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Macrophages recognize the Helicobacter pylori type IV secretion system in the absence of TLR signaling

ABSTRACT: Helicobacter pylori conquered the world by colonizing the human stomach. There are two major groups of strains, one with and one without a cag pathogenicity island (cagPAI), which result in different clinical outcomes with increased severity in cagPAI+ H. pylori infections such as higher inflammation and higher rates of gastric carcinogenesis. Since the gastro-intestinal tract is bombarded with nonspecific ligands that would induce innate signaling, tissue-resident immune cells are believed to lack toll-like receptor (TLR) signaling (anergy).To illuminate how anergic innate immune cells respond to H. pylori, we first investigated the transcriptome of H. pylori infected wild type and MyD88/Trif -/- macrophages, which lack TLR signaling. We observed that the majority of regulated genes in wt macrophages were dependent on TLR signaling. In addition, we found that some of the upregulated genes changed their kinetic behavior depending on TLR signaling. Only anergic macrophages were able to differentiate between cagPAI+ and cagPAI- H. pylori via their transcriptional kinetics of specific early response genes. These genes showed a strong bias towards adenylate-uridylate-rich elements (AREs) containing genes, including the prominent pro-inflammatory cytokines IL-1beta and TNF-alpha. Differentiation was dependent on the presence of the cag type 4 secretion system (cagT4SS), but not the CagA effector protein. Thus, we speculate that the direct recognition of the secretion system by tissue-resident macrophages enables the host to differentiate between pathogenic (cagPAI+) and commensal (cagPAI-) H. pylori variants.

ORGANISM(S): Mus musculus

PROVIDER: GSE56791 | GEO | 2015/09/01

SECONDARY ACCESSION(S): PRJNA244596

REPOSITORIES: GEO

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Macrophages recognize the Helicobacter pylori type IV secretion system in the absence of TLR signaling

Project description:Helicobacter pylori conquered the world by colonizing the human stomach. There are two major groups of strains, one with and one without a cag pathogenicity island (cagPAI), which result in different clinical outcomes with increased severity in cagPAI+ H. pylori infections such as higher inflammation and higher rates of gastric carcinogenesis. Since the gastro-intestinal tract is bombarded with nonspecific ligands that would induce innate signaling, tissue-resident immune cells are believed to lack toll-like receptor (TLR) signaling (anergy).To illuminate how anergic innate immune cells respond to H. pylori, we first investigated the transcriptome of H. pylori infected wild type and MyD88/Trif -/- macrophages, which lack TLR signaling. We observed that the majority of regulated genes in wt macrophages were dependent on TLR signaling. In addition, we found that some of the upregulated genes changed their kinetic behavior depending on TLR signaling. Only anergic macrophages were able to differentiate between cagPAI+ and cagPAI- H. pylori via their transcriptional kinetics of specific early response genes. These genes showed a strong bias towards adenylate-uridylate-rich elements (AREs) containing genes, including the prominent pro-inflammatory cytokines IL-1beta and TNF-alpha. Differentiation was dependent on the presence of the cag type 4 secretion system (cagT4SS), but not the CagA effector protein. Thus, we speculate that the direct recognition of the secretion system by tissue-resident macrophages enables the host to differentiate between pathogenic (cagPAI+) and commensal (cagPAI-) H. pylori variants. Microarray experiments were performed as dual-color hybridizations on Agilent mouse whole genome catalog 44K arrays. To compensate for dye-specific effects, a dye-reversal color-swap was applied. Cells were analyzed at 1h and 3h post infection

