Metallothionein is a crucial protective factor againstHelicobacter pylori-induced gastric erosive lesions in a mouse model

2008 ◽  
Vol 294 (4) ◽  
pp. G877-G884 ◽  
Author(s):  
Masaharu Mita ◽  
Masahiko Satoh ◽  
Akinori Shimada ◽  
Mina Okajima ◽  
Sadahiro Azuma ◽  
...  
Keyword(s):  
Metal Binding ◽  
Protective Factor ◽  
Histopathological Examination ◽  
Inflammatory Cells ◽  
Gastric Injury ◽  
Wild Type ◽  
Inflammatory Protein ◽  
Ros Scavenger ◽  
H Pylori

Infection with the gastric pathogen Helicobacter pylori ( H. pylori) causes chronic gastritis, peptic ulcer, and gastric adenocarcinoma. These diseases are associated with production of reactive oxygen species (ROS) from infiltrated macrophages and neutrophiles in inflammatory sites. Metallothionein (MT) is a low-molecular-weight, cysteine-rich protein that can act not only as a metal-binding protein, but also as a ROS scavenger. In the present study, we examined the role of MT in the protection against H. pylori-induced gastric injury using MT-null mice. Female MT-null and wild-type mice were challenged with H. pylori SS1 strain, and then histological changes were evaluated with the updated Sydney grading system at 17 and 21 wk after challenge. Although the colonization efficiency of H. pylori was essentially the same for MT-null and wild-type mice, the scores of activity of inflammatory cells were significantly higher in MT-null mice than in wild-type mice at 17 wk after challenge. Histopathological examination revealed erosive lesions accompanied by infiltration of inflammatory cells in the infected MT-null mice but not in wild-type mice. Furthermore, activation of NF-κB and expression of NF-κB-mediated chemokines such as macrophage inflammatory protein-1α and monocytes chemoattractant protein-1 in gastric cells were markedly higher in MT-null mice than in wild-type mice. These results suggest that MT in the gastric mucosa might play an important role in the protection against H. pylori-induced gastric ulceration.

scholarly journals E. coli Enterotoxin LtB Enhances Vaccine-Induced Anti-H. pylori Protection by Promoting Leukocyte Migration into Gastric Mucus via Inflammatory Lesions

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 982
Author(s):  
Xiaoyan Peng ◽  
Rongguang Zhang ◽  
Chen Wang ◽  
Feiyan Yu ◽  
Mingyang Yu ◽  
...  
Keyword(s):  
Cellular Immunity ◽  
Protective Efficacy ◽  
Gastric Injury ◽  
Oral Vaccines ◽  
Gastric Mucus ◽  
E Coli ◽  
Non Invasive ◽  
Considerable Impact ◽  
H Pylori

Current studies indicate that the anti-H. pylori protective efficacy of oral vaccines to a large extent depends on using mucosal adjuvants like E. coli heat-lable enterotoxin B unit (LtB). However, the mechanism by which Th17/Th1-driven cellular immunity kills H. pylori and the role of LtB remains unclear. Here, two L. lactis strains, expressing H. pylori NapA and LtB, respectively, were orally administrated to mice. As observed, the administration of LtB significantly enhanced the fecal SIgA level and decreased gastric H. pylori colonization, but also markedly aggravated gastric inflammatory injury. Both NapA group and NapA+LtB group had elevated splenocyte production of IL-8, IL-10, IL-12, IL-17, IL-23 and INF-γ. Notably, gastric leukocytes’ migration or leakage into the mucus was observed more frequently in NapA+LtB group than in NapA group. This report is the first that discusses how LtB enhances vaccine-induced anti-H. pylori efficacy by aggravating gastric injury and leukocytes’ movement into the mucus layer. Significantly, it brings up a novel explanation for the mechanism underlying mucosal cellular immunity destroying the non-invasive pathogens. More importantly, the findings suggest the necessity to further evaluate LtB’s potential hazards to humans before extending its applications. Thus, this report can provide considerable impact on the fields of mucosal immunology and vaccinology.

