scholarly journals Podoplanin Drives Motility of Active Macrophage via Regulating Filamin C During Helicobacter pylori Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Yi Ying Cheok ◽  
Grace Min Yi Tan ◽  
Keith Conrad Fernandez ◽  
Yee Teng Chan ◽  
Chalystha Yie Qin Lee ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Actin Polymerization ◽  
Cancer Metastasis ◽  
Transmembrane Protein ◽  
Ectopic Expression ◽  
Cellular Migration ◽  
Activated Macrophages ◽  
And Migration ◽  
H Pylori ◽  
Filamin C

Podoplanin (Pdpn) is a mucin-type transmembrane protein that has been implicated in multiple physiological settings including lymphangiogenesis, platelet aggregation, and cancer metastasis. Here, we reported an absence of Pdpn transcript expression in the resting mouse monocytic macrophages, RAW264.7 cells; intriguingly, a substantial upregulation of Pdpn was observed in activated macrophages following Helicobacter pylori or lipopolysaccharide stimulation. Pdpn-knockout macrophages demonstrated intact phagocytic and intracellular bactericidal activities comparable to wild type but exhibited impaired migration due to attenuated filopodia formation. In contrast, an ectopic expression of Pdpn augmented filopodia protrusion in activated macrophages. NanoString analysis uncovered a close dependency of Filamin C gene on the presence of Pdpn, highlighting an involvement of Filamin C in modulation of actin polymerization activity, which controls cell filopodia formation and migration. In addition, interleukin-1β production was significantly declined in the absence of Pdpn, suggesting a role of Pdpn in orchestrating inflammation during H. pylori infection besides cellular migration. Together, our findings unravel the Pdpn network that modulates movement of active macrophages.

Dissecting the Helicobacter pylori-regulated transcriptome of B cells

2020 ◽  
Vol 78 (7) ◽  
Author(s):  
Bianca E Chichirau ◽  
Tamara Scheidt ◽  
Sebastian Diechler ◽  
Theresa Neuper ◽  
Jutta Horejs-Hoeck ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Immune System ◽  
B Cells ◽  
Mhc Class Ii ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Group I ◽  
Cytotoxin Associated Gene A ◽  
And Migration ◽  
H Pylori

ABSTRACT Persistent infections with the bacterial group-I carcinogen Helicobacter pylori (H. pylori) have been associated with a broad range of gastric disorders, including gastritis, ulceration, gastric cancer or mucosa-associated lymphoid tissue (MALT) lymphoma. Pathogenesis of H. pylori requires a balance between immune tolerance and defense. Although H. pylori induces inflammatory responses, the immune system cannot eliminate the pathogen. The detailed molecular mechanisms of how H. pylori interferes with cells of the immune system, in particular infiltrated B cells, are not well investigated. Previously, it was shown that the bacterial effector and oncoprotein cytotoxin-associated gene A (CagA) is delivered into B cells followed by its tyrosine-phosphorylation. To investigate the functional consequences in B cells colonized by CagA-positive H. pylori, we analyzed the global transcriptome of H. pylori-infected Mec-1 cells by RNA sequencing. We found 889 differentially expressed genes (DEGs) and validated JUN, FOSL2, HSPA1B, SRC, CXCR3, TLR-4, TNF-α, CXCL8, CCL2, CCL4, MHC class I and MHC class II molecules by qPCR, western blot, flow cytometry and ELISA assays. The H. pylori-specific mRNA expression signature reveals a downregulation of inflammation- and migration-associated genes, whereas central signal transduction regulators of cell survival and death are upregulated.

scholarly journals Helicobacter pylori-Induced Heparanase Promotes H. pylori Colonization and Gastritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Li Tang ◽  
Bo Tang ◽  
Yuanyuan Lei ◽  
Min Yang ◽  
Sumin Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Heparan Sulfate ◽  
Chronic Gastritis ◽  
Immune Cells ◽  
Mapk Signaling ◽  
Inflammatory Conditions ◽  
Cytokines And Chemokines ◽  
And Migration ◽  
H Pylori

