scholarly journals Absence of Interleukin-4 Determines Less Severe Pulmonary Paracoccidioidomycosis Associated with Impaired Th2 Response

2004 ◽  
Vol 72 (4) ◽  
pp. 2369-2378 ◽  
Author(s):  
Adriana Pina ◽  
Rita C. Valente-Ferreira ◽  
Eugênia E. W. Molinari-Madlum ◽  
Celidéia A. C. Vaz ◽  
Alexandre C. Keller ◽  
...  
Keyword(s):  
Paracoccidioides Brasiliensis ◽  
Fungal Growth ◽  
Protective Role ◽  
Yeast Cells ◽  
Interleukin 4 ◽  
Delayed Type Hypersensitivity ◽  
Th2 Response ◽  
Leukocyte Influx ◽  
Ifn Γ

ABSTRACT Host resistance to paracoccidiodomycosis, the main deep mycosis in Latin America, is mainly due to cellular immunity and gamma interferon (IFN-γ) production. To assess the role of interleukin-4 (IL-4), a Th2-inducing cytokine, pulmonary paracoccidioidomycosis was studied in IL-4-deficient (IL-4−/−) and wild-type (WT) C57BL/6 mice at the innate and acquired phases of immune response. Forty-eight hours after infection, equivalent numbers of viable Paracoccidioides brasiliensis yeast cells were recovered from the lungs of IL-4−/− and WT mice intratracheally infected with one million fungal cells. Alveolar macrophages from infected IL-4−/− mice controlled in vitro fungal growth more efficiently than macrophages from WT mice and secreted higher levels of nitric oxide. Compared with WT mice, IL-4−/− animals presented increased levels of pulmonary IFN-γ and augmented polymorphonuclear leukocyte influx to the lungs. Decreased pulmonary fungal loads were characterized in deficient mice at week 2 postinfection, concomitant with diminished presence of IL-10. At week 8, lower numbers of yeasts were recovered from lungs and liver of IL-4−/− mice associated with increased production of IFN-γ but impaired synthesis of IL-5 and IL-10. However, a clear shift to a Th1 pattern was not characterized, since IL-4−/− mice did not alter delayed-type hypersensitivity anergy or IL-2 levels. In addition, IL-4 deficiency resulted in significantly reduced levels of pulmonary IL-12, granulocyte-macrophage colony-stimulating factor, IL-3, monocyte chemotactic protein 1, and specific antibody isotypes. In IL-4−/− mice, well-organized granulomas restraining fungal cells replaced the more extensive lesions containing high numbers of fungi and inflammatory leukocytes developed by IL-4-sufficient mice. These results clearly showed that genetically determined deficiency of IL-4 can exert a protective role in pulmonary paracoccidioidomycosis.

scholarly journals Protective Role of Gamma Interferon in Experimental Pulmonary Paracoccidioidomycosis

1998 ◽  
Vol 66 (2) ◽  
pp. 800-806 ◽  
Author(s):  
Luz E. Cano ◽  
Suely S. Kashino ◽  
Celina Arruda ◽  
Denise André ◽  
Cynthia F. Xidieh ◽  
...  
Keyword(s):  
Pulmonary Infection ◽  
Paracoccidioides Brasiliensis ◽  
Protective Role ◽  
Gamma Interferon ◽  
Interleukin 4 ◽  
Delayed Type Hypersensitivity ◽  
Mouse Strains ◽  
Histopathological Analysis ◽  
Specific Cellular Immune Response ◽  
Ifn Γ

