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Spermine oxidase mediates Helicobacter pylori-induced gastric inflammation, DNA damage, and carcinogenic signaling.
Sierra JC, Piazuelo MB, Luis PB, Barry DP, Allaman MM, Asim M, Sebrell TA, Finley JL, Rose KL, Hill S, Holshouser SL, Casero RA, Cleveland JL, Woster PM, Schey KL, Bimczok D, Schneider C, Gobert AP, Wilson KT
(2020) Oncogene 39: 4465-4474
MeSH Terms: Adenocarcinoma, Animals, Cell Transformation, Neoplastic, DNA Damage, Gastritis, Helicobacter Infections, Helicobacter pylori, Mice, Mice, Inbred C57BL, Mice, Knockout, Organoids, Oxidoreductases Acting on CH-NH Group Donors, Proteome, RNA, Messenger, Signal Transduction, Spermidine, Spermine, Stomach Neoplasms, beta Catenin
Show Abstract · Added May 1, 2020
Helicobacter pylori infection is the main risk factor for the development of gastric cancer, the third leading cause of cancer death worldwide. H. pylori colonizes the human gastric mucosa and persists for decades. The inflammatory response is ineffective in clearing the infection, leading to disease progression that may result in gastric adenocarcinoma. We have shown that polyamines are regulators of the host response to H. pylori, and that spermine oxidase (SMOX), which metabolizes the polyamine spermine into spermidine plus HO, is associated with increased human gastric cancer risk. We now used a molecular approach to directly address the role of SMOX, and demonstrate that Smox-deficient mice exhibit significant reductions of gastric spermidine levels and H. pylori-induced inflammation. Proteomic analysis revealed that cancer was the most significantly altered functional pathway in Smox gastric organoids. Moreover, there was also less DNA damage and β-catenin activation in H. pylori-infected Smox mice or gastric organoids, compared to infected wild-type animals or gastroids. The link between SMOX and β-catenin activation was confirmed in human gastric organoids that were treated with a novel SMOX inhibitor. These findings indicate that SMOX promotes H. pylori-induced carcinogenesis by causing inflammation, DNA damage, and activation of β-catenin signaling.
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19 MeSH Terms
Functional Properties of Helicobacter pylori VacA Toxin m1 and m2 Variants.
Caston RR, Sierra JC, Foegeding NJ, Truelock MD, Campbell AM, Frick-Cheng AE, Bimczok D, Wilson KT, McClain MS, Cover TL
(2020) Infect Immun 88:
MeSH Terms: Amino Acid Sequence, Bacterial Proteins, Bacterial Toxins, Gene Expression Regulation, Bacterial, Genetic Variation, Helicobacter Infections, Helicobacter pylori, Humans, Protein Domains, Protein Multimerization, Protein Transport, Vacuoles
Show Abstract · Added April 15, 2020
colonizes the gastric mucosa and secretes a pore-forming toxin (VacA). Two main types of VacA, m1 and m2, can be distinguished by phylogenetic analysis. Type m1 forms of VacA have been extensively studied, but there has been relatively little study of m2 forms. In this study, we generated strains producing chimeric proteins in which VacA m1 segments of a parental strain were replaced by corresponding m2 sequences. In comparison to the parental m1 VacA protein, a chimeric protein (designated m2/m1) containing m2 sequences in the N-terminal portion of the m region was less potent in causing vacuolation of HeLa cells, AGS gastric cells, and AZ-521 duodenal cells and had reduced capacity to cause membrane depolarization or death of AZ-521 cells. Consistent with the observed differences in activity, the chimeric m2/m1 VacA protein bound to cells at reduced levels compared to the binding levels of the parental m1 protein. The presence of two strain-specific insertions or deletions within or adjacent to the m region did not influence toxin activity. Experiments with human gastric organoids grown as monolayers indicated that m1 and m2/m1 forms of VacA had similar cell-vacuolating activities. Interestingly, both forms of VacA bound preferentially to the basolateral surface of organoid monolayers and caused increased cell vacuolation when interacting with the basolateral surface compared to the apical surface. These data provide insights into functional correlates of sequence variation in the VacA midregion (m region).
Copyright © 2020 American Society for Microbiology.
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12 MeSH Terms
Spotlight: Gastric Intestinal Metaplasia.
Shah SC, Gupta S, Li D, Morgan D, Mustafa RA, Gawron AJ
(2020) Gastroenterology 158: 704
MeSH Terms: Algorithms, Biopsy, Endoscopy, Gastrointestinal, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Humans, Metaplasia, Population Surveillance, Practice Guidelines as Topic, Precancerous Conditions, Risk Factors, Stomach Neoplasms
Added March 3, 2020
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13 MeSH Terms
AGA Technical Review on Gastric Intestinal Metaplasia-Epidemiology and Risk Factors.