Chronic gastritis caused by Helicobacter pylori (H. pylori) infection has been widely recognized as the most important risk factor for gastric cancer. Analysis of the interaction between the key participants in gastric mucosal immunity and H. pylori infection is expected to provide important insights for the treatment of chronic gastritis and the prevention of gastric cancer. Heparanase is an endoglycosidase that degrades heparan sulfate, resulting in remodeling of the extracellular matrix thereby facilitating the extravasation and migration of immune cells towards sites of inflammation. Heparanase also releases heparan sulfate-bound cytokines and chemokines that further promote directed motility and recruitment of immune cells. Heparanase is highly expressed in a variety of inflammatory conditions and diseases, but its role in chronic gastritis has not been sufficiently explored. In this study, we report that H. pylori infection promotes up-regulation of heparanase in gastritis, which in turn facilitates the colonization of H. pylori in the gastric mucosa, thereby aggravating gastritis. By sustaining continuous activation, polarization and recruitment of macrophages that supply pro-inflammatory and pro-tumorigenic cytokines (i.e., IL-1, IL-6, IL-1β, TNF-α, MIP-2, iNOS), heparanase participates in the generation of a vicious circle, driven by enhanced NFκB and p38-MAPK signaling, that supports the development and progression of gastric cancer. These results suggest that inhibition of heparanase may block this self-sustaining cycle, and thereby reduce the risk of gastritis and gastric cancer.

scholarly journals Adhesin HpaA of Helicobacter pylori Promoted Migration of AGS Cells via IL-21 Secretion From HpaA-induced CD4+T Cells

2020 ◽  
Vol 13 (9) ◽  
Author(s):  
Xianru Xia ◽  
Ying Hua ◽  
Pei Hu ◽  
Jie Li ◽  
Guolin Hu ◽  
...  
Keyword(s):  
T Cells ◽  
Helicobacter Pylori ◽  
Gastric Carcinoma ◽  
Cd4 T Cells ◽  
Cancer Metastasis ◽  
Infection Process ◽  
Ags Cells ◽  
Gastric Carcinoma Cell ◽  
Cell Metastasis ◽  
H Pylori

Background: As known, there is a high correlation between Helicobacter pylori infection and gastric carcinoma. Objectives: Concerning the important role of adhesin HpaA of H. pylori in the infection process, we aimed to explore whether HpaA promotes gastric cancer metastasis. Methods: In this study, the levels of IL-21, MMP-2, and MMP-9 in patients’ biopsies with H. pylori infection were compared with post-treatment condition. The levels of IL-21 from CD4+ T cells and culture supernatants with the recombinant HpaA treatment were detected, and then the levels of MMP-2, MMP-9, and metastasis were detected and verified via AGS cells co-cultured with aforesaid CD4+ T cells. Results: Our results showed that higher levels of IL-21, MMP-2, and MMP-9 in patients’ biopsies with H. pylori infection than without H.pylori infection. Adhesin HpaA induced more IL-21 via CD4+ T cells, and IL-21 induced high MMP-2 and MMP-9 via AGS cells. In particular, HpaA caused this serial reaction to improve the migration of AGS cells, and aptamer HA6 (our previous report) and anti-IL-21 mcAb reduced the above phenomenon remarkably. Conclusions: In summary, our research suggested that adhesin HpaA plays a significant role in the process of gastric carcinoma cell metastasis via IL-21 from HpaA-induced T cells, and aptamer HA6 may be a potential therapeutic agent for H. pylori treatment.

scholarly journals Activation of IκB Kinase β and NF-κB Is Essential for Helicobacter pylori-Induced Chronic Gastritis in Mongolian Gerbils

2007 ◽  
Vol 76 (2) ◽  
pp. 781-787 ◽  
Author(s):  
Ayako Yanai ◽  
Shin Maeda ◽  
Wataru Shibata ◽  
Yohko Hikiba ◽  
Kei Sakamoto ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Gastric Mucosa ◽  
Mongolian Gerbil ◽  
Proinflammatory Cytokine ◽  
Mongolian Gerbils ◽  
Activated Macrophages ◽  
Macrophage Depletion ◽  
Iκb Kinase ◽  
H Pylori

ABSTRACT The Mongolian gerbil model of Helicobacter pylori infection resembles human gastritis. In this study, we investigated the role of NF-κB activation in H. pylori-infected gerbils. Activated macrophages were significantly increased in H. pylori-infected gastric mucosa and were identified as being important cells with potent activation of NF-κB, which plays an important part in producing proinflammatory cytokines. Macrophage depletion by the administration of clodronate resulted in milder inflammation in gerbils infected with H. pylori. In macrophages, the inhibition of IκB kinase β (IKKβ), which is a critical kinase for NF-κB activation, resulted in lower proinflammatory cytokine expression caused by heat-killed H. pylori cells. Furthermore, treatment with IKKβ inhibitor resulted in milder inflammation in gerbils with H. pylori gastritis. Collectively, our data suggest that H. pylori-mediated gastric inflammation critically depends on the efficient recruitment and activation of macrophages, with sufficient NF-κB activation.

scholarly journals Engineered Endolysin-based "Artilysins" for Controlling the Gram-negative Pathogen Helicobacter Pylori

