scholarly journals Vaccine-Induced Protection against Helicobacter pylori in Mice Lacking Both Antibodies and Interleukin-4

2003 ◽  
Vol 71 (6) ◽  
pp. 3628-3633 ◽  
Author(s):  
Christine A. Garhart ◽  
John G. Nedrud ◽  
Frederick P. Heinzel ◽  
Norma E. Sigmund ◽  
Steven J. Czinn
Keyword(s):  
Helicobacter Pylori ◽  
B Cell ◽  
Knockout Mice ◽  
Cellular Responses ◽  
Interleukin 4 ◽  
Wild Type ◽  
Double Knockout ◽  
Th2 Response ◽  
H Pylori ◽  
Deficient Mice

ABSTRACT To test the hypothesis that a Th2 response to Helicobacter pylori is necessary for protection and to address the possibility that humoral and Th2 cellular responses may compensate for each other, we generated mice deficient in both interleukin-4 (IL-4) and antibodies. The immunized double-knockout mice were protected from H. pylori challenge, as were the parental strains and wild-type C57BL/6 mice. Neutralization of IL-4 in B-cell-deficient mice did not prevent protection. Immunized IL-5-deficient mice were also protected. Thus, IL-4 and IL-5 are not essential for protection.

scholarly journals Immunization of Mice with Urease Vaccine Affords Protection against Helicobacter pylori Infection in the Absence of Antibodies and Is Mediated by MHC Class II–restricted Responses

1998 ◽  
Vol 188 (12) ◽  
pp. 2277-2288 ◽  
Author(s):  
Thomas H. Ermak ◽  
Paul J. Giannasca ◽  
Richard Nichols ◽  
Gwendolyn A. Myers ◽  
John Nedrud ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Gastric Mucosa ◽  
B Cell ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Knockout Mice ◽  
Class Ii ◽  
Helicobacter Pylori Infection ◽  
Wild Type ◽  
H Pylori

We examined the roles of cell- and antibody-mediated immunity in urease vaccine–induced protection against Helicobacter pylori infection. Normal and knockout mice deficient in major histocompatibility complex (MHC) class I, MHC class II, or B cell responses were mucosally immunized with urease plus Escherichia coli heat-labile enterotoxin (LT), or parenterally immunized with urease plus aluminum hydroxide or a glycolipid adjuvant, challenged with H. pylori strain X47-2AL, and H. pylori organisms and leukocyte infiltration in the gastric mucosa quantified. In an adjuvant/route study in normal mice, there was a direct correlation between the level of protection and the density of T cells recruited to the gastric mucosa. In knockout studies, oral immunization with urease plus LT protected MHC class I knockout mice [β2-microglobulin (−/−)] but not MHC class II knockout mice [I-Ab (−/−)]. In B cell knockout mice [μMT (−/−)], vaccine-induced protection was equivalent to that observed in immunized wild-type (+/+) mice; no IgA+ cells were detected in the stomach, but levels of CD4+ cells equivalent to those in the wild-type strain (+/+) were seen. These studies indicate that protection of mice against H. pylori infection by immunization with the urease antigen is dependent on MHC class II–restricted, cell-mediated mechanisms, and antibody responses to urease are not required for protection.

scholarly journals Colonization of C57BL/6J and BALB/c Wild-Type and Knockout Mice with Helicobacter pylori: Effect of Vaccination and Implications for Innate and Acquired Immunity

2003 ◽  
Vol 71 (2) ◽  
pp. 794-800 ◽  
Author(s):  
Klaus Panthel ◽  
Gerhard Faller ◽  
Rainer Haas
Keyword(s):  
Helicobacter Pylori ◽  
Knockout Mice ◽  
Tumor Necrosis Factor Receptor ◽  
Bacterial Pathogen ◽  
Interleukin 4 ◽  
Wild Type ◽  
Ulcer Disease ◽  
Knockout Mutants ◽  
Prophylactic Vaccination ◽  
H Pylori