ABSTRACT We have developed a murine model of pulmonary infection byParacoccidioides brasiliensis in which resistance was associated with immunological activities governed by gamma interferon (IFN-γ). To better characterize this model, we measured type 1 and type 2 cytokines in the lungs and investigated the effect of endogenous IFN-γ depletion by monoclonal antibodies in the course of infection of susceptible (B10.A) and resistant (A/Sn) mice. At weeks 4 and 8 after infection, lungs from susceptible animals presented levels of IFN-γ, interleukin-4 (IL-4), IL-5, and IL-10 higher than those in resistant mice. In both mouse strains, neutralization of endogenous IFN-γ induced exacerbation of the pulmonary infection, earlier fungal dissemination to the liver and spleen, impairment of the specific cellular immune response resulting in significantly lower delayed-type hypersensitivity reactions, and increased levels of immunoglobulin G1 (IgG1)- and IgG2b-specific antibodies. Histopathological analysis demonstrated that depletion of IFN-γ changes the focal granulomatous lesions found in the lungs of B10.A and A/Sn mice into coalescent granulomata which destroy the pulmonary architecture. These results suggest that irrespective of the mouse strain, IFN-γ plays a protective role and that this cytokine is one major mediator of resistance against P. brasiliensis infection in mice.

scholarly journals Immunization with Brucella VirB Proteins Reduces Organ Colonization in Mice through a Th1-Type Immune Response and Elicits a Similar Immune Response in Dogs

2014 ◽  
Vol 22 (3) ◽  
pp. 274-281 ◽  
Author(s):  
Cora N. Pollak ◽  
María Magdalena Wanke ◽  
Silvia M. Estein ◽  
M. Victoria Delpino ◽  
Norma E. Monachesi ◽  
...  
Keyword(s):  
Immune Response ◽  
Mononuclear Cells ◽  
Interleukin 4 ◽  
Delayed Type Hypersensitivity ◽  
Peripheral Blood Mononuclear ◽  
Content Type ◽  
Type Iv ◽  
Ifn Γ ◽  
Organ Colonization

ABSTRACTVirB proteins fromBrucellaspp. constitute the type IV secretion system, a key virulence factor mediating the intracellular survival of these bacteria. Here, we assessed whether a Th1-type immune response against VirB proteins may protect mice fromBrucellainfection and whether this response can be induced in the dog, a natural host forBrucella. Splenocytes from mice immunized with VirB7 or VirB9 responded to their respective antigens with significant and specific production of gamma interferon (IFN-γ), whereas interleukin-4 (IL-4) was not detected. Thirty days after an intraperitoneal challenge with liveBrucella abortus, the spleen load of bacteria was almost 1 log lower in mice immunized with VirB proteins than in unvaccinated animals. As colonization reduction seemed to correlate with a Th1-type immune response against VirB proteins, we decided to assess whether such a response could be elicited in the dog. Peripheral blood mononuclear cells (PBMCs) from dogs immunized with VirB proteins (three subcutaneous doses in QuilA adjuvant) produced significantly higher levels of IFN-γ than cells from control animals uponin vitrostimulation with VirB proteins. A skin test to assess specific delayed-type hypersensitivity was positive in 4 out of 5 dogs immunized with either VirB7 or VirB9. As both proteins are predicted to locate in the outer membrane ofBrucellaorganisms, the ability of anti-VirB antibodies to mediate complement-dependent bacteriolysis ofB. caniswas assessedin vitro. Sera from dogs immunized with either VirB7 or VirB9, but not from those receiving phosphate-buffered saline (PBS), produced significant bacteriolysis. These results suggest that VirB-specific responses that reduce organ colonization byBrucellain mice can be also elicited in dogs.

scholarly journals Central Role for Interleukin-4 in Regulating Nitric Oxide-Mediated Inhibition of T-Cell Proliferation and Gamma Interferon Production in Schistosomiasis

2002 ◽  
Vol 70 (1) ◽  
pp. 177-184 ◽  
Author(s):  
Elisabeth A. Patton ◽  
Anne C. La Flamme ◽  
Joao A. Pedras-Vasoncelos ◽  
Edward J. Pearce
Keyword(s):  
Nitric Oxide ◽  
T Cell ◽  
Gamma Interferon ◽  
Interleukin 4 ◽  
T Cell Proliferation ◽  
Th2 Response ◽  
Cd8 Cells ◽  
Cell Functions ◽  
Ifn Γ