2021 ◽  
Author(s):  
Dengyuan Xu ◽  
Shanshan Zhao ◽  
Jun Dou ◽  
Xiaofeng Xu ◽  
Yanyan Zhi ◽  
...  
Keyword(s):  
Cell Wall ◽  
Helicobacter Pylori ◽  
Transmembrane Protein ◽  
Gastrointestinal Diseases ◽  
Amide Bond ◽  
Resistant Bacteria ◽  
Gram Negative ◽  
Antibiotic Overuse ◽  
H Pylori

Abstract Helicobacter pylori infection can cause a variety of gastrointestinal diseases. In severe cases, there is a risk of gastric cancer. Antibiotics are often used for clinical treatment of H. pylori infections. However, because of antibiotic overuse in recent years and the emergence of multidrug-resistant bacteria, there is an urgent need to develop new treatment methods and drugs to achieve complete eradication of H. pylori. Endolysins and holins encoded by bacterial viruses (i.e., phages) represent a promising avenue of investigation. These lyase-based antibacterial drugs act on the bacterial cell wall to destroy the bacteria. Currently, a type of endolysin that has been studied more frequently acts on the amide bond between peptidoglycans, and holin is a transmembrane protein that can punch holes in the cell membrane. However, as a Gram-negative bacterium, H. pylori possesses a layer of impermeable lipopolysaccharides on the cell wall, which prevents endolysin interaction with the cell wall. Therefore, we designed a genetic linkage between an endolysin enzyme and a holin enzyme with a section of polypeptides (e.g., polycations and hydrophobic peptides) that enable penetration of the outer membrane. These complexes were designated “artilysins” and were efficiently expressed in Escherichia coli. In vitro bacteriostasis experiments showed that the purified artilysins had strong bacteriostatic effects on H. pylori. In addition, the surface of H. pylori was perforated and destroyed, as confirmed by electron microscopy, which was proved that artilysins had bacteriolytic effect on H. pylori.

Helicobacter pylori CagA induces ornithine decarboxylase upregulation via Src/MEK/ERK/c-Myc pathway: implication for progression of gastric diseases

2012 ◽  
Vol 237 (4) ◽  
pp. 435-441 ◽  
Author(s):  
Xia Xu ◽  
Zhifang Liu ◽  
Ming Fang ◽  
Han Yu ◽  
Xiuming Liang ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Epithelial Cells ◽  
Ornithine Decarboxylase ◽  
Ectopic Expression ◽  
Negative Control ◽  
Mitogen Activated Protein Kinase ◽  
Gastric Epithelial Cells ◽  
Gastric Diseases ◽  
Key Enzyme ◽  
H Pylori

Helicobacter pylori (H. pylori) dysregulates the expression of various genes resulting in gastric precursor lesions and cancer. Meanwhile, ornithine decarboxylase (ODC) is a key enzyme that catalyzes the formation of polyamines which are critical for cell growth. So far, the possible regulation of ODC by H. pylori and its virulence factors, and the associated mechanism in gastric epithelial cells remains undefined. In the present study, we found that cellular ODC protein was upregulated by wild-type H. pylori infection and ectopic expression of a cytotoxin-associated gene A (CagA). As a negative control, there was no such effect by cagA-mutant H. pylori infection. Results of signal protein inhibitor treatment demonstrated that the Src, MEK (mitogen-activated protein kinase kinase) and ERK (extracellular signal-regulated kinase) pathway was involved. Moreover, when c-Myc was inhibited, the stimulatory effect of CagA on ODC expression was abolished. Clinically, a positive correlation between c-Myc and ODC expression was observed in patient-derived abnormal gastric tissues. These results implied that the Src/MEK/ERK/c-Myc pathway was required for CagA-mediated ODC induction. Finally, inhibition of ODC expression led to decreased foci formation of gastric epithelial cells before and after H. pylori infection, and ODC protein was over-expressed in precancerous gastric lesions and primary gastric cancer. Collectively, our findings provide new insights into the mechanism behind H. pylori-infection-associated gastric diseases.

scholarly journals Engineered endolysin-based “artilysins” for controlling the gram-negative pathogen Helicobacter pylori

AMB Express ◽  
2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dengyuan Xu ◽  
Shanshan Zhao ◽  
Jun Dou ◽  
Xiaofeng Xu ◽  
Yanyan Zhi ◽  
...  
Keyword(s):  
Cell Wall ◽  
Helicobacter Pylori ◽  
Transmembrane Protein ◽  
Gastrointestinal Diseases ◽  
Amide Bond ◽  
Resistant Bacteria ◽  
Gram Negative ◽  
Antibiotic Overuse ◽  
H Pylori

