastroenterology, XinQiao Hospital, Third Military Medical University, Chongqing, China
| | - Gang Guo
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Tao Liu
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Qian-fei Zuo
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Hui-jie Yang
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Liu-yang Yang
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Fang-yuan Mao
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Yi-pin Lv
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Quan-ming Zou
- Department of Microbiology and Biochemical Pharmacy, National Engineering Research Centre of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China
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Rubenstein JH, Shaheen NJ. Epidemiology, Diagnosis, and Management of Esophageal Adenocarcinoma. Gastroenterology 2015; 149:302-17.e1. [PMID: 25957861 PMCID: PMC4516638 DOI: 10.1053/j.gastro.2015.04.053] [Citation(s) in RCA: 257] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Revised: 03/27/2015] [Accepted: 04/02/2015] [Indexed: 02/06/2023]
Abstract
Esophageal adenocarcinoma (EAC) is rapidly increasing in incidence in Western cultures. Barrett's esophagus is the presumed precursor lesion for this cancer. Several other risk factors for this cancer have been described, including chronic heartburn, tobacco use, white race, and obesity. Despite these known associations, most patients with EAC present with symptoms of dysphagia from late-stage tumors; only a small number of patients are identified by screening and surveillance programs. Diagnostic analysis of EAC usually commences with upper endoscopy followed by cross-sectional imaging. Endoscopic ultrasonography is useful to assess the local extent of disease as well as the involvement of regional lymph nodes. T1a EAC may be treated endoscopically, and some patients with T1b disease may also benefit from endoscopic therapy. Locally advanced disease is generally managed with esophagectomy, often accompanied by neoadjuvant chemoradiotherapy or chemotherapy. The prognosis is based on tumor stage; patients with T1a tumors have an excellent prognosis, whereas few patients with advanced disease have long-term survival.
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Affiliation(s)
- Joel H Rubenstein
- Veterans Affairs Center for Clinical Management Research, Ann Arbor, Michigan; Barrett's Esophagus Program, Division of Gastroenterology, Department of Medicine, University of Michigan, Ann Arbor, Michigan.
| | - Nicholas J Shaheen
- Center for Esophageal Diseases and Swallowing, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina
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Sjökvist Ottsjö L, Flach CF, Nilsson S, de Waal Malefyt R, Walduck AK, Raghavan S. Defining the Roles of IFN-γ and IL-17A in Inflammation and Protection against Helicobacter pylori Infection. PLoS One 2015; 10:e0131444. [PMID: 26168305 PMCID: PMC4500503 DOI: 10.1371/journal.pone.0131444] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 06/02/2015] [Indexed: 01/13/2023] Open
Abstract
CD4+ T cells have been shown to be essential for vaccine-induced protection against Helicobacter pylori infection. However, the effector mechanisms leading to reductions in the gastric bacterial loads of vaccinated mice remain unclear. We have investigated the function of IFN-γ and IL-17A for vaccine-induced protection and inflammation (gastritis) using IFN-γ-gene-knockout (IFN-γ-/-) mice, after sublingual or intragastric immunization with H. pylori lysate antigens and cholera toxin. Bacteria were enumerated in the stomachs of mice and related to the gastritis score and cellular immune responses. We report that sublingually and intragastrically immunized IFN-γ-/- mice had significantly reduced bacterial loads similar to immunized wild-type mice compared to respective unimmunized infection controls. The reduction in bacterial loads in sublingually and intragastrically immunized IFN-γ-/- mice was associated with significantly higher levels of IL-17A in stomach extracts and lower gastritis scores compared with immunized wild-type mice. To study the role of IL-17A for vaccine-induced protection in sublingually immunized IFN-γ-/- mice, IL-17A was neutralized in vivo at the time of infection. Remarkably, the neutralization of IL-17A in sublingually immunized IFN-γ-/- mice completely abolished protection against H. pylori infection and the mild gastritis. In summary, our results suggest that IFN-γ responses in the stomach of sublingually immunized mice promote vaccine-induced gastritis, after infection with H. pylori but that IL-17A primarily functions to reduce the bacterial load.
