Helicobacter pylori gene silencing in vivo demonstrates urease is essential for chronic infection

Debowski, Aleksandra W.; Walton, Senta M.; Chua, Eng Guan; Tay, Chin Yen; Liao, Tingting; Lamichhane, Binit; Himbeck, Robyn; Stubbs, Keith A.; Marshall, Barry J.; Fulurija, Alma; Benghezal, Mohammed

doi:10.1371/journal.ppat.1006464

Cited by 60 publications

(53 citation statements)

References 73 publications

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“…H. pylori infection is a threat to human health, for example, the long-term colonization of H. pylori in the stomach can change PH of the stomach, promote chronic gastritis, gastric ulcers, even gastric cancer [2]. However, until now, the mechanism of H. pylori -associated chronic gastritis remains unclear, and it is believed that the interplays between host and bacterial virulence factors [14,20], such as VacA [21], urease [22], especially a major virulence factor cagA that can be injected into host cell by Type IV Secretion System (T4SS) [23], and the following persistent inflammation are likely the underlying causes.…”

Section: Discussionmentioning

confidence: 99%

Helicobacter pylori-induced adrenomedullin modulates IFN-γ-producing T-cell responses and contribute to gastritis

Zhuang

Kong

Zhang

et al. 2018

Preprint

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23Abbreviations used in this paper: Helicobacter pylori, H. pylori; adrenomedullin, ADM; interleukin, IL; 24 interferon, IFN; receptor activity modifying protein, RAMP; phosphoinositide 3-kinase, PI3K; signal 25 transducers and activators of transcription, STAT; wild-type, WT; knockout, KO; post infection, p.i.; 26 haematoxylin and eosin, H&E.Abstract 2 Adrenomedullin (ADM) is a multifunctional peptide that is expressed by many surface epithelial cells, 3 but its relevance to H. pylori-induced gastritis is unknown. Here, we found that gastric ADM 4 expression was elevated in gastric mucosa of H. pylori-infected patients and mice. In H. 5 pylori-infected human gastric mucosa, ADM expression was positively correlated with the degree of 6 gastritis, accordingly, blockade of ADM resulted in decreased inflammation within the gastric 7 mucosa of H. pylori-infected mice. During H. pylori infection, ADM production was promoted via 8 PI3K-AKT signaling pathway activation by gastric epithelial cells in a cagA-dependent manner, and 9 resulted in increased inflammation within the gastric mucosa. This inflammation was characterized 10 by the increased IFN-γ-producing T cells, whose differentiation was induced via the phosphorylation 11 of AKT and STAT3 by ADM derived from gastric epithelial cells. ADM also induced macrophages to 12 produce IL-12, which promoted the IFN-γ-producing T-cell responses, thereby contributing to the 13 development of H. pylori-associated gastritis. Accordingly, blockade of IFN-γ or knockout of IFN-γ 14 decreased inflammation within the gastric mucosa of H. pylori-infected mice. This study identifies a 15 novel regulatory network involving H. pylori, gastric epithelial cells, ADM, macrophages, T cells, and 16 IFN-γ, which collectively exert a pro-inflammatory effect within the gastric microenvironment.17 18 Author summary 19 H. pylori infect almost half the world's population. Once infected, most of people carry the bacteria 20 lifelong if left untreated, so that persistent H. pylori infection can lead to chronic gastritis, peptic 21 ulceration and ultimately gastric cancer. H. pylori infection is accompanied with increased 22 inflammation in gastric mucosa, but the mechanisms of chronic gastritis induced by H. pylori 23 infection remains poorly understood. We studied a multifunctional peptide known as adrenomedullin 24 (ADM) in gastric epithelial cells, which was known as a key factor of regulating gastrointestinal 25 physiology and pathology. Here, we found that gastric ADM expression was elevated in gastric 26 mucosa of H. pylori-infected patients and mice, and was positively correlated with the degree of 27 gastritis. ADM production was promoted via PI3K-AKT signaling pathway activation by gastric 28 epithelial cells in a cagA-dependent manner. Blockade of ADM during H. pylori infection resulted in 29 decreased gastric inflammation that was characterized by the increased IFN-γ-producing T cells 30 which was induced via the phosphorylation of AKT and STAT3 by ADM derived from gastric 1 epitheli...

