High Resolution Electron Microscopy of the &lt;em&gt;Helicobacter pylori&lt;/em&gt; Cag Type IV Secretion System Pili Produced in Varying Conditions of Iron Availability

Haley, Kathryn P.; Blanz, Eric Joshua; Gaddy, Jennifer A.

doi:10.3791/52122

Cited by 10 publications

(13 citation statements)

References 25 publications

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“…Role of ATPase activity on the above processes, however, could not be established. Not much is known about pilus biogenesis in Hp except a few recent reports [ 8 , 39 , 45 , 46 ]. In Hp prototypical pilus subunits are missing.…”

Section: Discussionmentioning

confidence: 99%

Biochemical Analysis of CagE: A VirB4 Homologue of Helicobacter pylori Cag-T4SS

et al. 2015

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Helicobacter pylori are among the most successful human pathogens that harbour a distinct genomic segment called cag Pathogenicity Island (cag-PAI). This genomic segment codes for a type IV secretion system (Cag-T4SS) related to the prototypical VirB/D4 system of Agrobacterium tumefaciens (Ag), a plant pathogen. Some of the components of Cag-T4SS share homology to that of VirB proteins including putative energy providing CagE (HP0544), the largest VirB4 homologue. In Ag, VirB4 is required for the assembly of the system, substrate translocation and pilus formation, however, very little is known about CagE. Here we have characterised the protein biochemically, genetically, and microscopically and report that CagE is an inner membrane associated active NTPase and has multiple interacting partners including the inner membrane proteins CagV and Cagβ. Through CagV it is connected to the outer membrane sub-complex proteins. Stability of CagE is not dependent on several of the cag-PAI proteins tested. However, localisation and stability of the pilus associated CagI, CagL and surface associated CagH are affected in its absence. Stability of the inner membrane associated energetic component Cagβ, a VirD4 homologue seems to be partially affected in its absence. Additionally, CagA failed to cross the membrane barriers in its absence and no IL-8 induction is observed under infection condition. These results thus suggest the importance of CagE in Cag-T4SS functions. In future it may help in deciphering the mechanism of substrate translocation by the system.

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Section: Discussionmentioning

confidence: 99%

Biochemical Analysis of CagE: A VirB4 Homologue of Helicobacter pylori Cag-T4SS

et al. 2015

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“…Many of the Fur regulated genes that are transcriptionally upregulated upon iron starvation facilitate the acquisition and trafficking of iron within the bacterial cell [ 60 – 62 ]. For example, when iron availability is low H. pylori increases the transcription of the high-affinity iron transporters feA1, fecA2, frpB1 , and feoB facilitating an influx of iron into the cytoplasm [ 60 – 65 ]. Additionally, H. pylori increases binding of the host chelating proteins, lactoferrin and transferrin, upon iron starvation, both of which can be used as a source of nutrient iron.…”

Section: H Pylori and Nutritionmentioning

confidence: 99%

“…Similarly, the human antimicrobial protein lactoferrin, which serves as an iron source for H. pylori , has been shown to repress the expression of both cagA and vacA , indicating that the human antimicrobial response can directly alter H. pylori virulence by altering the micronutrient gradient available to this bacterial pathogen [ 59 , 68 ]. Recently, our work has indicated that the biogenesis and activity of the cag- T4SS increase upon iron starvation [ 65 , 66 ]. Together these findings indicate that regulation of H. pylori toxin secretion is mediated by iron availability and that both toxins play a critical role in iron homeostasis.…”

Section: H Pylori and Nutritionmentioning

confidence: 99%

Nutrition andHelicobacter pylori: Host Diet and Nutritional Immunity Influence Bacterial Virulence and Disease Outcome

