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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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Systematic review with meta-analysis: association between Helicobacter pylori CagA seropositivity and odds of inflammatory bowel disease.
Tepler A, Narula N, Peek RM, Patel A, Edelson C, Colombel JF, Shah SC
(2019) Aliment Pharmacol Ther 50: 121-131
MeSH Terms: Adolescent, Adult, Antibodies, Bacterial, Antigens, Bacterial, Bacterial Proteins, Colitis, Ulcerative, Comorbidity, Crohn Disease, Female, Helicobacter Infections, Helicobacter pylori, Humans, Inflammatory Bowel Diseases, Male, Middle Aged, Seroepidemiologic Studies, Young Adult
Show Abstract · Added March 3, 2020
BACKGROUND - Accumulating data support a protective role of Helicobacter pylori against inflammatory bowel diseases (IBD), which might be mediated by strain-specific constituents, specifically cagA expression.
AIM - To perform a systematic review and meta-analysis to more clearly define the association between CagA seropositivity and IBD.
METHODS - We identified comparative studies that included sufficient detail to determine the odds or risk of IBD, Crohn's disease (CD) or ulcerative colitis (UC) amongst individuals with vs without evidence of cagA expression (eg CagA seropositivity). Estimates were pooled using a random effects model.
RESULTS - Three clinical studies met inclusion criteria. cagA expression was represented by CagA seropositivity in all studies. Compared to CagA seronegativity overall, CagA seropositivity was associated with lower odds of IBD (OR 0.31, 95% CI 0.21-0.44) and CD (OR 0.25, 95% CI 0.17-0.38), and statistically nonsignificant lower odds for UC (OR 0.68, 95% CI 0.35-1.32). Similarly, compared to H pylori non-exposed individuals, H pylori exposed, CagA seropositive individuals had lower odds of IBD (OR 0.26, 95% CI 0.16-0.41) and CD (OR 0.23, 95% CI 0.15-0.35), but not UC (OR 0.66, 0.34-1.27). However, there was no significant difference in the odds of IBD, CD or UC between H pylori exposed, CagA seronegative and H pylori non-exposed individuals.
CONCLUSION - We found evidence for a significant association between CagA seropositive H pylori exposure and reduced odds of IBD, particularly CD, but not for CagA seronegative H pylori exposure. Additional studies are needed to confirm these findings and define underlying mechanisms.
© 2019 John Wiley & Sons Ltd.
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17 MeSH Terms
Molecular Architecture of the Helicobacter pylori Cag Type IV Secretion System.
Hu B, Khara P, Song L, Lin AS, Frick-Cheng AE, Harvey ML, Cover TL, Christie PJ
(2019) mBio 10:
MeSH Terms: Antigens, Bacterial, Bacterial Proteins, Cryoelectron Microscopy, Genomic Islands, Helicobacter pylori, Humans, Type IV Secretion Systems
Show Abstract · Added July 14, 2019
colonizes about half of humans worldwide, and its presence in the gastric mucosa is associated with an increased risk of gastric adenocarcinoma, gastric lymphoma, and peptic ulcer disease. strains carrying the pathogenicity island (PAI) are associated with increased risk of disease progression. The PAI encodes the Cag type IV secretion system (Cag), which delivers the CagA oncoprotein and other effector molecules into human gastric epithelial cells. We visualized structures of native and mutant Cag machines on the cell envelope by cryoelectron tomography. Individual cells contain multiple Cag nanomachines, each composed of a wheel-shaped outer membrane complex (OMC) with 14-fold symmetry and an inner membrane complex (IMC) with 6-fold symmetry. CagX, CagY, and CagM are required for assembly of the OMC, whereas strains lacking Cag3 and CagT produce outer membrane complexes lacking peripheral components. The IMC, which has never been visualized in detail, is configured as six tiers in cross-section view and three concentric rings surrounding a central channel in end-on view. The IMC contains three T4SS ATPases: (i) VirB4-like CagE, arranged as a hexamer of dimers at the channel entrance; (ii) a hexamer of VirB11-like Cagα, docked at the base of the CagE hexamer; and (iii) VirD4-like Cagβ and other unspecified Cag subunits, associated with the stacked CagE/Cagα complex and forming the outermost rings. The Cag and recently solved Dot/Icm system comprise new structural prototypes for the T4SS superfamily. Bacterial type IV secretion systems (T4SSs) have been phylogenetically grouped into two subfamilies. The T4ASSs, represented by the VirB/VirD4, include "minimized" machines assembled from 12 VirB- and VirD4-like subunits and compositionally larger systems such as the Cag T4BSSs encompass systems closely related in subunit composition to the Dot/Icm Here, we present structures of native and mutant Cag machines determined by cryoelectron tomography. We identify distinct outer and inner membrane complexes and, for the first time, visualize structural contributions of all three "signature" ATPases of T4SSs at the cytoplasmic entrance of the translocation channel. Despite their evolutionary divergence, the Cag aligns structurally much more closely to the Dot/Icm than an available VirB/VirD4 subcomplex. Our findings highlight the diversity of T4SSs and suggest a structural classification scheme in which T4SSs are grouped as minimized VirB/VirD4-like or larger Cag-like and Dot/Icm-like systems.