ABSTRACT The gram-negative bacterial pathogen Helicobacter pylori is a major cause of peptic ulcer disease and a risk factor for gastric cancer in humans. Adapted H. pylori strains, such as strain SS1, are able to infect mice and are a useful model for gastric colonization and vaccination studies. In this study we used a streptomycin-resistant derivative of H. pylori SS1 to analyze the colonization behavior and the success of vaccination in wild-type (wt) and various knockout mice of the BALB/c and C57BL/6J genetic backgrounds. We here report that BALB/c interleukin-4 knockout (IL-4−/−) mice are weakly overcolonized compared to the wt strain but that the IL-12−/− knockout results in a strong overcolonization (500%). Unexpectedly, in the C57BL/6J background the same knockouts behaved in diametrically opposed manners. The IL-4−/− mutation caused a 50% reduction and the IL-12−/− knockout caused a 95% reduction compared to the wt colonization rate. For C57BL/6J mice we further analyzed the IL-18−/− and Toll-like receptor 2 knockout mutations, which showed reductions to 66 and 57%, respectively, whereas mice with the IL-10−/− phenotype were hardly infected at all (5%). In contrast, the tumor necrosis factor receptor knockout (p55−/− and p55/75−/−) mice showed an overcolonization compared to the C57BL/6J wt strain. With exception of the low-level infected C57BL/6J IL-10−/− and IL-12−/− knockout mice, all knockout mutants were accessible to a prophylactic vaccination and their vaccination behavior was comparable to that of the wt strains.

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 Are B Lymphocytes of Importance in Severe Staphylococcus aureus Infections?

2000 ◽  
Vol 68 (5) ◽  
pp. 2431-2434 ◽  
Author(s):  
Inger Gjertsson ◽  
Olof Hörnquist Hultgren ◽  
Martin Stenson ◽  
Rikard Holmdahl ◽  
Andrzej Tarkowski
Keyword(s):  
Staphylococcus Aureus ◽  
B Cells ◽  
B Cell ◽  
Interleukin 4 ◽  
Wild Type ◽  
Toxic Shock ◽  
Toxic Shock Syndrome Toxin ◽  
Deficient Mice ◽  
Wild Type Control

ABSTRACT To investigate the role of B cells in experimental, superantigen-mediated Staphylococcus aureus arthritis and sepsis, we used gene-targeted B-cell-deficient mice. The mice were inoculated intravenously with a toxic shock syndrome toxin 1 (TSST-1)-producing S. aureus strain. The B-cell-deficient and thus agamma-globulinemic mice showed striking similarities to the wild-type control animals with respect to the development of arthritis, the mortality rate, and the rate of bacterial clearance. Surprisingly, we found that the levels of gamma interferon in serum were significantly lower (P < 0.0001) in B-cell-deficient mice than in the controls, possibly due to impaired superantigen presentation and a diminished expression of costimulatory molecules. In contrast, the levels of interleukin-4 (IL-4), IL-6, and IL-10 in serum were equal in both groups. Our findings demonstrate that neither mature B cells nor their products significantly contribute to the course ofS. aureus-induced septic arthritis.

scholarly journals MFN1 and MFN2 Are Dispensable for Sperm Development and Functions in Mice

2021 ◽  
Vol 22 (24) ◽  
pp. 13507
Author(s):  
Junru Miao ◽  
Wei Chen ◽  
Pengxiang Wang ◽  
Xin Zhang ◽  
Lei Wang ◽  
...  
Keyword(s):  
Germ Cells ◽  
Knockout Mice ◽  
Seminiferous Tubules ◽  
Wild Type ◽  
Double Knockout ◽  
Wild Type Littermate ◽  
Mitofusin 2 ◽  
Sperm Development ◽  
Mitofusin 1 ◽  
Deficient Mice