ABSTRACT Schistosoma mansoni-infected wild-type (WT) mice develop a Th2 response and chronic disease. In contrast, infected interleukin-4 double-deficient (IL-4−/−) mice develop a Th1-like response and an acute, lethal syndrome. Disease severity in these animals correlates with excessive and prolonged production of nitric oxide (NO) associated with enhanced antigen-driven gamma interferon (IFN-γ) production in the absence of IL-4. Strikingly, splenic lymphocytes from infected IL-4−/− mice failed to proliferate as well as those from infected WT mice following stimulation in vitro with antigen or anti-CD3 antibody. Contrary to antigen-driven IFN-γ responses, anti-CD3 antibody stimulation of splenocytes resulted in significantly less IFN-γ being produced by CD8 cells from infected IL-4−/− mice than by those from infected WT mice or normal mice. NO is largely responsible for the impaired T-cell functions in infected IL-4−/− mice, as inhibition of iNOS significantly enhanced proliferation and IFN-γ production.

scholarly journals Up-Regulation of CD40 Ligand and Induction of a Th2 Response in Children Immunized with Pneumococcal Polysaccharide Vaccines

2001 ◽  
Vol 8 (2) ◽  
pp. 233-240 ◽  
Author(s):  
Lily E. Leiva ◽  
Boyd Butler ◽  
James Hempe ◽  
Alejandro P. Ortigas ◽  
Ricardo U. Sorensen
Keyword(s):  
Mrna Expression ◽  
Mononuclear Cells ◽  
Cd40 Ligand ◽  
Interleukin 4 ◽  
Enzyme Linked Immunosorbent Assay ◽  
Th2 Response ◽  
Polysaccharide Antigens ◽  
Ifn Γ ◽  
Antibody Levels

ABSTRACT We wished to determine whether pneumococcal polysaccharide antigens induce mRNA expression of CD40 ligand (CD40L) and Th1 or Th2 cytokines in unimmunized individuals in vitro and whether immunization with the 23-valent pneumococcal polysaccharide vaccine induces changes in CD40L and cytokine mRNA expression. Children with recurrent respiratory infections were studied before and 4 to 6 weeks after receiving the pneumococcal vaccine. One patient who failed to respond to the polysacharide vaccine subsequently received a single dose of the experimental 7-valent pneumococcal conjugate vaccine. Unimmunized healthy adults were included as controls. Quantification of mRNA expression of CD40L, interleukin-4 (IL-4), IL-12p40, and gamma interferon (IFN-γ) was performed by reverse transcription-PCR and enzyme-linked immunosorbent assay (ELISA)-PCR with resting and stimulated peripheral blood mononuclear cells. Serum immunoglobulin G (IgG) anti pneumococcal antibody levels were measured by ELISA. The results showed a significant increase in the expression of mRNAs for CD40L and IL-4, but not IL-12p40 or IFN-γ, in stimulated cultures from unimmunized individuals. CD40L and IL-4 mRNA expression was significantly higher in postimmunization than in preimmunization samples stimulated with the individual pneumococcal serotypes. These results suggest that pneumococcal polysaccharide antigens specifically up-regulate CD40L expression and induce a Th2 response in vitro which parallels the increase in IgG antipneumococcal antibody levels in serum.

scholarly journals The PbMDJ1 Gene Belongs to a Conserved MDJ1/LON Locus in Thermodimorphic Pathogenic Fungi and Encodes a Heat Shock Protein That Localizes to both the Mitochondria and Cell Wall of Paracoccidioides brasiliensis

2006 ◽  
Vol 5 (2) ◽  
pp. 379-390 ◽  
Author(s):  
Wagner L. Batista ◽  
Alisson L. Matsuo ◽  
Luciane Ganiko ◽  
Tânia F. Barros ◽  
Thiago R. Veiga ◽  
...  
Keyword(s):  
Cell Wall ◽  
Heat Shock ◽  
Cell Surface ◽  
Paracoccidioides Brasiliensis ◽  
Pathogenic Fungus ◽  
Fungal Growth ◽  
Pathogenic Fungi ◽  
Yeast Cells ◽  
Shock Proteins