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Affiliation(s)
| | - Carl-Fredrik Flach
- Department of Microbiology & Immunology, University of Gothenburg, Gothenburg, Sweden
| | - Staffan Nilsson
- Department of Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden
| | - Rene de Waal Malefyt
- Department of Immunology, Merck Research Laboratories, Palo Alto, California, United States of America
| | - Anna K. Walduck
- School of Applied Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Sukanya Raghavan
- Department of Microbiology & Immunology, University of Gothenburg, Gothenburg, Sweden
- * E-mail:
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Howe SE, Konjufca VH. Per-oral immunization with antigen-conjugated nanoparticles followed by sub-cutaneous boosting immunization induces long-lasting mucosal and systemic antibody responses in mice. PLoS One 2015; 10:e0118067. [PMID: 25710518 PMCID: PMC4339372 DOI: 10.1371/journal.pone.0118067] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Accepted: 01/04/2015] [Indexed: 01/22/2023] Open
Abstract
Food or water-borne enteric pathogens invade their hosts via intestinal mucosal surfaces, thus developing effective oral vaccines would greatly reduce the burden of infectious diseases. The nature of the antigen, as well as the mode of its internalization in the intestinal mucosa affects the ensuing immune response. We show that model protein antigen ovalbumin (Ova) given per-orally (p.o.) induces oral tolerance (OT), characterized by systemic IgG1—dominated antibody response, which cannot be boosted by sub-cutaneous (s.c.) immunization with Ova in complete Freund’s adjuvant (CFA). Intestinal IgA generated in response to Ova feeding diminished over time and was abrogated by s.c. immunization with Ova+CFA. Humoral response to Ova was altered by administering Ova conjugated to 20 nm nanoparticles (NP-Ova). P.o. administration of NP-Ova induced systemic IgG1/IgG2c, and primed the intestinal mucosa for secretion of IgA. These responses were boosted by secondary s.c. immunization with Ova+CFA or p.o. immunization with NP-Ova. However, only in s.c.-boosted mice serum and mucosal antibody titers remained elevated for 6 months after priming. In contrast, s.c. priming with NP-Ova induced IgG1-dominated serum antibodies, but did not prime the intestinal mucosa for secretion of IgA, even after secondary p.o. immunization with NP-Ova. These results indicate that Ova conjugated to NPs reaches the internal milieu in an immunogenic form and that mucosal immunization with NP-Ova is necessary for induction of a polarized Th1/Th2 immune response, as well as intestinal IgA response. In addition, mucosal priming with NP-Ova, followed by s.c. boosting induces superior systemic and mucosal memory responses. These findings are important for the development of efficacious mucosal vaccines.
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Affiliation(s)
- Savannah E. Howe
- Department of Microbiology, Southern Illinois University, Carbondale, Illinois, United States of America
| | - Vjollca H. Konjufca
- Department of Microbiology, Southern Illinois University, Carbondale, Illinois, United States of America
- * E-mail:
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48
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Susceptibility to pediatric Helicobacter pylori infection correlates with the host responses of regulatory and effector T cells. Pediatr Infect Dis J 2014; 33:1277-82. [PMID: 25389709 DOI: 10.1097/inf.0000000000000464] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND Tolerance to the early acquisition of Helicobacter pylori is suggested because of a biased ratio of regulatory to effector T cells in a mice model. This study investigated whether the CD4CD25 regulatory T (Treg) and CD4+CD25- effector T (Teff) cell responses after H. pylori exposure determine H. pylori susceptibility in children. METHODS Treg and Teff cells from peripheral blood mononuclear cells (PBMCs) of H. pylori-infected and non-infected children were incubated with H. pylori protein. The cytokine levels and fraction of FOXP3+ to T cells were measured. FOXP3 expression was assessed by Western blotting and immunohistochemistry of gastric biopsies from dyspeptic children. RESULTS The fraction of FOXP3+ to CD4+CD25 high cells in PBMCs, FOXP3-positive staining and translation level in gastric tissues were higher in H. pylori-infected children than in controls (P < 0.05). The translation levels of TGF-β1 in gastric tissues were higher in H. pylori-infected children than in controls (P < 0.05). After H. pylori challenge, H. pylori-infected children had a positive net-change in TGF-β1 from Treg cells, and a negative net-change of IFN-γ from Teff cells. Paradoxically, the non-infected controls had a negative net-change in TGF-β1 from Treg cells, and a positive net-change of IFN-γ from Teff cells. CONCLUSIONS The host response of Treg cells with increases in FOXP3 and TGF-β1 combined with a reduction in IFN-γ by Teff cells may contribute to H. pylori susceptibility in children.