2015-09-01 | E-GEOD-56791 | biostudies-arrayexpress

Helicobacter pylori colonization ameliorates glucose homeostasis in mice

Project description:Background: Helicobacter pylori has been shown to alter the secretion of gastric hormones that modulate body fat deposition. Since cag-positive H. pylori strains interact intimately with the host gastric epithelial cells and trigger higher inflammation than cag-negative strains, we hypothesized that gastric colonization with H. pylori strains without functional cagA ameliorates obesity and its complications by modulating gastric gene expression and inflammation. Methodology/Principal Findings: To test this hypothesis we examined the effects of gastric colonization on metabolic and inflammatory markers in mice infected with two isogenic strains of H. pylori: 26695 strain 98-325 (cagA+ wild-type) and its cag pathogenicity island (cagPAI) mutant strain 99-305, a knockout made by inserting a chloramphenicol resistance cassette. Only the cagPAI mutant decreased fasting blood glucose levels, improved glucose tolerance and suppressed weight gain in db/db mice and mice with diet-induced obesity. These effects were associated with increased gastric leptin levels, suppressed infiltration of macrophages, enhanced influx of regulatory T cells (Treg) in adipose tissue and suppressed gastric inflammation. Gene set enrichment analyses of gastric mucosal samples identified six differentially modulated pathways, including the Hedgehog signaling pathway that is associated with control of cellular proliferation and gastric carcinogenesis as well as the insulin signaling pathway. Conclusions/Significance: Gastric colonization with cagPAI-negative strains of H. pylori ameliorate obesity and inflammation by modulating gastric gene expression, suggesting that cag-negative H. pylori strains might be beneficial in ameliorating obesity and its co-morbidities. Gastric mucosa from three groups of mice: uninfected, infected with H. pylori 26695 strain 98-325 (cagA+ wild-type) or infected with H. pylori mutant strain 99-305 (lacking cag pathogenicity island; cagA-)

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Helicobacter pylori colonization ameliorates glucose homeostasis in mice

2010-11-13 | GSE21833 | GEO

Mus musculus

Project description:Macrophages recognize the Helicobacter pylori type IV secretion system in the absence of TLR signaling

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H. pylori infection blocks DNA damage induced apoptosis by T4SS-dependent upregulation of miR-155

Project description:The innate immune response against Helicobacter pylori is mainly controlled by pattern recognition receptors that lead to the up-regulation of pro-inflammatory cytokines. A new player in this field is the miR-155 being regulated by TLR ligands in monocytic derived cells influencing certain intracellular pathways by down-regulating targets involved in signaling and development. By using primary bone marrow derived macrophages (BMMs) from mice deficient in the key TLR signals the regulation of miR-155 was explored. Further on the biological impact of a lack of miR-155 in BMMs was analyzed by micro-array studies and apoptosis assays. We observed that miR-155 is up-regulated in response to H. pylori via TLR2 and TLR4 in a NF-M-NM-:B dependent manner, but also identified a TLR2/TLR4 independent mechanism that was strongly connected to a functional TypeIV secretion system. Down-stream the high expression of miR-155 down-regulated many mRNA targets during H. pylori infection. Thereby we could validate Tspan14, Lpin1, and Pmaip1 as new targets of miR-155 and identified their binding site. These and other already published targets showed a substantial pro-apoptotic potential. We observed that H. pylori infected wild type BMMs were much more resistant to DNA damage induced apoptosis by cisplatin when compared to their respective miR-155-/- BMMs. Our data strongly suggests that there is an additional innate immune mechanism of BMMs leading to the upregulation of the anti-apoptotic miR-155 that causes resistance to DNA damage in BMMs. Microarray experiments were performed as dual-color hybridizations. To compensate for dye-specific effects, an independent dye-reversal color-swap was applied. Bone marrow derived macrophages were 'in vitro' infected with H.pylori P12 and the expression changes were measured.

2012-04-02 | E-GEOD-29388 | biostudies-arrayexpress

Comparative genomic hybridization of single colony purified H. pylori adhesin phenotyped isolates obtained from 25 cases and 71 controls in a Swedish case-control study of gastric cancer