ABSTRACT J-domain (DnaJ) proteins, of the Hsp40 family, are essential cofactors of their cognate Hsp70 chaperones, besides acting as independent chaperones. In the present study, we have demonstrated the presence of Mdj1, a mitochondrial DnaJ member, not only in the mitochondria, where it is apparently sorted, but also in the cell wall of Paracoccidioides brasiliensis, a thermodimorphic pathogenic fungus. The molecule (PbMdj1) was localized to fungal yeast cells using both confocal and electron microscopy and also flow cytometry. The anti-recombinant PbMdj1 antibodies used in the reactions specifically recognized a single 55-kDa mitochondrial and cell wall (alkaline β-mercaptoethanol extract) component, compatible with the predicted size of the protein devoid of its matrix peptide-targeting signal. Labeling was abundant throughout the cell wall and especially in the budding regions; however, anti-PbMdj1 did not affect fungal growth in the concentrations tested in vitro, possibly due to the poor access of the antibodies to their target in growing cells. Labeled mitochondria stood preferentially close to the plasma membrane, and gold particles were detected in the thin space between them, toward the cell surface. We show that Mdj1 and the mitochondrial proteinase Lon homologues are heat shock proteins in P. brasiliensis and that their gene organizations are conserved among thermodimorphic fungi and Aspergillus, where the genes are adjacent and have a common 5′ region. This is the first time a DnaJ member has been observed on the cell surface, where its function is speculative.

scholarly journals Interleukin-4 and Interleukin-10 Are Involved in Host Resistance to Staphylococcus aureus Infection through Regulation of Gamma Interferon

2000 ◽  
Vol 68 (5) ◽  
pp. 2424-2430 ◽  
Author(s):  
Sanae Sasaki ◽  
Shinsuke Nishikawa ◽  
Tomisato Miura ◽  
Mayuko Mizuki ◽  
Kyogo Yamada ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Survival Rates ◽  
Interleukin 10 ◽  
Protective Role ◽  
Gamma Interferon ◽  
Interleukin 4 ◽  
T Helper 1 ◽  
Th2 Response ◽  
Ifn Γ

ABSTRACT Our previous study showed that gamma interferon (IFN-γ), a T-helper 1 (Th1)-type cytokine, plays a detrimental role inStaphylococcus aureus infection in mice. In this study, the role of Th2-type cytokines such as interleukin-4 (IL-4) and IL-10 inS. aureus infection was investigated. IL-10 mRNA was induced in parallel with IFN-γ in the spleens and kidneys of mice during S. aureus infection, whereas IL-4 mRNA was induced in the spleens but not in the kidneys of these animals. Spleen cells obtained from S. aureus-infected mice produced lower titers of IFN-γ and higher titers of IL-4 and IL-10 in response to heat-killed S. aureus than did those from uninfected mice. Administration of anti-IL-4 monoclonal antibody (MAb) or anti-IL-10 MAb inhibited the elimination of S. aureus cells from the kidneys of mice. IFN-γ mRNA expression was enhanced in the spleens of anti-IL-4 MAb- or anti-IL-10 MAb-treated mice and also in the kidneys of anti-IL-4 MAb-treated animals. Next, we evaluated the role of IFN-γ in S. aureus infection in IFN-γ−/−mice. An increase in survival rates, a decrease in bacterial numbers in the kidneys, and an amelioration of histologic abnormalities in these organs were observed in IFN-γ−/− mice compared with those in IFN-γ+/+ mice. Administration of MAb against IL-4 or IL-10 failed to affect bacterial growth in the spleens and kidneys of IFN-γ−/− mice irrespective of the expression of Th2 response. These results suggest that S. aureusinfection induced a Th2 response and that IL-4 and IL-10 might play a protective role through the regulation of IFN-γ in S. aureus infection.

scholarly journals IFN-γ Mediates Crescent Formation and Cell-Mediated Immune Injury in Murine Glomerulonephritis

