Gastric Antimicrobial Peptides Fail to Eradicate Helicobacter pylori Infection Due to Selective Induction and Resistance

Nuding, Sabine; Gersemann, Michael; Hosaka, Yoshio; Konietzny, Sabrina; Schaefer, Christian; Beisner, Julia; Schroeder, Bjoern O.; Ostaff, Maureen J.; Saigenji, K; Ott, German; Schaller, Martin; Stange, Eduard F.; Wehkamp, Jan

doi:10.1371/journal.pone.0073867

Cited by 37 publications

(34 citation statements)

References 43 publications

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“…Furthermore, cag PAI-dependent induction of BD2 was also observed in MKN45 cells infected with H. pylori (38). The binding of BD2 on the surface of H. pylori cells was recently shown (39), and it is a phenomenon that may explain the absence of detection of BD2 proteins in the cell culture supernatants. Our results support the view that BD2 is expressed in response to early and chronic H. pylori infection and that the cag PAI is involved in this antimicrobial peptide mRNA induction.…”

Section: Discussionmentioning

confidence: 91%

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: 91%

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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“…While the study of Nuding et al. revealed that HBD1 transcripts did not differ significantly between H. pylori‐ negative and ‐positive subjects, another study reported just the opposite . Not only did H. pylori ‐infected patients express less HBD1 in the gastric mucosa than the healthy counterparts, but notably, this correlates with an increased burden of infection and a higher inflammatory score.…”

Section: Host and Bacteria Interplay: Evolution Of Virulence Factorsmentioning

confidence: 92%

Pathogenesis of Helicobacter pylori Infection

Bernard

Josenhans

2014

Helicobacter

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Helicobacter pylori relies on multiple colonization and virulence factors to persist in the human stomach for life. In addition, these factors can be modulated and vary to suit the ever-changing environment within the host individual. This article outlines the novel developments in this field of research during the past year, highlighting the cag pathogenicity island, VacA, c-glutamyl-transpeptidase as well as including recent advances in protein structure, bacteria-host interaction, and the role of stomach microbiota. Helicobacter pylori ColonizationIt is well established that flagella are essential for the motility of Helicobacter pylori and are particularly crucial at early stages of infection. In a recent study [1], seeking to learn more about the proteins that, as VacA, are secreted via the autotransporter (Type V) pathway, it has been demonstrated that one of the three VacA-like proteins, namely flagella-associated autotransporter A (FaaA), is enriched in the sheath covering the flagella filament and their terminal bulb, unlike the other two that localize on the surface of the bacteria. Interestingly, mutants lacking the faaA gene show a mislocalization of flagella, which also appear more fragile. This characteristic probably depends on the effect that FaaA exerts on the stability of the major flagellar protein FlaA that, despite an increased mRNA expression, is reduced in faaA deletion mutants. The latter show a reduced motility in vitro but, more importantly, a reduced ability in colonizing the stomach of mice [1].In conjunction with motility, bacterial shape is an important persistence factor. Recently, novel determinants for H. pylori cell shape, which, among others, depend on factors involved in peptidoglycan (PG) biosynthesis and degradation, were identified using a transposon mutagenesis-based approach coupled to flow cytometry [2]. Enriched clones contained insertions in known PG endopeptidases and novel genes involved in PG biosynthesis initiation and PG cleavage.A second step in colonization is supposed to be adherence. Earlier on, it had been reported that H. pylori can bind to trefoil factor 1 (TFF1), one of several peptides released during tissue trauma. Novel data on TFF1 now suggest that H. pylori binding to TFF1 dimer and to TFF1-overproducing gastric cells is dependent on copper availability in the environment [3]. It remains unclear how these in vitro findings translate to the in vivo situation in the human stomach.Similarly, further investigations are required to demonstrate the role in vivo of the recently identified twinarginine translocation system (Tat) of H. pylori [4]. In H. pylori, this system was predicted to be composed of three proteins, TatA, TatB, and TatC, and to permit the translocation of four substrates: the catalase accessory protein, KapA; the hydrogenase small-subunit protein HydA; a putative biotin sulfoxide reductase BisC; and the cytochrome oxidase Rieske subunit protein FbcF. tatB deletion was found to be compatible with H. pylori survival, while deletion o...

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“…H. pylori in particular utilizes host cholesterol to change its membrane makeup gaining resistance against LL- 37 (McGee et al 2011 ), and, while inducing hBD-2, it seemingly avoids the upregulation of hBD-3 (Bauer et al 2013 ). The latter, while having the potential to kill H. pylori effectively, can consequently not help in eradicating it from gastric epithelia, while hBD-2, which is readily induced, only shows minor activity against the pathogen (Nuding et al 2013 ).…”

Section: Amp In the Upper Gastrointestinal Tractmentioning

confidence: 99%

Antimicrobial Peptides

2016

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Gastric Antimicrobial Peptides Fail to Eradicate Helicobacter pylori Infection Due to Selective Induction and Resistance

Cited by 37 publications

References 43 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

Pathogenesis of Helicobacter pylori Infection

Antimicrobial Peptides

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