scholarly journals Systems Modeling of the Role of Interleukin-21 in the Maintenance of Effector CD4+ T Cell Responses during Chronic Helicobacter pylori Infection

mBio ◽  
2014 ◽  
Vol 5 (4) ◽  
Author(s):  
Adria Carbo ◽  
Danyvid Olivares-Villagómez ◽  
Raquel Hontecillas ◽  
Josep Bassaganya-Riera ◽  
Rupesh Chaturvedi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
T Cell ◽  
Wild Type ◽  
Content Type ◽  
Interleukin 21 ◽  
H Pylori ◽  
Deficient Mice

ABSTRACTThe development of gastritis duringHelicobacter pyloriinfection is dependent on an activated adaptive immune response orchestrated by T helper (Th) cells. However, the relative contributions of the Th1 and Th17 subsets to gastritis and control of infection are still under investigation. To investigate the role of interleukin-21 (IL-21) in the gastric mucosa duringH. pyloriinfection, we combined mathematical modeling of CD4+T cell differentiation within vivomechanistic studies. We infected IL-21-deficient and wild-type mice withH. pyloristrain SS1 and assessed colonization, gastric inflammation, cellular infiltration, and cytokine profiles. ChronicallyH. pylori-infected IL-21-deficient mice had higherH. pyloricolonization, significantly less gastritis, and reduced expression of proinflammatory cytokines and chemokines compared to these parameters in infected wild-type littermates. Thesein vivodata were used to calibrate anH. pyloriinfection-dependent, CD4+T cell-specific computational model, which then described the mechanism by which IL-21 activates the production of interferon gamma (IFN-γ) and IL-17 during chronicH. pyloriinfection. The model predicted activated expression of T-bet and RORγt and the phosphorylation of STAT3 and STAT1 and suggested a potential role of IL-21 in the modulation of IL-10. Driven by our modeling-derived predictions, we found reduced levels of CD4+splenocyte-specifictbx21androrcexpression, reduced phosphorylation of STAT1 and STAT3, and an increase in CD4+T cell-specific IL-10 expression inH. pylori-infected IL-21-deficient mice. Our results indicate that IL-21 regulates Th1 and Th17 effector responses during chronicH. pyloriinfection in a STAT1- and STAT3-dependent manner, therefore playing a major role controllingH. pyloriinfection and gastritis.IMPORTANCEHelicobacter pyloriis the dominant member of the gastric microbiota in more than 50% of the world’s population.H. pyloricolonization has been implicated in gastritis and gastric cancer, as infection withH. pyloriis the single most common risk factor for gastric cancer. Current data suggest that, in addition to bacterial virulence factors, the magnitude and types of immune responses influence the outcome of colonization and chronic infection. This study uses a combined computational and experimental approach to investigate how IL-21, a proinflammatory T cell-derived cytokine, maintains the chronic proinflammatory T cell immune response driving chronic gastritis duringH. pyloriinfection. This research will also provide insight into a myriad of other infectious and immune disorders in which IL-21 is increasingly recognized to play a central role. The use of IL-21-related therapies may provide treatment options for individuals chronically colonized withH. pylorias an alternative to aggressive antibiotics.

scholarly journals Growth Phase Regulation of flaA Expression in Helicobacter pylori Is luxS Dependent

2004 ◽  
Vol 72 (9) ◽  
pp. 5506-5510 ◽  
Author(s):  
John T. Loh ◽  
Mark H. Forsyth ◽  
Timothy L. Cover
Keyword(s):  
Helicobacter Pylori ◽  
Growth Phase ◽  
Wild Type ◽  
Phase Dependence ◽  
Autoinducer 2 ◽  
Extracellular Signaling ◽  
Reporter Strains ◽  
Phase Regulation ◽  
H Pylori

ABSTRACT LuxS plays a role in the synthesis of an extracellular signaling molecule, autoinducer 2 (AI-2). To analyze a possible role of AI-2 in regulating Helicobacter pylori gene expression, we constructed a panel of transcriptional reporter strains. We show that the expression of H. pylori flaA is growth phase dependent and that flaA transcription increases in association with increased culture density. Mutating the luxS gene eliminates growth-phase-dependent control of flaA, and this growth phase dependence is restored when the luxS mutant strain is complemented with the wild-type luxS gene.

scholarly journals Role of Gamma Interferon in Helicobacter pylori Induction of Inflammatory Mediators during Murine Infection

