A novel NOD1- and CagA-independent pathway of interleukin-8 induction mediated by the<i>Helicobacter pylori</i>type IV secretion system

Gorrell, Rebecca J.; Guan, Jye Swei; Xin, Yue; Tafreshi, Mona; Hutton, Melanie L.; McGuckin, Michael A.; Ferrero, Richard L.; Kwok, Terry

doi:10.1111/cmi.12055

Cited by 85 publications

(114 citation statements)

References 67 publications

(132 reference statements)

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“…Furthermore, it seems that H. pylori can ensure PG translocation inside host cells through the outer membrane vesicles that are constantly released by the bacterium (29). Recently, it was suggested that CagL, via interactions with host integrins, can trigger proinflammatory responses independently of CagA translocation or NOD1 signaling (30). As a result, the TIVSS apparatus per se could elicit host proinflammatory responses independently of its substrates (30).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it was suggested that CagL, via interactions with host integrins, can trigger proinflammatory responses independently of CagA translocation or NOD1 signaling (30). As a result, the TIVSS apparatus per se could elicit host proinflammatory responses independently of its substrates (30). Finally, chemokine production during H. pylori infection could also be induced by other bacterial virulence factors.…”

Section: Discussionmentioning

confidence: 99%

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Chemokines and Antimicrobial Peptides Have a cag -Dependent Early Response to Helicobacter pylori Infection in Primary Human Gastric Epithelial Cells

et al. 2014

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e Helicobacter pylori infection systematically causes chronic gastric inflammation that can persist asymptomatically or evolve toward more severe gastroduodenal pathologies, such as ulcer, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. The cag pathogenicity island (cag PAI) of H. pylori allows translocation of the virulence protein CagA and fragments of peptidoglycan into host cells, thereby inducing production of chemokines, cytokines, and antimicrobial peptides. In order to characterize the inflammatory response to H. pylori, a new experimental protocol for isolating and culturing primary human gastric epithelial cells was established using pieces of stomach from patients who had undergone sleeve gastrectomy. Isolated cells expressed markers indicating that they were mucin-secreting epithelial cells. Challenge of primary epithelial cells with H. pylori B128 underscored early dose-dependent induction of expression of mRNAs of the inflammatory mediators CXCL1 to -3, CXCL5, CXCL8, CCL20, BD2, and tumor necrosis factor alpha (TNF-␣). In AGS cells, significant expression of only CXCL5 and CXCL8 was observed following infection, suggesting that these cells were less reactive than primary epithelial cells. Infection of both cellular models with H. pylori B128⌬cagM, a cag PAI mutant, resulted in weak inflammatory-mediator mRNA induction. At 24 h after infection of primary epithelial cells with H. pylori, inflammatory-mediator production was largely due to cag PAI substrate-independent virulence factors. Thus, H. pylori cag PAI substrate appears to be involved in eliciting an epithelial response during the early phases of infection. Afterwards, other virulence factors of the bacterium take over in development of the inflammatory response. Using a relevant cellular model, this study provides new information on the modulation of inflammation during H. pylori infection.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Chemokines and Antimicrobial Peptides Have a cag -Dependent Early Response to Helicobacter pylori Infection in Primary Human Gastric Epithelial Cells

et al. 2014

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“…Previous work had shown that imaA mutants cause a strong host inflammatory response that is dependent on the cag PAI (24). The cag PAI has multiple ways to trigger inflammation, including by the delivery of CagA and by direct interactions between its T4SS and the host cell (10,28,29). We therefore first addressed which of these attributes were influenced by ImaA by determining whether the imaA phenotype was dependent on CagA.…”

Section: Resultsmentioning

confidence: 99%

The Helicobacter pylori Autotransporter ImaA Tempers the Bacterium's Interaction with α ₅ β ₁ Integrin

et al. 2017

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The human pathogen Helicobacter pylori uses the host receptor ␣ 5 ␤ 1 integrin to trigger inflammation in host cells via its cag pathogenicity island (cag PAI) type IV secretion system (T4SS). Here, we report that the H. pylori ImaA protein (HP0289) decreases the action of the cag PAI T4SS via tempering the bacterium's interaction with ␣ 5 ␤ 1 integrin. Previously, imaA-null mutants were found to induce an elevated inflammatory response that was dependent on the cag PAI T4SS; here we extend those findings to show that the elevated response is independent of the CagA effector protein. To understand how ImaA could be affecting cag PAI T4SS activity at the host cell interface, we utilized the Phyre structural threading program and found that ImaA has a region with remote homology to bacterial integrinbinding proteins. This region was required for ImaA function. Unexpectedly, we observed that imaA mutants bound higher levels of ␣ 5 ␤ 1 integrin than wild-type H. pylori, an outcome that required the predicted integrin-binding homology region of ImaA. Lastly, we report that ImaA directly affected the amount of host cell ␤1 integrin but not other cellular integrins. Our results thus suggest a model in which H. pylori employs ImaA to regulate interactions between integrin and the T4SS and thus alter the host inflammatory strength.KEYWORDS autotransporter proteins, inflammation, pathogenesis, secretion systems, virulence factors T he human pathogen Helicobacter pylori is one of the world's most common pathogens, chronically colonizing the stomachs of at least one-third of the world's population, with the populations of many countries experiencing rates of colonization of over 50% (1, 2). The outcomes of this infection vary on the basis of a combination of bacterial genetics, host genetics, and environmental factors (3). Ten to 15% of those infected go on to develop severe diseases, including ulcers and gastric adenocarcinoma (4-6). H. pylori-triggered diseases cause significant mortality and morbidity worldwide. For example, gastric adenocarcinoma killed over 700,000 people worldwide in 2012, and in the United States, 26,370 people were expected to have been diagnosed with this disease in 2016 (7,8).One of the main factors that influences the H. pylori disease outcome is whether a person is infected with a strain that possesses the cytotoxin-associated gene (cag) pathogenicity island (cag PAI). cag PAI-positive strains are associated with severe inflammation, peptic ulcers, and gastric cancer (9). The cag PAI encodes a type IV secretion system (T4SS), a large multiprotein system that triggers a host inflammatory response directly via interactions with the host cells (10) and also via delivery of proinflammatory cargo: the protein CagA and the bacterial molecule peptidoglycan (11,12).Given the cost and consequence of producing an active cag PAI T4SS, its function is controlled at several levels (2, 13, 14). While there is some transcriptional modulation