Altayar O, Davitkov P, Shah SC, Gawron AJ, Morgan DR, Turner K, Mustafa RA
(2020) Gastroenterology 158: 732-744.e16
MeSH Terms: Ethnic Groups, European Continental Ancestry Group, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Humans, Metaplasia, Precancerous Conditions, Risk Factors, Stomach Neoplasms, United States
Added March 3, 2020
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11 MeSH Terms
AGA Technical Review on Gastric Intestinal Metaplasia-Natural History and Clinical Outcomes.
Gawron AJ, Shah SC, Altayar O, Davitkov P, Morgan D, Turner K, Mustafa RA
(2020) Gastroenterology 158: 705-731.e5
MeSH Terms: Biopsy, Disease Progression, Endoscopy, Gastrointestinal, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Humans, Metaplasia, Population Surveillance, Precancerous Conditions, Prevalence, Risk Factors, Stomach Neoplasms, United States
Added March 3, 2020
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14 MeSH Terms
Bacterial Energetic Requirements for Helicobacter pylori Cag Type IV Secretion System-Dependent Alterations in Gastric Epithelial Cells.
Lin AS, Dooyema SDR, Frick-Cheng AE, Harvey ML, Suarez G, Loh JT, McDonald WH, McClain MS, Peek RM, Cover TL
(2020) Infect Immun 88:
MeSH Terms: Antigens, Bacterial, Bacterial Proteins, Biological Transport, DNA, Bacterial, Epithelial Cells, Helicobacter pylori, Humans, Interleukin-8, Lipopolysaccharides, NF-kappa B, Peptidoglycan, Toll-Like Receptor 9, Type IV Secretion Systems, Virulence Factors
Show Abstract · Added March 3, 2020
colonizes the stomach in about half of the world's population. strains containing the pathogenicity island ( PAI) are associated with a higher risk of gastric adenocarcinoma or peptic ulcer disease than PAI-negative strains. The PAI encodes a type IV secretion system (T4SS) that mediates delivery of the CagA effector protein as well as nonprotein bacterial constituents into gastric epithelial cells. -induced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and interleukin-8 (IL-8) secretion are attributed to T4SS-dependent delivery of lipopolysaccharide metabolites and peptidoglycan into host cells, and Toll-like receptor 9 (TLR9) activation is attributed to delivery of bacterial DNA. In this study, we analyzed the bacterial energetic requirements associated with these cellular alterations. Mutant strains lacking Cagα, Cagβ, or CagE (putative ATPases corresponding to VirB11, VirD4, and VirB4 in prototypical T4SSs) were capable of T4SS core complex assembly but defective in CagA translocation into host cells. Thus, the three Cag ATPases are not functionally redundant. Cagα and CagE were required for -induced NF-κB activation, IL-8 secretion, and TLR9 activation, but Cagβ was dispensable for these responses. We identified putative ATP-binding motifs (Walker-A and Walker-B) in each of the ATPases and generated mutant strains in which these motifs were altered. Each of the Walker box mutant strains exhibited properties identical to those of the corresponding deletion mutant strains. These data suggest that Cag T4SS-dependent delivery of nonprotein bacterial constituents into host cells occurs through mechanisms different from those used for recruitment and delivery of CagA into host cells.
Copyright © 2020 American Society for Microbiology.
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MeSH Terms
Bacterial Pathogens Hijack the Innate Immune Response by Activation of the Reverse Transsulfuration Pathway.
Gobert AP, Latour YL, Asim M, Finley JL, Verriere TG, Barry DP, Milne GL, Luis PB, Schneider C, Rivera ES, Lindsey-Rose K, Schey KL, Delgado AG, Sierra JC, Piazuelo MB, Wilson KT
(2019) mBio 10:
MeSH Terms: Animals, Bacteria, Gene Silencing, Helicobacter pylori, Histones, Humans, Immune Evasion, Immunity, Innate, Immunoglobulins, Macrophages, Male, Metabolic Networks and Pathways, Mice, Mice, Inbred C57BL, Nitric Oxide Synthase Type II, Phosphatidylinositol 3-Kinases, Polyamines, RAW 264.7 Cells, Spermidine, Spermine, Sulfur, Transcription Factors
Show Abstract · Added November 1, 2019
The reverse transsulfuration pathway is the major route for the metabolism of sulfur-containing amino acids. The role of this metabolic pathway in macrophage response and function is unknown. We show that the enzyme cystathionine γ-lyase (CTH) is induced in macrophages infected with pathogenic bacteria through signaling involving phosphatidylinositol 3-kinase (PI3K)/MTOR and the transcription factor SP1. This results in the synthesis of cystathionine, which facilitates the survival of pathogens within myeloid cells. Our data demonstrate that the expression of CTH leads to defective macrophage activation by (i) dysregulation of polyamine metabolism by depletion of -adenosylmethionine, resulting in immunosuppressive putrescine accumulation and inhibition of spermidine and spermine synthesis, and (ii) increased histone H3K9, H3K27, and H3K36 di/trimethylation, which is associated with gene expression silencing. Thus, CTH is a pivotal enzyme of the innate immune response that disrupts host defense. The induction of the reverse transsulfuration pathway by bacterial pathogens can be considered an unrecognized mechanism for immune escape. Macrophages are professional immune cells that ingest and kill microbes. In this study, we show that different pathogenic bacteria induce the expression of cystathionine γ-lyase (CTH) in macrophages. This enzyme is involved in a metabolic pathway called the reverse transsulfuration pathway, which leads to the production of numerous metabolites, including cystathionine. Phagocytized bacteria use cystathionine to better survive in macrophages. In addition, the induction of CTH results in dysregulation of the metabolism of polyamines, which in turn dampens the proinflammatory response of macrophages. In conclusion, pathogenic bacteria can evade the host immune response by inducing CTH in macrophages.