2002 ◽  
Vol 70 (6) ◽  
pp. 3295-3299 ◽  
Author(s):  
Marygorret Obonyo ◽  
Donald G. Guiney ◽  
Julia Harwood ◽  
Joshua Fierer ◽  
Sheri P. Cole
Keyword(s):  
Helicobacter Pylori ◽  
Gene Knockout ◽  
Gamma Interferon ◽  
Epithelial Cell Line ◽  
Inos Mrna ◽  
Inflammatory Protein ◽  
Ifn Γ ◽  
H Pylori ◽  
Oxide Synthase

ABSTRACT Gamma interferon (IFN-γ) has been proposed to play an important role in Helicobacter-related gastritis. Using the IFN-γ gene knockout (IFN-γ−/−) mouse model and a murine gastric epithelial cell line, GSM06, we demonstrated that Helicobacter pylori maximally induced macrophage inflammatory protein-2 (MIP-2) and inducible nitric oxide synthase (iNOS) mRNA only in wild-type mice. MIP-2 and iNOS mRNA were also induced by H. pylori in GSM06 cells. Induction of cyclooxygenase 2 mRNA through IFN-γ was demonstrated in GSM06 cells. These data indicate that IFN-γ mediates the induction of MIP-2 and iNOS mRNA expression by H. pylori in mice.

scholarly journals Colonization and Inflammation Deficiencies in Mongolian Gerbils Infected by Helicobacter pylori Chemotaxis Mutants

2005 ◽  
Vol 73 (3) ◽  
pp. 1820-1827 ◽  
Author(s):  
David J. McGee ◽  
Melanie L. Langford ◽  
Emily L. Watson ◽  
J. Elliot Carter ◽  
Yu-Ting Chen ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Immune Cell ◽  
Response Regulator ◽  
Critical Role ◽  
Mongolian Gerbils ◽  
Wild Type ◽  
In The Wild ◽  
H Pylori

ABSTRACT Helicobacter pylori causes disease in the human stomach and in mouse and gerbil stomach models. Previous results have shown that motility is critical for H. pylori to colonize mice, gerbils, and other animal models. The role of chemotaxis, however, in colonization and disease is less well understood. Two genes in the H. pylori chemotaxis pathway, cheY and tlpB, which encode the chemotaxis response regulator and a methyl-accepting chemoreceptor, respectively, were disrupted. The cheY mutation was complemented with a wild-type copy of cheY inserted into the chromosomal rdxA gene. The cheY mutant lost chemotaxis but retained motility, while all other strains were motile and chemotactic in vitro. These strains were inoculated into gerbils either alone or in combination with the wild-type strain, and colonization and inflammation were assessed. While the cheY mutant completely failed to colonize gerbil stomachs, the tlpB mutant colonized at levels similar to those of the wild type. With the tlpB mutant, there was a substantial decrease in inflammation in the gerbil stomach compared to that with the wild type. Furthermore, there were differences in the numbers of each immune cell in the tlpB-mutant-infected stomach: the ratio of lymphocytes to neutrophils was about 8 to 1 in the wild type but only about 1 to 1 in the mutant. These results suggest that the TlpB chemoreceptor plays an important role in the inflammatory response while the CheY chemotaxis regulator plays a critical role in initial colonization. Chemotaxis mutants may provide new insights into the steps involved in H. pylori pathogenesis.

scholarly journals Impaired Pulmonary NF-κB Activation in Response to Lipopolysaccharide in NADPH Oxidase-Deficient Mice

2001 ◽  
Vol 69 (10) ◽  
pp. 5991-5996 ◽  
Author(s):  
M. Audrey Koay ◽  
John W. Christman ◽  
Brahm H. Segal ◽  
Annapurna Venkatakrishnan ◽  
Thomas R. Blackwell ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Intracellular Signaling ◽  
Lung Inflammation ◽  
Nuclear Translocation ◽  
Binding Activity ◽  
Wild Type ◽  
Inflammatory Protein ◽  
Macrophage Inflammatory Protein ◽  
Deficient Mice

