scholarly journals CCR7-Dependent Immunity during Acute Toxoplasma gondii Infection

2010 ◽  
Vol 78 (5) ◽  
pp. 2257-2263 ◽  
Author(s):  
Shahani Noor ◽  
Andrew S. Habashy ◽  
J. Philip Nance ◽  
Robin T. Clark ◽  
Kiav Nemati ◽  
...  
Keyword(s):  
T Cell ◽  
Toxoplasma Gondii ◽  
Immune Responses ◽  
Parasite Burden ◽  
Serum Levels ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Monocyte Chemoattractant Protein 1 ◽  
Absolute Requirement ◽  
Ifn Γ

ABSTRACT The chemokine receptor CCR7 is a well-established homing receptor for dendritic cells and T cells. Interactions with its ligands, CCL19 and CCL21, facilitate priming of immune responses in lymphoid tissue, yet CCR7-independent immune responses can be generated in the presence of sufficient antigen. In these studies, we investigated the role of CCR7 signaling in the generation of protective immune responses to the intracellular protozoan parasite Toxoplasma gondii. The results demonstrated a significant increase in the expression of CCL19, CCL21, and CCR7 in peripheral and central nervous system (CNS) tissues over the course of infection. Unexpectedly, despite the presence of abundant antigen, CCR7 was an absolute requirement for protective immunity to T. gondii, as CCR7−/− mice succumbed to the parasite early in the acute phase of infection. Although serum levels of interleukin 12 (IL-12), IL-6, tumor necrosis factor alpha (TNF-α), and IL-10 remained unchanged, there was a significant decrease in CCL2/monocyte chemoattractant protein 1 (MCP-1) and inflammatory monocyte recruitment to the site of infection. In addition, CCR7−/− mice failed to produce sufficient gamma interferon (IFN-γ), a critical Th1-associated effector cytokine required to control parasite replication. As a result, there was increased parasite dissemination and a significant increase in parasite burden in the lungs, livers, and brains of infected mice. Adoptive-transfer experiments revealed that expression of CCR7 on the T-cell compartment alone is sufficient to enable T-cell priming, increase IFN-γ production, and allow the survival of CCR7−/− mice. These data demonstrate an absolute requirement for T-cell expression of CCR7 for the generation of protective immune responses to Toxoplasma infection.

scholarly journals Immediate Interferon Gamma Induction Determines Murine Host Compatibility Differences between Toxoplasma gondii and Neospora caninum

2020 ◽  
Vol 88 (4) ◽  
Author(s):  
Rachel S. Coombs ◽  
Matthew L. Blank ◽  
Elizabeth D. English ◽  
Yaw Adomako-Ankomah ◽  
Ifeanyi-Chukwu Samuel Urama ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Immune Responses ◽  
Interferon Gamma ◽  
Neospora Caninum ◽  
Ectopic Expression ◽  
Parasite Burden ◽  
Interleukin 12 ◽  
Content Type ◽  
Ifn Γ ◽  
And Control

ABSTRACT Rodents are critical for the transmission of Toxoplasma gondii to the definitive feline host via predation, and this relationship has been extensively studied as a model for immune responses to parasites. Neospora caninum is a closely related coccidian parasite of ruminants and canines but is not naturally transmitted by rodents. We compared mouse innate immune responses to N. caninum and T. gondii and found marked differences in cytokine levels and parasite growth kinetics during the first 24 h postinfection (hpi). N. caninum-infected mice produced significantly higher levels of interleukin-12 (IL-12) and interferon gamma (IFN-γ) by as early as 4 hpi, but the level of IFN-γ was significantly lower or undetectable in T. gondii-infected mice during the first 24 hpi. “Immediate” IFN-γ and IL-12p40 production was not detected in MyD88−/− mice. However, unlike IL-12p40−/− and IFN-γ−/− mice, MyD88−/− mice survived N. caninum infections at the dose used in this study. Serial measures of parasite burden showed that MyD88−/− mice were more susceptible to N. caninum infections than wild-type (WT) mice, and control of parasite burdens correlated with a pulse of serum IFN-γ at 3 to 4 days postinfection in the absence of detectable IL-12. Immediate IFN-γ was partially dependent on the T. gondii mouse profilin receptor Toll-like receptor 11 (TLR11), but the ectopic expression of N. caninum profilin in T. gondii had no impact on early IFN-γ production or parasite proliferation. Our data indicate that T. gondii is capable of evading host detection during the first hours after infection, while N. caninum is not, and this is likely due to the early MyD88-dependent recognition of ligands other than profilin.

scholarly journals Interleukin-18 (IL-18) Enhances Innate IL-12-Mediated Resistance to Toxoplasma gondii

2000 ◽  
Vol 68 (12) ◽  
pp. 6932-6938 ◽  
Author(s):  
Guifang Cai ◽  
Robert Kastelein ◽  
Christopher A. Hunter
Keyword(s):  
Toxoplasma Gondii ◽  
Nk Cells ◽  
Nk Cell ◽  
Parasite Burden ◽  
Scid Mice ◽  
Interleukin 12 ◽  
Cell Mediated Immunity ◽  
Protective Effects ◽  
Innate Resistance ◽  
Ifn Γ