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Wang YC, Chen CL, Sheu BS, Yang YJ, Tseng PC, Hsieh CY, Lin CF. Helicobacter pylori infection activates Src homology-2 domain-containing phosphatase 2 to suppress IFN-γ signaling. THE JOURNAL OF IMMUNOLOGY 2014; 193:4149-58. [PMID: 25225672 DOI: 10.4049/jimmunol.1400594] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Helicobacter pylori infection not only induces gastric inflammation but also increases the risk of gastric tumorigenesis. IFN-γ has antimicrobial effects; however, H. pylori infection elevates IFN-γ-mediated gastric inflammation and may suppress IFN-γ signaling as a strategy to avoid immune destruction through an as-yet-unknown mechanism. This study was aimed at investigating the mechanism of H. pylori-induced IFN-γ resistance. Postinfection of viable H. pylori decreased IFN-γ-activated signal transducers and activators of transcription 1 and IFN regulatory factor 1 not only in human gastric epithelial MKN45 and AZ-521 but also in human monocytic U937 cells. H. pylori caused an increase in the C-terminal tyrosine phosphorylation of Src homology-2 domain-containing phosphatase (SHP) 2. Pharmacologically and genetically inhibiting SHP2 reversed H. pylori-induced IFN-γ resistance. In contrast to a clinically isolated H. pylori strain HP238, the cytotoxin-associated gene A (CagA) isogenic mutant strain HP238(CagAm) failed to induce IFN-γ resistance, indicating that CagA regulates this effect. Notably, HP238 and HP238(CagAm) differently caused SHP2 phosphorylation; however, imaging and biochemical analyses demonstrated CagA-mediated membrane-associated binding with phosphorylated SHP2. CagA-independent generation of reactive oxygen species (ROS) contributed to H. pylori-induced SHP2 phosphorylation; however, ROS/SHP2 mediated IFN-γ resistance in a CagA-regulated manner. This finding not only provides an alternative mechanism for how CagA and ROS coregulate SHP2 activation but may also explain their roles in H. pylori-induced IFN-γ resistance.
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Affiliation(s)
- Yu-Chih Wang
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; Department of Microbiology and Immunology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Chia-Ling Chen
- Center of Translational Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Bor-Shyang Sheu
- Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
| | - Yao-Jong Yang
- Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
| | - Po-Chun Tseng
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
| | - Chia-Yuan Hsieh
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
| | - Chiou-Feng Lin
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; Department of Microbiology and Immunology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 701, Taiwan; and Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
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Carbo A, Olivares-Villagómez D, Hontecillas R, Bassaganya-Riera J, Chaturvedi R, Piazuelo MB, Delgado A, Washington MK, Wilson KT, Algood HMS. Systems modeling of the role of interleukin-21 in the maintenance of effector CD4+ T cell responses during chronic Helicobacter pylori infection. mBio 2014; 5:e01243-14. [PMID: 25053783 PMCID: PMC4120195 DOI: 10.1128/mbio.01243-14] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Accepted: 06/25/2014] [Indexed: 01/25/2023] Open
Abstract
The development of gastritis during Helicobacter pylori infection is dependent on an activated adaptive immune response orchestrated by T helper (Th) cells. However, the relative contributions of the Th1 and Th17 subsets to gastritis and control of infection are still under investigation. To investigate the role of interleukin-21 (IL-21) in the gastric mucosa during H. pylori infection, we combined mathematical modeling of CD4(+) T cell differentiation with in vivo mechanistic studies. We infected IL-21-deficient and wild-type mice with H. pylori strain SS1 and assessed colonization, gastric inflammation, cellular infiltration, and cytokine profiles. Chronically H. pylori-infected IL-21-deficient mice had higher H. pylori colonization, significantly less gastritis, and reduced expression of proinflammatory cytokines and chemokines compared to these parameters in infected wild-type littermates. These in vivo data were used to calibrate an H. pylori infection-dependent, CD4(+) T cell-specific computational model, which then described the mechanism by which IL-21 activates the production of interferon gamma (IFN-γ) and IL-17 during chronic H. pylori infection. The model predicted activated expression of T-bet and RORγt and the phosphorylation of STAT3 and STAT1 and suggested a potential role of IL-21 in the modulation of IL-10. Driven by our modeling-derived predictions, we found reduced levels of CD4(+) splenocyte-specific tbx21 and rorc expression, reduced phosphorylation of STAT1 and STAT3, and an increase in CD4(+) T cell-specific IL-10 expression in H. pylori-infected IL-21-deficient mice. Our results indicate that IL-21 regulates Th1 and Th17 effector responses during chronic H. pylori infection in a STAT1- and STAT3-dependent manner, therefore playing a major role controlling H. pylori infection and gastritis. Importance: Helicobacter pylori is the dominant member of the gastric microbiota in more than 50% of the world's population. H. pylori colonization has been implicated in gastritis and gastric cancer, as infection with H. pylori is the single most common risk factor for gastric cancer. Current data suggest that, in addition to bacterial virulence factors, the magnitude and types of immune responses influence the outcome of colonization and chronic infection. This study uses a combined computational and experimental approach to investigate how IL-21, a proinflammatory T cell-derived cytokine, maintains the chronic proinflammatory T cell immune response driving chronic gastritis during H. pylori infection. This research will also provide insight into a myriad of other infectious and immune disorders in which IL-21 is increasingly recognized to play a central role. The use of IL-21-related therapies may provide treatment options for individuals chronically colonized with H. pylori as an alternative to aggressive antibiotics.
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Affiliation(s)
| | - Danyvid Olivares-Villagómez
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | | | | | - Rupesh Chaturvedi
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - M Blanca Piazuelo
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Alberto Delgado
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - M Kay Washington
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
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