ABSTRACT Reactive oxygen species (ROS) are thought to be involved in intracellular signaling, including activation of the transcription factor NF-κB. We investigated the role of NADPH oxidase in the NF-κB activation pathway by utilizing knockout mice (p47phox−/−) lacking the p47phox component of NADPH oxidase. Wild-type (WT) controls and p47phox−/−mice were treated with intraperitoneal (i.p.) Escherichia coli lipopolysaccharide (LPS) (5 or 20 μg/g of body weight). LPS-induced NF-κB binding activity and accumulation of RelA in nuclear protein extracts of lung tissue were markedly increased in WT compared to p47phox−/− mice 90 min after treatment with 20 but not 5 μg of i.p. LPS per g. In another model of lung inflammation, RelA nuclear translocation was reduced in p47phox−/− mice compared to WT mice following treatment with aerosolized LPS. In contrast to NF-κB activation in p47phox−/− mice, LPS-induced production of macrophage inflammatory protein 2 in the lungs and neutrophilic lung inflammation were not diminished in these mice compared to WT mice. We conclude that LPS-induced NF-κB activation is deficient in the lungs of p47phox−/− mice compared to WT mice, but this abnormality does not result in overt alteration in the acute inflammatory response.

scholarly journals In Helicobacter pylori, LuxS Is a Key Enzyme in Cysteine Provision through a Reverse Transsulfuration Pathway

2010 ◽  
Vol 192 (5) ◽  
pp. 1184-1192 ◽  
Author(s):  
Neil C. Doherty ◽  
Feifei Shen ◽  
Nigel M. Halliday ◽  
David A. Barrett ◽  
Kim R. Hardie ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Wild Type ◽  
Metabolic Role ◽  
Absolute Requirement ◽  
Transsulfuration Pathway ◽  
Cysteine Synthesis ◽  
Key Enzyme ◽  
H Pylori ◽  
Isogenic Strains

ABSTRACT In many bacteria, LuxS functions as a quorum-sensing molecule synthase. However, it also has a second, more central metabolic function in the activated methyl cycle (AMC), which generates the S-adenosylmethionine required by methyltransferases and recycles the product via methionine. Helicobacter pylori lacks an enzyme catalyzing homocysteine-to-methionine conversion, rendering the AMC incomplete and thus making any metabolic role of H. pylori LuxS (LuxSHp) unclear. Interestingly, luxS Hp is located next to genes annotated as cysK Hp and metB Hp, involved in other bacteria in cysteine and methionine metabolism. We showed that isogenic strains carrying mutations in luxS Hp, cysK Hp, and metB Hp could not grow without added cysteine (whereas the wild type could), suggesting roles in cysteine synthesis. Growth of the ΔluxS Hp mutant was restored by homocysteine or cystathionine and growth of the ΔcysK Hp mutant by cystathionine only. The ΔmetB Hp mutant had an absolute requirement for cysteine. Metabolite analyses showed that S-ribosylhomocysteine accumulated in the ΔluxS Hp mutant, homocysteine in the ΔcysK Hp mutant, and cystathionine in the ΔmetB Hp mutant. This suggests that S-ribosylhomocysteine is converted by LuxSHp to homocysteine (as in the classic AMC) and thence by CysKHp to cystathionine and by MetBHp to cysteine. In silico analysis suggested that cysK-metB-luxS were acquired by H. pylori from a Gram-positive source. We conclude that cysK-metB-luxS encode the capacity to generate cysteine from products of the incomplete AMC of H. pylori in a process of reverse transsulfuration. We recommend that the misnamed genes cysK Hp and metB Hp be renamed mccA (methionine-to-cysteine-conversion gene A) and mccB, respectively.

scholarly journals Role of Tachykinins in the Host Response to Murine Gammaherpesvirus Infection

2001 ◽  
Vol 75 (21) ◽  
pp. 10467-10471 ◽  
Author(s):  
Catherine M. Payne ◽  
Caroline J. Heggie ◽  
David G. Brownstein ◽  
James P. Stewart ◽  
John P. Quinn
Keyword(s):  
Virus Infection ◽  
Host Response ◽  
Infectious Virus ◽  
Inflammatory Cells ◽  
Direct Influence ◽  
Wild Type ◽  
Murine Gammaherpesvirus ◽  
Latently Infected ◽  
Infected Cells

