The Helicobacter pylori Autotransporter ImaA (HP0289) Modulates the Immune Response and Contributes to Host Colonization

Sause, William E.; Castillo, Andrea; Ottemann, Karen M.

doi:10.1128/iai.00312-12

Cited by 23 publications

(40 citation statements)

References 90 publications

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“…In H. pylori, the passenger domain of the VacAlike autotransporter, which likely confers the effector function of this protein, contains three VacA2 regions. Although these VacA2 regions show low similarity to the VacA toxin, they do not correspond to a functional portion of VacA (39). In our study, the passenger domains of the VacA-like autotransporters of all H. heilmannii strains also contained three VacA2 regions, whereas in H. ailurogastricus strains, which have low colonization capacity in Mongolian gerbils (8), this passenger domain contained four VacA2 regions.…”

Section: Discussionmentioning

confidence: 65%

“…One of the major protein toxins secreted by H. pylori is the vacuolating cytotoxin A (VacA), which belongs to an additional family of OMPs called autotransporters (39). The VacA toxin binds to host cells and is internalized, causing severe "vacuolation" characterized by the accumulation of large vesicles that possess hallmarks of both late endosomes and early lysosomes (40) (15).…”

Section: Resultsmentioning

confidence: 99%

“…3). The passenger domain represents the surfaceexposed component of the protein and adopts an extended righthanded ␤-helix structure (39). Also other canine, feline, and porcine gastric Helicobacter species harbor a copy of a vacA-like autotransporter gene.…”

Section: Resultsmentioning

confidence: 99%

“…H. pylori harbors three such autotransporters, which belong to an additional OMP family and have been shown to enhance the ability of H. pylori to colonize the stomach (39,41). Only one copy is present among the canine, feline, and porcine gastric helicobacters.…”

Section: Discussionmentioning

confidence: 99%

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Divergence between the Highly Virulent Zoonotic Pathogen Helicobacter heilmannii and Its Closest Relative, the Low-Virulence “Helicobacter ailurogastricus” sp. nov

et al. 2016

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h Helicobacter heilmannii naturally colonizes the stomachs of dogs and cats and has been associated with gastric disorders in humans. Nine feline Helicobacter strains, classified as H. heilmannii based on ureAB and 16S rRNA gene sequences, were divided into a highly virulent and a low-virulence group. The genomes of these strains were sequenced to investigate their phylogenetic relationships, to define their gene content and diversity, and to determine if the differences in pathogenicity were associated with the presence or absence of potential virulence genes. The capacities of these helicobacters to bind to the gastric mucosa were investigated as well. Our analyses revealed that the low-virulence strains do not belong to the species H. heilmannii but to a novel, closely related species for which we propose the name Helicobacter ailurogastricus. Several homologs of H. pylori virulence factors, such as IceA1, HrgA, and jhp0562-like glycosyltransferase, are present in H. heilmannii but absent in H. ailurogastricus. Both species contain a VacA-like autotransporter, for which the passenger domain is remarkably larger in H. ailurogastricus than in H. heilmannii. In addition, H. ailurogastricus shows clear differences in binding to the gastric mucosa compared to H. heilmannii. These findings highlight the low-virulence character of this novel Helicobacter species. Helicobacter pylori is considered one of the most successful human pathogens. Infection with this agent has been associated with a wide range of gastric disorders. However, H. pylori is not the only Helicobacter species causing gastric disease in humans. Helicobacter heilmannii (sensu stricto), a zoonotic bacterium naturally colonizing the stomachs of cats and dogs, has been associated with gastritis, peptic and duodenal ulcers, and mucosa-associated lymphoid tissue (MALT) lymphoma in humans (1-6). This Helicobacter species is highly prevalent in the stomachs of clinically healthy cats and dogs as well as in those of animals showing chronic active gastritis (1, 4). Its pathogenic significance in these animals remains unclear and is probably strain dependent or related to host differences (1).Little information is available regarding the pathogenesis of H. heilmannii infections in humans (1, 7). A recent experimental infection study, using Mongolian gerbils as an in vivo model to study Helicobacter-related gastric pathology in humans, investigated the colonization capacities and virulence of nine different Helicobacter strains (8). These helicobacters had been isolated from the gastric mucosae of stray cats and had been classified as H. heilmannii on the basis of the ureAB and 16S rRNA gene sequences (9). At 9 weeks postinfection, the induction of an antrum-dominant chronic active gastritis associated with the formation of lymphocytic aggregates and upregulation of the proinflammatory cytokine interleukin 1␤ (IL-1␤) was shown for seven strains. However, differences in the expression of IL-1␤ were noted, together with differences in the intensity of the obser...

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Section: Discussionmentioning

confidence: 65%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Divergence between the Highly Virulent Zoonotic Pathogen Helicobacter heilmannii and Its Closest Relative, the Low-Virulence “Helicobacter ailurogastricus” sp. nov

et al. 2016

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“…Mutants lacking imaA induce higher levels of interleukin-8 (IL-8) from infected gastric epithelial cells than wild-type H. pylori does, a response that depends on the cag PAI (24). ImaA is a member of the classical autotransporter family, also called type Va (25).…”

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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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Virulence Mechanisms of Helicobacter pylori: An Overview

Praszkier

Sutton

Ferrero

2016

Helicobacter Pylori Research

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The Helicobacter pylori Autotransporter ImaA (HP0289) Modulates the Immune Response and Contributes to Host Colonization

Cited by 23 publications

References 90 publications

Divergence between the Highly Virulent Zoonotic Pathogen Helicobacter heilmannii and Its Closest Relative, the Low-Virulence “Helicobacter ailurogastricus” sp. nov

Divergence between the Highly Virulent Zoonotic Pathogen Helicobacter heilmannii and Its Closest Relative, the Low-Virulence “Helicobacter ailurogastricus” sp. nov

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

Virulence Mechanisms of Helicobacter pylori: An Overview

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The Helicobacter pylori Autotransporter ImaA (HP0289) Modulates the Immune Response and Contributes to Host Colonization

Cited by 23 publications

References 90 publications

Divergence between the Highly Virulent Zoonotic Pathogen Helicobacter heilmannii and Its Closest Relative, the Low-Virulence “Helicobacter ailurogastricus” sp. nov

Divergence between the Highly Virulent Zoonotic Pathogen Helicobacter heilmannii and Its Closest Relative, the Low-Virulence “Helicobacter ailurogastricus” sp. nov

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

Virulence Mechanisms of Helicobacter pylori: An Overview

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