MFN1 (Mitofusin 1) and MFN2 (Mitofusin 2) are GTPases essential for mitochondrial fusion. Published studies revealed crucial roles of both Mitofusins during embryonic development. Despite the unique mitochondrial organization in sperm flagella, the biological requirement in sperm development and functions remain undefined. Here, using sperm-specific Cre drivers, we show that either Mfn1 or Mfn2 knockout in haploid germ cells does not affect male fertility. The Mfn1 and Mfn2 double knockout mice were further analyzed. We found no differences in testis morphology and weight between Mfn-deficient mice and their wild-type littermate controls. Spermatogenesis was normal in Mfn double knockout mice, in which properly developed TRA98+ germ cells, SYCP3+ spermatocytes, and TNP1+ spermatids/spermatozoa were detected in seminiferous tubules, indicating that sperm formation was not disrupted upon MFN deficiency. Collectively, our findings reveal that both MFN1 and MFN2 are dispensable for sperm development and functions in mice.

scholarly journals B-Cell Deficiency Suppresses Vaccine-Induced Protection against Murine Filariasis but Does Not Increase the Recovery Rate for Primary Infection

2001 ◽  
Vol 69 (11) ◽  
pp. 7067-7073 ◽  
Author(s):  
Coralie Martin ◽  
Michael Saeftel ◽  
Phat N. Vuong ◽  
Simon Babayan ◽  
Kerstin Fischer ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Recovery Rate ◽  
Primary Infection ◽  
Subcutaneous Tissue ◽  
Interleukin 4 ◽  
Wild Type ◽  
Good Opportunity ◽  
Challenge Inoculation ◽  
Deficient Mice

ABSTRACT To establish the role of B cells and antibodies in destroying filariae, mice lacking mature B cells and therefore unable to produce antibodies were used. Litomosoides sigmodontis offers a good opportunity for this study because it is the only filarial species that completes its life cycle in mice. Its development was compared in B-cell-deficient mice (BALB/c μMT mice) and wild-type BALB/c mice in two different in vivo situations, vaccination with irradiated larvae and primary infection. In all cases, mice were challenged with subcutaneous inoculation of 40 infective larvae. Vaccine-induced protection was suppressed in B-cell-deficient mice. In these mice, eosinophils infiltrated the subcutaneous tissue normally during immunization; however, their morphological state did not change following challenge inoculation, whereas in wild-type mice the percentage of degranulated eosinophils was markedly increased. From this, it may be deduced that the eosinophil–antibody–B-cell complex is the effector mechanism of protection in vaccinated mice and that its action is fast and takes place in the subcutaneous tissue. In primary infection, the filarial survival and growth was not modified by the absence of B cells. However, no female worm had uterine microfilariae, nor did any mice develop a patent infection. In these mice, concentrations of type 1 (gamma interferon) and type 2 (interleukin-4 [IL-4], IL-5 and IL-10) cytokines in serum were lower and pleural neutrophils were more numerous. The effects of the μMT mutation therefore differ from those in B1-cell-deficient mice described on the same BALB/c background, which reveal a higher filarial recovery rate and microfilaremia. This outlines B2-cell-dependent mechanisms as favorable to the late maturation of L. sigmodontis.

scholarly journals Development of an Interleukin-12-Deficient Mouse Model That Is Permissive for Colonization by a Motile KE26695 Strain of Helicobacter pylori

2003 ◽  
Vol 71 (5) ◽  
pp. 2534-2541 ◽  
Author(s):  
Paul S. Hoffman ◽  
Neeraj Vats ◽  
Donna Hutchison ◽  
Jared Butler ◽  
Kenneth Chisholm ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Immune Modulation ◽  
Limit Of Detection ◽  
Genomic Research ◽  
Interleukin 12 ◽  
Deficient Mouse ◽  
Loss Of Function ◽  
Double Knockout ◽  
H Pylori ◽  
Deficient Mice