1999 ◽  
Vol 10 (4) ◽  
pp. 752-759
Author(s):  
A. RICHARD KITCHING ◽  
STEPHEN R. HOLDSWORTH ◽  
PETER G. TIPPING
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cd4 T Cells ◽  
Crescentic Glomerulonephritis ◽  
Interleukin 2 ◽  
Interleukin 4 ◽  
Delayed Type Hypersensitivity ◽  
Th2 Response ◽  
Immune Injury ◽  
Ifn Γ

Abstract. Features of crescentic glomerulonephritis suggest that it results from a T helper 1 (Th1) nephritogenic immune response. Interferon-γ (IFN-γ), produced by Th1 cells, is involved in T cell-directed macrophage activation in effector Th1 responses. The hypothesis that endogenous IFN-γ contributes to the development of crescentic glomerulonephritis was tested by comparing the development of glomerulonephritis (induced by a planted antigen) and immune responses in normal C57BL/6 mice (IFN-γ +/+) and in mice genetically deficient in IFN-γ (IFN-γ -/-). Ten days after the initiation of glomerulonephritis, IFN-γ -/- mice developed fewer glomerular crescents (5 ± 1% versus 26 ± 3%, P < 0.005), less severe glomerular injury, and less renal impairment. Effectors of delayed-type hypersensitivity (CD4+ T cells, macrophages, and fibrin) in glomeruli were reduced in IFN-γ -/- mice. Skin delayed-type hypersensitivity to sheep globulin was reduced. Total antigen-specific Ig and splenocyte interleukin-2 production were unchanged, but antigen-specific serum IgG2a was reduced. Markers of an antigen-specific Th2 response (serum IgG1, splenocyte interleukin-4) were unchanged. Studies 22 d after the initiation of glomerulonephritis showed that IFN-γ -/- mice still had fewer crescents (11 ± 2% versus 22 ± 3%, P = 0.02) and glomerular CD4+ T cells and macrophages than IFN-γ +/+ mice. These studies demonstrate that endogenous IFN-γ mediates crescentic glomerulonephritis by promoting cell-mediated immune injury. They support the hypothesis that crescentic glomerulonephritis is a manifestation of a Th1 nephritogenic immune response.

MyD88-Dependent Glucose Restriction and Itaconate Production Control Brucella Infection

2021 ◽  
Author(s):  
Carolyn A. Lacey ◽  
Bárbara Ponzilacqua-Silva ◽  
Catherine A. Chambers ◽  
Alexis S. Dadelahi ◽  
Jerod A. Skyberg
Keyword(s):  
Glucose Transporter ◽  
Production Control ◽  
Brucella Melitensis ◽  
Underlying Mechanism ◽  
Protective Role ◽  
Ifn Γ ◽  
Glucose Restriction ◽  
Myd88 Signaling

Brucellosis is one of the most common global zoonoses and is caused by facultative intracellular bacteria of the genus Brucella . Numerous studies have found that MyD88 signaling contributes to protection against Brucella , however the underlying mechanism has not been entirely defined. Here we show that MyD88 signaling in hematopoietic cells contributes both to inflammation and to control of Brucella melitensis infection in vivo . While the protective role of MyD88 in Brucella infection has often been attributed to promotion of IFN-γ production, we found that MyD88 signaling restricts host colonization by B. melitensis even in the absence of IFN-γ. In vitro , we show that MyD88 promotes macrophage glycolysis in response to B. melitensis . Interestingly, a B. melitensis mutant lacking the glucose transporter, GluP, was more highly attenuated in MyD88 -/- than in WT mice, suggesting MyD88 deficiency results in an increased availability of glucose in vivo which Brucella can exploit via GluP. Metabolite profiling of macrophages identified several metabolites regulated by MyD88 in response to B. melitensis , including itaconate. Subsequently, we found that itaconate has antibacterial effects against Brucella and also regulates the production of pro-inflammatory cytokines in B. melitensis -infected macrophages. Mice lacking the ability to produce itaconate were also more susceptible to B. melitensis in vivo . Collectively, our findings indicate that MyD88-dependent changes in host metabolism contribute to control of Brucella infection.

scholarly journals The influence of carbohydrates in the interaction of Paracoccidioides brasiliensis with CCL-6 cells in vitro