Copyright © 2019 Hu et al.
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Role of a Stem-Loop Structure in Transcript Stability.
Loh JT, Lin AS, Beckett AC, McClain MS, Cover TL
(2019) Infect Immun 87:
MeSH Terms: Antigens, Bacterial, Bacterial Proteins, DNA, Bacterial, Helicobacter Infections, Helicobacter pylori, Humans, Mutagenesis, Site-Directed, RNA Stability, RNA, Messenger
Show Abstract · Added February 7, 2019
CagA is a secreted effector protein that contributes to gastric carcinogenesis. Previous studies showed that there is variation among strains in the steady-state levels of CagA and that a strain-specific motif downstream of the transcriptional start site (the +59 motif) is associated with both high levels of CagA and premalignant gastric histology. The 5' untranslated region contains a predicted stem-loop-forming structure adjacent to the +59 motif. In the current study, we investigated the effect of the +59 motif and the adjacent stem-loop on transcript levels and mRNA stability. Using site-directed mutagenesis, we found that mutations predicted to disrupt the stem-loop structure resulted in decreased steady-state levels of both the transcript and the CagA protein. Additionally, these mutations resulted in a decreased mRNA half-life. Mutagenesis of the +59 motif without altering the stem-loop structure resulted in reduced steady-state transcript and CagA protein levels but did not affect transcript stability. transcript stability was not affected by increased sodium chloride concentrations, an environmental factor known to augment transcript levels and CagA protein levels. These results indicate that both a predicted stem-loop structure and a strain-specific +59 motif in the 5' untranslated region influence the levels of expression.
Copyright © 2019 American Society for Microbiology.
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9 MeSH Terms
Human mAbs to Staphylococcus aureus IsdA Provide Protection Through Both Heme-Blocking and Fc-Mediated Mechanisms.
Bennett MR, Bombardi RG, Kose N, Parrish EH, Nagel MB, Petit RA, Read TD, Schey KL, Thomsen IP, Skaar EP, Crowe JE
(2019) J Infect Dis 219: 1264-1273
MeSH Terms: Animals, Antibodies, Monoclonal, Antigens, Bacterial, Bacterial Proteins, Disease Models, Animal, Female, Hemeproteins, Humans, Hydrogen Deuterium Exchange-Mass Spectrometry, Mice, Mice, Inbred BALB C, Receptors, Cell Surface, Staphylococcal Infections, Staphylococcus aureus
Show Abstract · Added March 31, 2019
The nutrient metal iron plays a key role in the survival of microorganisms. The iron-regulated surface determinant (Isd) system scavenges heme-iron from the human host, enabling acquisition of iron in iron-deplete conditions in Staphylococcus aureus during infection. The cell surface receptors IsdB and IsdH bind hemoproteins and transfer heme to IsdA, the final surface protein before heme-iron is transported through the peptidoglycan. To define the human B-cell response to IsdA, we isolated human monoclonal antibodies (mAbs) specific to the surface Isd proteins and determined their mechanism of action. We describe the first isolation of fully human IsdA and IsdH mAbs, as well as cross-reactive Isd mAbs. Two of the identified IsdA mAbs worked in a murine septic model of infection to reduce bacterial burden during staphylococcal infection. Their protection was a result of both heme-blocking and Fc-mediated effector functions, underscoring the importance of targeting S. aureus using diverse mechanisms.
© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
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14 MeSH Terms
How Superantigens Bind MHC.
Van Kaer L
(2018) J Immunol 201: 1817-1818
MeSH Terms: Animals, Antigens, Bacterial, Clonal Deletion, Enterotoxins, Histocompatibility Antigens, Humans, Lymphocyte Activation, Minor Lymphocyte Stimulatory Antigens, Peptide Fragments, Protein Binding, Receptors, Antigen, T-Cell, alpha-beta, Superantigens, T-Lymphocytes
Added March 26, 2019
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13 MeSH Terms
Helicobacter pylori pathogen regulates p14ARF tumor suppressor and autophagy in gastric epithelial cells.
Horvat A, Noto JM, Ramatchandirin B, Zaika E, Palrasu M, Wei J, Schneider BG, El-Rifai W, Peek RM, Zaika AI
(2018) Oncogene 37: 5054-5065
MeSH Terms: Antigens, Bacterial, Autophagy, Bacterial Proteins, Cell Line, Tumor, Down-Regulation, Epithelial Cells, Gastric Mucosa, HCT116 Cells, Helicobacter Infections, Helicobacter pylori, Humans, Signal Transduction, Stomach, Stomach Neoplasms, Tumor Suppressor Protein p14ARF, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases, Up-Regulation, Virulence Factors
Show Abstract · Added September 25, 2018
Infection with Helicobacter pylori is one of the strongest risk factors for development of gastric cancer. Although these bacteria infect approximately half of the world's population, only a small fraction of infected individuals develops gastric malignancies. Interactions between host and bacterial virulence factors are complex and interrelated, making it difficult to elucidate specific processes associated with H. pylori-induced tumorigenesis. In this study, we found that H. pylori inhibits p14ARF tumor suppressor by inducing its degradation. This effect was found to be strain-specific. Downregulation of p14ARF induced by H. pylori leads to inhibition of autophagy in a p53-independent manner in infected cells. We identified TRIP12 protein as E3 ubiquitin ligase that is upregulated by H. pylori, inducing ubiquitination and subsequent degradation of p14ARF protein. Using isogenic H. pylori mutants, we found that induction of TRIP12 is mediated by bacterial virulence factor CagA. Increased expression of TRIP12 protein was found in infected gastric epithelial cells in vitro and human gastric mucosa of H. pylori-infected individuals. In conclusion, our data demonstrate a new mechanism of ARF inhibition that may affect host-bacteria interactions and facilitate tumorigenic transformation in the stomach.
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19 MeSH Terms
Pneumococcal Community-Acquired Pneumonia Detected by Serotype-Specific Urinary Antigen Detection Assays.
Wunderink RG, Self WH, Anderson EJ, Balk R, Fakhran S, Courtney DM, Qi C, Williams DJ, Zhu Y, Whitney CG, Moore MR, Bramley A, Jain S, Edwards KM, Grijalva CG
(2018) Clin Infect Dis 66: 1504-1510
MeSH Terms: Adult, Aged, Antigens, Bacterial, Community-Acquired Infections, Diagnostic Tests, Routine, Female, Humans, Male, Middle Aged, Pneumococcal Infections, Pneumonia, Bacterial, Serogroup, Urinalysis
Show Abstract · Added July 27, 2018
Background - Streptococcus pneumoniae is considered the leading bacterial cause of pneumonia in adults. Yet, it was not commonly detected by traditional culture-based and conventional urinary testing in a recent multicenter etiology study of adults hospitalized with community-acquired pneumonia (CAP). We used novel serotype-specific urinary antigen detection (SSUAD) assays to determine whether pneumococcal cases were missed by traditional testing.