Haley

Gaddy

2016

Gastroenterology Research and Practice

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Helicobacter pylori colonizes the stomachs of greater than 50% of the world's human population making it arguably one of the most successful bacterial pathogens. Chronic H. pylori colonization results in gastritis in nearly all patients; however in a subset of people, persistent infection with H. pylori is associated with an increased risk for more severe disease outcomes including B-cell lymphoma of mucosal-associated lymphoid tissue (MALT lymphoma) and invasive adenocarcinoma. Research aimed at elucidating determinants that mediate disease progression has revealed genetic differences in both humans and H. pylori which increase the risk for developing gastric cancer. Furthermore, host diet and nutrition status have been shown to influence H. pylori-associated disease outcomes. In this review we will discuss how H. pylori is able to create a replicative niche within the hostile host environment by subverting and modifying the host-generated immune response as well as successfully competing for limited nutrients such as transition metals by deploying an arsenal of metal acquisition proteins and virulence factors. Lastly, we will discuss how micronutrient availability or alterations in the gastric microbiome may exacerbate negative disease outcomes associated with H. pylori colonization.

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“…Given its role in immune modulation and iron acquisition, it is not surprising that Fur has been implicated as a potential regulator of cagA expression (Pich et al, 2012 ; Vannini et al, 2014 ). Along with these observations, our work has shown that conditions of low nutrient iron availability induce expression of the Cag-T4SS pili at the host-pathogen interface, and also enhance the activity of the Cag-T4SS (Noto et al, 2013 , 2014 ; Haley et al, 2014 ). Additionally, transcription of cagA has shown to be upregulated in iron-replete conditions suggesting Fe-Fur activation of cagA (Pich et al, 2012 ).…”

Section: Ironmentioning

confidence: 57%

Metalloregulation of Helicobacter pylori physiology and pathogenesis

Haley

Gaddy

2015

Front. Microbiol.

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Helicobacter pylori is a Gram-negative spiral-shaped bacterium that colonizes over half of the world's population. Chronic H. pylori infection is associated with increased risk for numerous disease outcomes including gastritis, dysplasia, neoplasia, B-cell lymphoma of mucosal-associated lymphoid tissue (MALT lymphoma), and invasive adenocarcinoma. The complex interactions that occur between pathogen and host are dynamic and exquisitely regulated, and the relationship between H. pylori and its human host are no exception. To successfully colonize, and subsequently persist, within the human stomach H. pylori must temporally regulate numerous genes to ensure localization to the gastric lumen and coordinated expression of virulence factors to subvert the host's innate and adaptive immune response. H. pylori achieves this precise gene regulation by sensing subtle environmental changes including host-mediated alterations in nutrient availability and responding with dramatic global changes in gene expression. Recent studies revealed that the presence or absence of numerous metal ions encountered in the lumen of the stomach, or within host tissues, including nickel, iron, copper and zinc, can influence regulatory networks to alter gene expression in H. pylori. These expression changes modulate the deployment of bacterial virulence factors that can ultimately influence disease outcome. In this review we will discuss the environmental stimuli that are detected by H. pylori as well as the trans regulatory elements, specifically the transcription regulators and transcription factors, that allow for these significant transcriptional shifts.

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High Resolution Electron Microscopy of the <em>Helicobacter pylori</em> Cag Type IV Secretion System Pili Produced in Varying Conditions of Iron Availability

Abstract: Helicobacter pylori is a helical-shaped, gram negative bacterium that colonizes the human gastric niche of half of the human population 1,2 . H. pylori is the primary cause of gastric cancer, the second leading cause of cancer-related deaths worldwide 3

Cited by 10 publications

References 25 publications

Biochemical Analysis of CagE: A VirB4 Homologue of Helicobacter pylori Cag-T4SS

Biochemical Analysis of CagE: A VirB4 Homologue of Helicobacter pylori Cag-T4SS

Nutrition andHelicobacter pylori: Host Diet and Nutritional Immunity Influence Bacterial Virulence and Disease Outcome

Metalloregulation of Helicobacter pylori physiology and pathogenesis

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