2012 ◽  
Vol 45 (6) ◽  
pp. 739-744 ◽  
Author(s):  
Francisco Laurindo da Silva ◽  
Raphael Sanzio Pimenta ◽  
Juliana Fonseca Moreira da Silva ◽  
Déborah Aparecida Negrão Corrêa ◽  
Ary Corrêa Junior
Keyword(s):  
Epithelial Cell ◽  
Paracoccidioides Brasiliensis ◽  
Yeast Cells ◽  
Epithelial Cell Line ◽  
Con A ◽  
Culture Methods ◽  
Disease Treatment ◽  
Adhesion Behavior ◽  
And Control

INTRODUCTION: Little is known about the early events in the interaction between Paracoccidioides brasiliensis and its host. To understand the effect of carbohydrates in the interaction between the fungus and epithelial cell in culture, we analyzed the influence of different carbohydrate solutions on the adhesion of P. brasiliensis yeast cells to CCL-6 cells in culture. METHODS: Fungal cells were cultivated with the epithelial cell line, and different concentrations of D-fucose, N-acetyl-glucosamine, D-mannose, D-glucosamine, D-galactosamine, sorbitol and fructose were added at the beginning of the experiment. Six hours after the treatment, the cells were fixed and observed by light microscopy. The number of P. brasiliensis cells that were adhered to the CCL-6 monolayer was estimated. RESULTS: The number of adhesion events was diminished following treatments with D-fucose, N-acetyl-glucosamine, D-mannose, D-glucosamine and D-galactosamine as compared to the untreated controls. Sorbitol and fructose-treated cells had the same adhesion behavior as the observed in the control. P. brasiliensis propagules were treated with fluorescent lectins. The FITC-labeled lectins WGA and Con-A bound to P. brasiliensis yeast cells, while SBA and PNA did not. CONCLUSIONS: The perceptual of adhesion between P. brasiliensis and CCL-6 cells decreased with the use of D-mannose, N-acetyl-glucosamine and D-glucosamine. The assay using FITC-labeled lectins suggests the presence of N-acetyl-glucosamine, α-mannose and α-glucose on the P. brasiliensis cell surface. An enhanced knowledge of the mediators of adhesion on P. brasiliensis could be useful in the future for the development of more efficient and less harmful methods for disease treatment and control.

scholarly journals A Signal Transducer and Activator of  Transcription (Stat)4-independent Pathway for the Development of  T Helper Type 1 Cells

1998 ◽  
Vol 188 (6) ◽  
pp. 1191-1196 ◽  
Author(s):  
Mark H. Kaplan ◽  
Andrea L. Wurster ◽  
Michael J. Grusby
Keyword(s):  
Delayed Type Hypersensitivity ◽  
Th2 Cells ◽  
Signal Transducer ◽  
T Helper ◽  
Th1 Cell ◽  
Th Cells ◽  
Th Cell ◽  
Ifn Γ

The differentiation of T helper (Th) cells is regulated by members of the signal transducer and activator of transcription (STAT) family of signaling molecules. We have generated mice lacking both Stat4 and Stat6 to examine the ability of Th cells to develop in the absence of these two transcription factors. Stat4, Stat6−/− lymphocytes fail to differentiate into interleukin (IL)-4–secreting Th2 cells. However, in contrast to Stat4−/− lymphocytes, T cells from Stat4, Stat6−/− mice produce significant amounts of interferon (IFN)-γ when activated in vitro. Although Stat4, Stat6−/− lymphocytes produce less IFN-γ than IL-12–stimulated control lymphocytes, equivalent numbers of IFN-γ–secreting cells can be generated from cultures of Stat4, Stat6−/− lymphocytes activated under neutral conditions and control lymphocytes activated under Th1 cell–promoting conditions. Moreover, Stat4, Stat6−/− mice are able to mount an in vivo Th1 cell–mediated delayed-type hypersensitivity response. These results support a model of Th cell differentiation in which the generation of Th2 cells requires Stat6, whereas a Stat4-independent pathway exists for the development of Th1 cells.

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