Methods - We studied adult patients hospitalized with CAP at 5 hospitals in Chicago and Nashville (2010-2012) and enrolled in the Etiology of Pneumonia in the Community (EPIC) study. Traditional diagnostic testing included blood and sputum cultures and conventional urine antigen detection (ie, BinaxNOW). We applied SSUAD assays that target serotypes included in the 13-valent pneumococcal conjugate vaccine (PCV13) to stored residual urine specimens.
Results - Among 1736 patients with SSUAD and ≥1 traditional pneumococcal test performed, we identified 169 (9.7%) cases of pneumococcal CAP. Traditional tests identified 93 (5.4%) and SSUAD identified 76 (4.4%) additional cases. Among 14 PCV13-serotype cases identified by culture, SSUAD correctly identified the same serotype in all of them. Cases identified by SSUAD vs traditional tests were similar in most demographic and clinical characteristics, although disease severity and procalcitonin concentration were highest among those with positive blood cultures. The proportion of pneumonia cases caused by serotypes exclusively covered by PCV13 was not significantly different between the first and second July-June study periods (6.4% vs 4.0%).
Conclusions - Although restricted to the detection of only 13 serotypes, SSUAD testing substantially increased the detection of pneumococcal pneumonia among adults hospitalized with CAP.
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13 MeSH Terms
Helicobacter pylori Makes a Molecular Incision to Gain Epithelial Entry.
Noto JM, Peek RM
(2017) Cell Host Microbe 22: 434-436
MeSH Terms: Antigens, Bacterial, Bacterial Proteins, Epithelial Cells, Helicobacter Infections, Helicobacter pylori, Humans, Oncogene Proteins
Show Abstract · Added March 14, 2018
Helicobacter pylori type IV secretion system injects the oncoprotein CagA into epithelial cells to drive carcinogenesis. In this issue of Cell Host & Microbe, Tegtmeyer et al. (2017) show that a secreted bacterial protease disrupts apical-junctional complexes, paving the way for H. pylori to access the basolateral compartment and trigger pathogenesis.
Copyright © 2017 Elsevier Inc. All rights reserved.
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7 MeSH Terms
Genetic Manipulation of Virulence Function by Host Carcinogenic Phenotypes.
Suarez G, Romero-Gallo J, Sierra JC, Piazuelo MB, Krishna US, Gomez MA, Wilson KT, Peek RM
(2017) Cancer Res 77: 2401-2412
MeSH Terms: Animals, Antigens, Bacterial, Bacterial Proteins, Carcinogenesis, Disease Models, Animal, Gastric Mucosa, Gerbillinae, Helicobacter Infections, Helicobacter pylori, Humans, Risk Factors, Stomach Neoplasms
Show Abstract · Added February 18, 2017
is the strongest risk factor for gastric adenocarcinoma, yet only a minority of infected persons ever develop this malignancy. One cancer-linked locus is the type 4 secretion system (T4SS), which translocates an oncoprotein into host cells. A structural component of the T4SS is CagY, which becomes rapidly altered during adaptation in mice and rhesus monkeys, rendering the T4SS nonfunctional; however, these models rarely develop gastric cancer. We previously demonstrated that the strain 7.13 rapidly induces gastric cancer in Mongolian gerbils. We now use this model, in conjunction with samples from patients with premalignant lesions, to define the effects of a carcinogenic host environment on the virulence phenotype of to understand how only a subset of infected individuals develop cancer. sequence differences and T4SS function were directly related to the severity of inflammation in human gastric mucosa in either a synchronous or metachronous manner. Serial infections of Mongolian gerbils with strain 7.13 identified an oscillating pattern of T4SS function. The development of dysplasia or cancer selected for attenuated virulence phenotypes, but robust T4SS function could be restored upon infection of new hosts. Changes in the genetic composition of mirrored T4SS function, although the mechanisms of alterations differed in human isolates (mutations) versus gerbil isolates (addition/deletion of motifs). These results indicate that host carcinogenic phenotypes modify T4SS function via altering allowing the bacteria to persist and induce carcinogenic consequences in the gastric niche. .
©2017 American Association for Cancer Research.
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12 MeSH Terms