AbstractHelicobacter pylori infection can cause a variety of gastrointestinal diseases. In severe cases, there is a risk of gastric cancer. Antibiotics are often used for clinical treatment of H. pylori infections. However, because of antibiotic overuse in recent years and the emergence of multidrug-resistant bacteria, there is an urgent need to develop new treatment methods and drugs to achieve complete eradication of H. pylori. Endolysins and holins encoded by bacterial viruses (i.e., phages) represent a promising avenue of investigation. These lyase-based antibacterial drugs act on the bacterial cell wall to destroy the bacteria. Currently, a type of endolysin that has been studied more frequently acts on the amide bond between peptidoglycans, and holin is a transmembrane protein that can punch holes in the cell membrane. However, as a Gram-negative bacterium, H. pylori possesses a layer of impermeable lipopolysaccharides on the cell wall, which prevents endolysin interaction with the cell wall. Therefore, we designed a genetic linkage between an endolysin enzyme and a holin enzyme with a section of polypeptides (e.g., polycations and hydrophobic peptides) that enable penetration of the outer membrane. These complexes were designated “artilysins” and were efficiently expressed in Escherichia coli. In vitro bacteriostasis experiments showed that the purified artilysins had strong bacteriostatic effects on H. pylori. In addition, the surface of H. pylori was perforated and destroyed, as confirmed by electron microscopy, which was proved that artilysins had bacteriolytic effect on H. pylori.

The rod-to-coccoid body transformation in cultures of Helicobacter pylori

1990 ◽  
Vol 48 (3) ◽  
pp. 626-627
Author(s):  
A. R. Crooker ◽  
W. G. Kraft ◽  
T. L. Beard ◽  
M. C. Myers
Keyword(s):  
Helicobacter Pylori ◽  
Growth Cycle ◽  
Negative Bacterium ◽  
Body Formation ◽  
Coccoid Form ◽  
Spiral Form ◽  
Prolonged Culture ◽  
H Pylori ◽  
Upper Gastrointestinal

Helicobacter pylori is a microaerophilic, gram-negative bacterium found in the upper gastrointestinal tract of humans. There is strong evidence that H. pylori is important in the etiology of gastritis; the bacterium may also be a major predisposing cause of peptic ulceration. On the gastric mucosa, the organism exists as a spiral form with one to seven sheathed flagella at one (usually) or both poles. Short spirals were seen in the first successful culture of the organism in 1983. In 1984, Marshall and Warren reported a coccoid form in older cultures. Since that time, other workers have observed rod and coccal forms in vitro; coccoid forms predominate in cultures 3-7 days old. We sought to examine the growth cycle of H. pylori in prolonged culture and the mode of coccoid body formation.

Peptische Ulzera und Helicobacter pylori: Wie wir wissen, was wir wissen

2015 ◽  
Vol 72 (7) ◽  
pp. 475-480
Author(s):  
Raphael Scholl
Keyword(s):  
Helicobacter Pylori ◽  
Kontrollierte Studie ◽  
H Pylori ◽  
Peptische Ulzera

Zusammenfassung. Zu den wichtigsten Ursachen peptischer Ulzera gehört das Bakterium Helicobacter pylori. Aber wie wurde dieser ursächliche Zusammenhang nachgewiesen? Aufschluss darüber gibt die Geschichte und Theorie einer Reihe einschlägiger Studien, die in den 1980er Jahren durchgeführt wurden. Am Anfang stand die Entdeckung einer blossen Korrelation zwischen dem neu entdeckten Bakterium und peptischen Ulzera in Magenbiopsien. Unklar blieb, ob das Bakterium die Krankheit verursachte, oder ob es bloss eine opportunistische bakterielle Besiedlung darstellte. Ohne Tiermodell war der experimentelle Nachweis der Richtung der Verursachung jedoch schwierig: Zwar wurde in einem couragierten Selbstversuch mit einer geschluckten Bakterienkultur eine Gastritis beobachtet – aber der Einzelfall war wenig aussagekräftig. Die Schwächen des Selbstversuchs liessen sich durch eine randomisierte, Plazebo-kontrollierte Studie beheben, die den Anforderungen des dritten Koch’schen Postulats gerecht wurde. Darüber hinaus war es notwendig, erste Aufschlüsse über den Mechanismus der ursächlichen Verbindung zwischen H. pylori und peptischen Ulzera zu gewinnen: Wie zum Beispiel kann das Bakterium im sauren Milieu des Magens überleben? Die wissenschaftshistorische und wissenschaftstheoretische Betrachtung des Falls illustriert, wie medizinisches Wissen schrittweise aufgebaut wird.

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