ABSTRACT The identification of genes associated with colonization and persistence of Helicobacter pylori in the gastric mucosa has been limited by the lack of robust animal models that support infection by strains whose genomes have been completely sequenced. Here we report that an interleukin-12 (IL-12)-deficient mouse (IL-12−/− p40 subunit knockout in C57BL/6 mouse) is permissive for infection by a motile variant (KE88-3887) of The Institute For Genomic Research-sequenced strain (KE26695) of H. pylori. The IL-12-deficient mouse was also more permissive for colonization by the mouse-colonizing Sydney 1 strain of H. pylori than were wild-type C57BL/6 mice. Differences in colonization efficiency were demonstrated by mouse challenge with SS1 strains containing loss-of-function mutations in two genes (hspR and hrcA), whose products negatively regulate several heat shock genes. At 5 weeks postinfection, double-knockout mutants (SS1 hspR hrcA) efficiently colonized IL-12-deficient mice (5 of 5 animals compared to 4 of 10 for C57BL6 mice) and bacterial counts were higher in stomachs of IL-12-deficient mice (106 versus 105 CFU/g of stomach, respectively). IL-12-deficient mice were efficiently colonized by KE88-3887 (29 of 30), but not by nonmotile KE26695, and bacterial numbers (104 to 105 CFU/g of stomach) were unchanged over an 8-week period postinfection. In contrast, C57BL/6 mice were inefficiently colonized by KE88-3887 (8 of 20 animals with bacterial loads at the limit of detection, ∼103 CFU/g), and infection did not persist much beyond 5 weeks. Cytokine responses (tumor necrosis factor alpha and gamma interferon), pathology, and antral-predominant infection were indistinguishable between IL-12-deficient and C57BL/6 mice. The increased permissiveness of the IL-12-deficient mouse for infection with H. pylori should facilitate whole-genome-based strategies to study genes associated with virulence and immune modulation.

scholarly journals Partial Protection against Helicobacter pylori in the Absence of Mast Cells in Mice

2009 ◽  
Vol 77 (12) ◽  
pp. 5543-5550 ◽  
Author(s):  
Hua Ding ◽  
John G. Nedrud ◽  
Barry Wershil ◽  
Raymond W. Redline ◽  
Thomas G. Blanchard ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Mast Cell ◽  
Mast Cells ◽  
Bacterial Load ◽  
Interleukin 17 ◽  
Wild Type ◽  
Spleen Cells ◽  
Tnf Α ◽  
H Pylori ◽  
Deficient Mice

ABSTRACT The goal of this study is to evaluate the contribution of mast cells to Helicobacter pylori immunity in a model of vaccine-induced protection. Mast cell-deficient KitlSl /KitlSl-d and control mice were immunized with H. pylori sonicate plus cholera toxin and challenged with H. pylori, and the bacterial loads, inflammatory infiltrates, and cytokine responses were evaluated and compared at 1, 2, and 4 weeks postchallenge. In vitro stimulation assays were performed using bone marrow-derived mast cells, and recall assays were performed with spleen cells of immunized mast cell-deficient and wild-type mice. Bacterial clearance was observed by 2 weeks postchallenge in mast cell-deficient mice. The bacterial load was reduced by 4.0 log CFU in wild-type mice and by 1.5 log CFU in mast cell-deficient mice. Neutrophil numbers in the gastric mucosa of immune KitlSl /KitlSl-d mice were lower than those for immune wild-type mice (P < 0.05). Levels of gastric interleukin-17 (IL-17) and tumor necrosis factor alpha (TNF-α) were also significantly lower in immune KitlSl /KitlSl-d mice than in wild-type mice (P < 0.001). Immunized mast cell-deficient and wild-type mouse spleen cells produced IFN-γ and IL-17 in response to H. pylori antigen stimulation. TNF-α and CXC chemokines were detected in mast cell supernatants after 24 h of stimulation with H. pylori antigen. The results indicate that mast cells are not essential for but do contribute to vaccine-induced immunity and that mast cells contribute to neutrophil recruitment and inflammation in response to H. pylori.

scholarly journals T-Cell-Dependent Control of Acute Giardia lamblia Infections in Mice