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Section: Discussionmentioning

confidence: 99%

Helicobacter pylori-induced adrenomedullin modulates IFN-γ-producing T-cell responses and contribute to gastritis

Zhuang

Kong

Zhang

et al. 2018

Preprint

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“…26 27 While urease appeared to be less essential after established colonization, chronic infection was restored by a positive selection process that altered the repressor protein, supporting a continual requirement for urease. 27 This approach may be applied to other virulence factors for understanding their roles under certain conditions, in either in vitro or in vivo studies. Additional initial colonization factors studied included GGT and RhpA, an RNA helicase protein, mutants of which showed colonization attenuation in the animal model.…”

Section: Non-cag Virulence Factorsmentioning

confidence: 99%

“…A new gene‐silencing technique using the modification of the ure A promoter with a tet ‐system developed by Debowski et al. shed new insight on the role of urease during chronic infection . While urease appeared to be less essential after established colonization, chronic infection was restored by a positive selection process that altered the repressor protein, supporting a continual requirement for urease .…”

Section: Virulence Factorsmentioning

confidence: 99%

Pathogenesis of Helicobacter pylori infection

2018

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In this review, we highlight progress in the last year in characterizing known virulence factors like flagella and the Cag type IV secretion system with sophisticated structural and biochemical approaches to yield new insight on the assembly and functions of these critical virulence determinants. Several aspects of Helicobacter pylori physiology were newly explored this year and evaluated for their functions during stomach colonization, including a fascinating role for the essential protease HtrA in allowing access of H. pylori to the basolateral side of the gastric epithelium through cleavage of the tight junction protein E-cadherin to facilitate CagA delivery. Molecular biology tools standard in model bacteria, including regulated gene expression during animal infection and fluorescent reporter gene fusions, were newly applied to H. pylori to explore functions for urease beyond initial colonization and establish high salt consumption as a mediator of gene expression changes. New sequencing technologies enabled validation of long postulated roles for DNA methylation in regulating H. pylori gene expression. On the cell biology side, elegant work using lineage tracing in the murine model and organoid primary cell culture systems has provided new insights into how H. pylori manipulates gastric tissue functions, locally and at a distance, to promote its survival in the stomach and induce pathologic changes. Finally, new work has bolstered the case for genomic variation as an important mechanism to generate phenotypic diversity during changing environmental conditions in the context of diet manipulation in animal infection models and during human experimental infection after vaccination.

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“…This recombinant experiment was fashioned in H. pylori and the gene expression was regulated . This gene silencing experiment concluded that the loss of urease activity could prove to be pernicious for H. pylori …”

Section: Ureasementioning

confidence: 99%

Unraveling the factors and mechanism involved in persistence: Host‐pathogen interactions in Helicobacter pylori

Gupta

Maurya

Verma

et al. 2019

J of Cellular Biochemistry

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Helicobacter pylori and humans have one of the most complex relationships in nature. How a bacterium manages to live in one of the harshest and hostile environments is a topic of unraveling mysteries. H. pylori is a prevalent species and it colonizes the human gut of more than 50% of the world population. It infects the epithelial region of antrum and persists there for a long period. Over the time of evolution, H. pylori has developed complex strategies to extend the degree of inflammation in gastric mucosa. H. pylori needs specific adaptations for initial colonization into the host environment like helical shape, flagellar movement, chemotaxis, and the production of urease enzyme that neutralizes acidic environment of the stomach. There are several factors from the bacterium as well as from the host that participate in these complex interactions. On the other hand, to establish the persistent infection, H. pylori escapes the immune system by mimicking the host antigens. This pathogen has the ability to dodge the immune system and then persist there in the form of host cell, which leads to immune tolerance. H. pylori has an ability to manipulate its own pathogen‐associated molecular patterns, which leads to an inhibition in the binding with specific pattern recognition receptors of the host to avoid immune cell detection. Also, it manipulates the host metabolic homeostasis in the gastric epithelium. Besides, it has several genes, which may get involved in the acquisition of nutrition from the host to survive longer in the host. Due to the persistence of H. pylori, it causes chronic inflammation and raises the chances of gastric cancer. This review highlights the important elements, which are certainly responsible for the persistence of H. pylori in the human host.

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Helicobacter pylori gene silencing in vivo demonstrates urease is essential for chronic infection

Cited by 60 publications

References 73 publications

Helicobacter pylori-induced adrenomedullin modulates IFN-γ-producing T-cell responses and contribute to gastritis

Helicobacter pylori-induced adrenomedullin modulates IFN-γ-producing T-cell responses and contribute to gastritis

Pathogenesis of Helicobacter pylori infection

Unraveling the factors and mechanism involved in persistence: Host‐pathogen interactions in Helicobacter pylori

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