Project description:Helicobacter pylori enhances the risk for ulcer disease and gastric cancer, yet only a minority of H. pylori-colonized individuals develop disease. We examined the ability of two H. pylori isolates to induce differential host responses in vivo or in vitro, and then used an H. pylori whole genome microarray to identify bacterial determinants related to pathogenesis. Gastric ulcer strain B128 induced more severe gastritis, proliferation, and apoptosis in gerbil mucosa than did duodenal ulcer strain G1.1, and gastric ulceration and atrophy occurred only in B128+ gerbils. In vitro, gerbil-passaged B128 derivatives significantly increased IL-8 secretion and apoptosis compared with G1.1 strains. DNA hybridization to the microarray identified several strain-specific differences in gene composition including a large deletion of the cag pathogenicity island in strain G1.1. Partial and complete disruption of the cag island in strain B128 attenuated induction of IL-8 in vitro and significantly decreased gastric inflammation in vivo. These results indicate that the ability of H. pylori to regulate epithelial cell responses related to inflammation depends on the presence of an intact cag pathogenicity island. Use of an H pylori whole genome microarray is an effective method to identify differences in gene content between H. pylori strains that induce distinct pathological outcomes in a rodent model of H. pylori infection.

2005-06-30 | E-SMDB-1587 | biostudies-arrayexpress

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2005-08-16 | E-GEOD-3135 | biostudies-arrayexpress

H. pylori induces an antimicrobial host response in rhesus macaques in a Cag Pathogenicity Island-Dependent Manner

Project description:We used the rhesus macaque model to study the effects of the cag pathogenicity island (cag PAI) on the H. pylori host-pathogen interaction. Specific pathogen free (SPF) monkeys with no prior exposure to H. pylori were experimentally challenged with wild type (WT) H. pylori strain J166 (N=4) or its cag PAI isogenic knockout (KO, N=4). Animals underwent endoscopy before and 1, 4, 8, and 13 wks after challenge. Gastric biopsies were collected for quantitative culture, histopathology, and host gene expression. Quantitative cultures showed that all experimentally challenged animals were infected with WT H. pylori or its isogenic cag PAI KO. Histopathology demonstrated that inflammation and expansion of the lamina propria were attenuated in animals infected with KO compared to WT. Microarray analysis was performed on challenged animals before and 1 and 13 wks after challenge, and on unchallenged control animals (N=4). Of the 119 up-regulated genes in the WT-infected animals, several encode innate antimicrobial effector proteins, including elafin, siderocalin, DMBT, DUOX2, and several novel paralogues of human defensin-2. Quantitative RT-PCR analysis showed that high level induction of each of these genes was dependent upon the presence of the cag PAI. Immunohistochemistry confirmed increased defensin epithelial cell staining in animals challenged with WT H. pylori compared to either KO-challenged or uninfected control animals. We propose that one function of the cag PAI is to induce an antimicrobial host response that serves to increase the competitive advantage of H. pylori in the gastric niche. Keywords: Transcript profiling , Wild type H. pylori, cag-PAI KO H. pylori

2008-02-01 | GSE8749 | GEO

H. pylori strain comparisons

2005-08-16 | GSE3135 | GEO

Effect of Helicobacter pylori on ATM-dependent DNA damage responses [cell lines]

Project description:Carcinogenic bacteria, Helicobacter pylori, induce DNA double-strand breaks in infected host cells. Therefore, we have investigated which genes are upregulated after the infection. Although Helicobacter pylori infection is etiologically related to the inflammation-related malignancy, gastric cancers, it role in the molecular pathogenesis of disease remains unclear. In vitro studies have suggested the infection may cause breaks in double-stranded DNA. We used microarray analysis of H. pylori-infected human gastric biopsies to investigate the effect of H. pylori on gene expression genes involved in DNA repair and DNA damage response. Micro-array analysis and immunohistochemistory showed that ATM (ataxia-telangiectasia mutated) was upregulated in H. pylori gastritis but down regulated in the premalignant lesion, intestinal metaplasia. Studies in gastric cancer cell lines showed that H. pylori-infection induced activation of ATM and formation of γ-H2AX. γ-H2AX formation was present following infection with bout cag pathogenicity island (PAI)- positive and negative strains but more robust with cag PAI positive strains consistent with the fact that both cag PAI positive negative strains are associated with gastric cancer but the risk is higher with cag PAI positive strains. Eradication of H. pylori infection is associated with a reduction in cancer risk even in the most high risk populations. These data provide a plausible molecular mechanism for a direct bacterial-host interaction increasing cancer risk.

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