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“…pylori culture H. pylori strain P12, previously designated strain 888-0, was isolated from a duodenal ulcer patient and contains both the vacA cytotoxin and a functional cagPAI (Fischer et al 2010;Haas et al 1993). H. pylori isogenic mutants P12ΔcagL (Gorrell et al 2013), P12ΔcagL/cagL (Gorrell et al 2013), P12ΔcagPAI Selbach 2002) and P12ΔcagA (kindly provided by S. Backert, Erlangen, Germany) were cultured and maintained as described previously (Gorrell et al 2013). Broth cultures were shaken at 120 rpm overnight (approximately 16 h) prior to the day of infection and cell cultures were infected with H. pylori cultures that had attained an OD 550nm of 0.5-2.0.…”

Section: Mammalian Cell Culturementioning

confidence: 99%

“…The human gastric adenocarcinoma cell line AGS was cultured for infection experiments and inoculated with H. pylori liquid culture as described previously (Gorrell et al 2013). AGS cells were plated in a 6-well dish (1 × 10 5 /well) or a 10-cm dish (7.5 × 10 5 /well) 48 h prior to infection in RPMI media supplemented with 10 % heat inactivated FBS.…”

Section: Infection Of Ags Cells With Isogenic Mutant Strains Of H Pymentioning

confidence: 99%

The Helicobacter pylori cytotoxin CagA is essential for suppressing host heat shock protein expression

Lang

Gorrell

Tafreshi

et al. 2016

Cell Stress and Chaperones

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Bacterial infections typically elicit a strong Heat Shock Response (HSR) in host cells. However, the gastric pathogen Helicobacter pylori has the unique ability to repress this response, the mechanism of which has yet to be elucidated. This study sought to characterize the underlying mechanisms by which H. pylori down-modulates host HSP expression upon infection. Examination of isogenic mutant strains of H. pylori defective in components of the type IV secretion system (T4SS), identified the secretion substrate, CagA, to be essential for down-modulation of the HSPs HSPH1 (HSP105), HSPA1A (HSP72), and HSPD1 (HSP60) upon infection of the AGS gastric adenocarcinoma cell line. Ectopic expression of CagA by transient transfection was insufficient to repress HSP expression in AGS or HEK293T cells, suggesting that additional H. pylori factors are required for HSP repression. RT-qPCR analysis of HSP gene expression in AGS cells infected with wild-type H. pylori or isogenic cagA-deletion mutant found no significant change to account for reduced HSP levels. In summary, this study identified CagA to be an essential bacterial factor for H. pylori-mediated suppression of host HSP expression. The novel finding that HSPH1 is down-modulated by H. pylori further highlights the unique ability of H. pylori to repress the HSR within host cells. Elucidation of the mechanism by which H. pylori achieves HSP repression may prove to be beneficial in the identification of novel mechanisms to inhibit the HSR pathway and provide further insight into the interactions between H. pylori and the host gastric epithelium.

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A novel NOD1- and CagA-independent pathway of interleukin-8 induction mediated by theHelicobacter pyloritype IV secretion system

Cited by 85 publications

References 67 publications

Chemokines and Antimicrobial Peptides Have a cag -Dependent Early Response to Helicobacter pylori Infection in Primary Human Gastric Epithelial Cells

Chemokines and Antimicrobial Peptides Have a cag -Dependent Early Response to Helicobacter pylori Infection in Primary Human Gastric Epithelial Cells

The Helicobacter pylori Autotransporter ImaA Tempers the Bacterium's Interaction with α ₅ β ₁ Integrin

The Helicobacter pylori cytotoxin CagA is essential for suppressing host heat shock protein expression

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A novel NOD1- and CagA-independent pathway of interleukin-8 induction mediated by theHelicobacter pyloritype IV secretion system

Cited by 85 publications

References 67 publications

Chemokines and Antimicrobial Peptides Have a cag -Dependent Early Response to Helicobacter pylori Infection in Primary Human Gastric Epithelial Cells

Chemokines and Antimicrobial Peptides Have a cag -Dependent Early Response to Helicobacter pylori Infection in Primary Human Gastric Epithelial Cells

The Helicobacter pylori Autotransporter ImaA Tempers the Bacterium's Interaction with α 5 β 1 Integrin

The Helicobacter pylori cytotoxin CagA is essential for suppressing host heat shock protein expression

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The Helicobacter pylori Autotransporter ImaA Tempers the Bacterium's Interaction with α ₅ β ₁ Integrin