ABSTRACT Tachykinins function not only as neurotransmitters but also as immunological mediators. We used infection of tachykinin-deficient (PPT-A −/−) mice and wild-type controls with murine gammaherpesvirus to assess the role of tachykinins in the host response to a virus infection. Although infection was ultimately controlled in PPT-A −/− mice, there were higher titers of infectious virus in the lungs, accompanied by a more rapid influx of inflammatory cells. Clearance of latently infected cells from the spleen was also delayed. This is the first report of the direct influence of tachykinins in the host response to a virus infection.

scholarly journals The Regulator PerR Is Involved in Oxidative Stress Response and Iron Homeostasis and Is Necessary for Full Virulence of Streptococcus pyogenes

2002 ◽  
Vol 70 (9) ◽  
pp. 4968-4976 ◽  
Author(s):  
Susanna Ricci ◽  
Robert Janulczyk ◽  
Lars Björck
Keyword(s):  
Oxidative Stress ◽  
Streptococcus Pyogenes ◽  
Stress Responses ◽  
Metal Binding ◽  
Iron Homeostasis ◽  
Bacterial Species ◽  
Transcriptional Analysis ◽  
Wild Type ◽  
Allelic Replacement

ABSTRACT Ferric uptake regulator (Fur) and Fur-like proteins form an important family of transcriptional regulators in many bacterial species. In this work we have characterized a Fur-like protein, the peroxide regulator PerR, in an M1 serotype of Streptococcus pyogenes. To determine the role of PerR in S. pyogenes, we inactivated the gene by allelic replacement. PerR-deficient bacteria showed 48% reduction of 55Fe incorporation from the culture medium. Transcriptional analysis revealed that mtsA, encoding a metal-binding protein of an ABC transporter in S. pyogenes, was transcribed at lower levels than were wild-type cells. Although total iron accumulation was reduced, the growth of the mutant strain was not significantly hampered. The mutant showed hyperresistance to hydrogen peroxide, and this response was induced in wild-type cells by growth in aerobiosis, suggesting that PerR acts as an oxidative stress-responsive repressor. PerR may also participate in the response to superoxide stress, as the perR mutant was more sensitive to the superoxide anion and had a reduced transcription of sodA, which encodes the sole superoxide dismutase of S. pyogenes. Complementation of the mutation with a functional perR gene restored 55Fe incorporation, response to peroxide stress, and transcription of both mtsA and sodA to levels comparable to those of wild-type bacteria. Finally, the perR mutant was attenuated in virulence in a murine air sac model of infection (P < 0.05). These results demonstrate that PerR is involved in the regulation of iron homeostasis and oxidative stress responses and that it contributes to the virulence of S. pyogenes.

scholarly journals Effect of CAP10 gene on immune response in mice infected with Cryptococcus neoformans

2019 ◽  
Author(s):  
Ni Lin ◽  
Liping Lin ◽  
Xiaoyu Li ◽  
Xianghui Li ◽  
Juan Wu ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Cryptococcus Neoformans ◽  
Histopathological Examination ◽  
Inflammatory Cells ◽  
Expression Plasmid ◽  
Shrna Expression ◽  
Molecular Therapeutic ◽  
Capsular Formation

Abstract ABSTRACT Background Capsule is an vital virulence factor in Cryptococcus neoformans infection. Recent studies show CAP10 is a key gene in capsular formation. However, the role of CAP10 in the pathophysiology of cryptococcosis is still not well understood. This study aims to investigate the association of CAP10 expression with the immune responses to infected mice. Methods The shRNA expression plasmid was designed to interfere with the synthesis of CAP10. The animal model was established with C. neoformans wt strain H99, cap10-shRNA C. neoformans and PBS control in the respiratory tract. On the 7 days and 21 days after infection, mice lung histopathological examination and homogenate culture were performed, and cytokines expression level in the serum of mice were quantitatively detected. Results The lower degree of edema and infiltration of inflammatory cells were observed in cap10-shRNA group. The growth rate of cap10-shRNA strain was significantly reduced. In addition, interference with CAP10 altered the expression profile of Th1, Th2, Th17 and Treg type cytokine. Down-regulation of CAP10 was beneficial to the balance of Th1/Th2, Th17/Treg ratio. Conclusions Taken together, our results indicated the expression of the CAP10 was associated with an antifungal immune response to mice infected with C. neoformans. CAP10 might play an important role in regulating the inflammatory response, and could expected to be a new molecular therapeutic target in cryptococcosis.

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