2000 ◽  
Vol 68 (1) ◽  
pp. 170-175 ◽  
Author(s):  
Steven M. Singer ◽  
Theodore E. Nash
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Giardia Lamblia ◽  
Cell Receptor ◽  
Interleukin 4 ◽  
Wild Type ◽  
Adult Mice ◽  
Giardia Muris ◽  
Deficient Mice

ABSTRACTWe have studied immune mechanisms responsible for control of acuteGiardia lambliaandGiardia murisinfections in adult mice. Association of chronicG. lambliainfection with hypogammaglobulinemia and experimental infections of mice withG. murishave led to the hypothesis that antibodies are required to control these infections. We directly tested this hypothesis by infecting B-cell-deficient mice with eitherG. lambliaorG. muris. Both wild-type mice and B-cell-deficient mice eliminated the vast majority of parasites between 1 and 2 weeks postinfection withG. lamblia. G. muriswas also eliminated in both wild-type and B-cell-deficient mice. In contrast, T-cell-deficient andscidmice failed to controlG. lambliainfections, as has been shown previously forG. muris. Treatment of wild-type or B-cell-deficient mice with antibodies to CD4 also prevented elimination ofG. lamblia, confirming a role for T cells in controlling infections. By infecting mice deficient in either αβ- or γδ-T-cell receptor (TCR)-expressing T cells, we show that the αβ-TCR-expressing T cells are required to control parasites but that the γδ-TCR-expressing T cells are not. Finally, infections in mice deficient in production of gamma interferon or interleukin 4 (IL-4) and mice deficient in responding to IL-4 and IL-13 revealed that neither the Th1 nor the Th2 subset is absolutely required for protection fromG. lamblia. We conclude that a T-cell-dependent mechanism is essential for controlling acuteGiardiainfections and that this mechanism is independent of antibody and B cells.

scholarly journals The Helicobacter pylori Autotransporter ImaA (HP0289) Modulates the Immune Response and Contributes to Host Colonization

2012 ◽  
Vol 80 (7) ◽  
pp. 2286-2296 ◽  
Author(s):  
William E. Sause ◽  
Andrea R. Castillo ◽  
Karen M. Ottemann
Keyword(s):  
Immune Response ◽  
Helicobacter Pylori ◽  
Membrane Protein ◽  
Outer Membrane ◽  
Outer Membrane Protein ◽  
Dependent Manner ◽  
Wild Type ◽  
Content Type ◽  
H Pylori ◽  
Murine Infections

ABSTRACTThe human pathogenHelicobacter pyloriemploys a diverse collection of outer membrane proteins to colonize, persist, and drive disease within the acidic gastric environment. In this study, we sought to elucidate the function of the host-induced geneHP0289, which encodes an uncharacterized outer membrane protein. We first generated an isogenicH. pylorimutant that lacksHP0289and found that the mutant has a colonization defect in single-strain infections and is greatly outcompeted in mouse coinfection experiments with wild-typeH. pylori. Furthermore, we used protease assays and biochemical fractionation coupled with an HP0289-targeted peptide antibody to verify that the HP0289 protein resides in the outer membrane. Our previous findings showed that theHP0289promoter is upregulated in the mouse stomach, and here we demonstrate thatHP0289expression is induced under acidic conditions in an ArsRS-dependent manner. Finally, we have shown that theHP0289mutant induces greater expression of the chemokine interleukin-8 (IL-8) and the cytokine tumor necrosis factor alpha (TNF-α) in gastric carcinoma cells (AGS). Similarly, transcription of the IL-8 homolog keratinocyte-derived chemokine (KC) is elevated in murine infections with the HP0289 mutant than in murine infections with wild-typeH. pylori. On the basis of this phenotype, we renamed HP0289 ImaA forimmunomodulatoryautotransporter protein. Our work has revealed that genes inducedin vivoplay an important role inH. pyloripathogenesis. Specifically, the outer membrane protein ImaA modulates a component of the host inflammatory response, and thus may allowH. pylorito fine tune the host immune response based on ImaA expression.

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