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22 MeSH Terms
Targeted mobilization of Lrig1 gastric epithelial stem cell populations by a carcinogenic type IV secretion system.
Wroblewski LE, Choi E, Petersen C, Delgado AG, Piazuelo MB, Romero-Gallo J, Lantz TL, Zavros Y, Coffey RJ, Goldenring JR, Zemper AE, Peek RM
(2019) Proc Natl Acad Sci U S A 116: 19652-19658
MeSH Terms: Adenocarcinoma, Animals, Carcinogenesis, Disease Models, Animal, Epithelial Cells, Female, Gastric Mucosa, Gastritis, Helicobacter Infections, Helicobacter pylori, Humans, Male, Membrane Glycoproteins, Mice, Mice, Knockout, Nerve Tissue Proteins, Precancerous Conditions, Primary Cell Culture, Risk Factors, Stem Cells, Stomach, Stomach Neoplasms, Type IV Secretion Systems
Show Abstract · Added September 27, 2019
-induced gastritis is the strongest risk factor for gastric adenocarcinoma, a malignancy preceded by a series of well-defined histological stages, including metaplasia. One microbial constituent that augments cancer risk is the type 4 secretion system (T4SS), which translocates the oncoprotein CagA into host cells. Aberrant stem cell activation is linked to carcinogenesis, and Lrig1 (leucine-rich repeats and Ig-like domains 1) marks a distinct population of progenitor cells. We investigated whether microbial effectors with carcinogenic potential influence Lrig1 progenitor cells ex vivo and via lineage expansion within -infected gastric mucosa. Lineage tracing was induced in (Lrig1/YFP) mice that were uninfected or subsequently infected with or an isogenic mutant (nonfunctional T4SS). In contrast to infection with wild-type (WT) for 2 wk, infection for 8 wk resulted in significantly increased inflammation and proliferation in the corpus and antrum compared with uninfected or mice infected with the mutant. WT -infected mice harbored significantly higher numbers of Lrig1/YFP epithelial cells that coexpressed UEA1 (surface cell marker). The number of cells coexpressing intrinsic factor (chief cell marker), YFP (lineage marker), and GSII lectin (spasmolytic polypeptide-expressing metaplasia marker) were increased only by WT In human samples, Lrig1 expression was significantly increased in lesions with premalignant potential compared with normal mucosa or nonatrophic gastritis. In conclusion, chronic infection stimulates Lrig1-expressing progenitor cells in a -dependent manner, and these reprogrammed cells give rise to a full spectrum of differentiated cells.
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23 MeSH Terms
Preventing Gastric Cancer Development by Inhibiting the Virulence of H. pylori Infection.
Wilson KT
(2019) Oncology (Williston Park) 33: 227-31
MeSH Terms: Antineoplastic Agents, Eflornithine, Helicobacter Infections, Helicobacter pylori, Humans, Stomach Neoplasms, Virulence
Added July 11, 2019
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7 MeSH Terms
Structure of the Cag type IV secretion system.
Chung JM, Sheedlo MJ, Campbell AM, Sawhney N, Frick-Cheng AE, Lacy DB, Cover TL, Ohi MD
(2019) Elife 8:
MeSH Terms: Bacterial Outer Membrane Proteins, Helicobacter pylori, Models, Molecular, Type IV Secretion Systems
Show Abstract · Added July 14, 2019
Bacterial type IV secretion systems (T4SSs) are molecular machines that can mediate interbacterial DNA transfer through conjugation and delivery of effector molecules into host cells. The Cag T4SS translocates CagA, a bacterial oncoprotein, into gastric cells, contributing to gastric cancer pathogenesis. We report the structure of a membrane-spanning Cag T4SS assembly, which we describe as three sub-assemblies: a 14-fold symmetric outer membrane core complex (OMCC), 17-fold symmetric periplasmic ring complex (PRC), and central stalk. Features that differ markedly from those of prototypical T4SSs include an expanded OMCC and unexpected symmetry mismatch between the OMCC and PRC. This structure is one of the largest bacterial secretion system assemblies ever reported and illustrates the remarkable structural diversity that exists among bacterial T4SSs.
© 2019, Chung et al.
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4 MeSH Terms