ABSTRACT Innate resistance to Toxoplasma gondii is dependent on the ability of interleukin-12 (IL-12) to stimulate natural killer (NK) cell production of gamma interferon (IFN-γ). Since IL-18 is a potent enhancer of IL-12-induced production of IFN-γ by NK cells, SCID mice (which lack an adaptive immune response) were used to assess the role of IL-18 in innate resistance to T. gondii. Administration of anti-IL-18 to SCID mice infected with T. gondii resulted in an early reduction in serum levels of IFN-γ but did not significantly decrease resistance to this infection. In contrast, administration of exogenous IL-18 to infected SCID mice resulted in increased production of IFN-γ, reduced parasite burden, and a delay in time to death. The protective effects of IL-18 treatment correlated with increased NK cell numbers and cytotoxic activity at the local site of administration and with elevated levels of inducible nitrous oxide synthose in the spleens of treated mice. In addition, in vivo depletion studies demonstrated that the ability of exogenous IL-18 to enhance resistance to T. gondii was dependent on IL-12, IFN-γ, and NK cells. Together, these studies demonstrate that although endogenous IL-18 appears to have a limited role in innate resistance to T. gondii, treatment with IL-18 can augment NK cell-mediated immunity to this pathogen.

scholarly journals Clinical and Immunologic Features of an Atypical Intracranial Mycobacterium avium Complex (MAC) Infection Compared with Those of Pulmonary MAC Infections

2008 ◽  
Vol 15 (10) ◽  
pp. 1580-1589 ◽  
Author(s):  
Mouhannad Sadek ◽  
Feng Yun Yue ◽  
Erika Yue Lee ◽  
Gabor Gyenes ◽  
R. Brad Jones ◽  
...  
Keyword(s):  
T Cell ◽  
Mycobacterium Avium ◽  
The Body ◽  
Interleukin 12 ◽  
Elderly Persons ◽  
Necrosis Factor Alpha ◽  
Healthy Elderly ◽  
Tnf Α ◽  
Ifn Γ ◽  
The Individual

ABSTRACT Members of the Mycobacterium avium complex (MAC) may cause chronic pulmonary infections in otherwise healthy elderly persons but rarely invade parts of the body outside of the lungs in immunocompetent hosts. We present a case of an isolated intracranial MAC infection in an apparently immunocompetent individual and review previous reports. We studied the T-cell and monocyte responses in healthy volunteers, individuals with a pulmonary MAC infection, and one individual with an isolated intracranial MAC infection. Genomic DNA from the individual with the brain MAC infection was studied for gamma interferon (IFN-γ) receptor mutations. Individuals with localized pulmonary MAC infections showed increased activation of monocytes and enhanced monocyte and T-cell tumor necrosis factor alpha (TNF-α) production in response to lipopolysaccharide and MAC antigens but defects in T-cell IFN-γ secretion. The individual with an intracranial MAC infection showed a lack of monocyte activation and deficiencies in both monocyte and T-cell TNF-α production and monocyte interleukin-12 (IL-12) production but had preserved T-cell IFN-γ production. Mutations or deletions in the IFN-γ receptor were not detected in the individual with the intracranial MAC infection. Our data suggest that distinct immune defects characterize two different manifestations of MAC infection. A relative defect in IFN-γ production in response to MAC may predispose an individual to localized but partially controlled lung disease, whereas defects leading to reduced IL-12 and TNF-α production may allow the dissemination of MAC. Further studies delineating the potential role of TNF-α in limiting the spread of MAC outside the lung are warranted.

scholarly journals Nocardia farcinica Activates Human Dendritic Cells and Induces Secretion of Interleukin-23 (IL-23) Rather than IL-12p70

2012 ◽  
Vol 80 (12) ◽  
pp. 4195-4202 ◽  
Author(s):  
Martin Eisenblätter ◽  
Ariane Buchal ◽  
Hermine Gayum ◽  
Edith Jasny ◽  
Pablo Renner Viveros ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
Characteristic Functions ◽  
Interleukin 12 ◽  
Adjuvant Effect ◽  
Phagocytic Capacity ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Nocardia Farcinica

ABSTRACTStudying the interaction of dendritic cells (DCs) with bacteria controlled by T-cell-mediated immune responses may reveal novel adjuvants for the induction of cellular immunity. Murine studies and the observation that nocardias infect predominantly immunosuppressed patients have suggested that these bacteria may possess an adjuvant potential. Moreover, adjuvants on the basis of the nocardial cell wall have been applied in clinical studies. Since the handling of adjuvants by DCs may determine the type of immune responses induced by a vaccine, the present study aimed at investigating the interaction of immature human monocyte-derived DCs with live or inactivatedNocardia farcinicain vitroand determining the cellular phenotypic changes as well as alterations in characteristic functions, such as phagocytosis, induction of T-cell proliferation, and cytokine secretion. Human DCs ingestedN. farcinicaand eradicated the bacterium intracellularly. DCs exposed to inactivatedN. farcinicawere activated, i.e., they developed a mature phenotype, downregulated their phagocytic capacity, and stimulated allogeneic T cells in mixed leukocyte reactions. Soluble factors were not involved in this process. To elucidate the potential adjuvant effect ofN. farcinicaon the induction of T-cell-mediated immune responses, we characterized the cytokines produced by nocardia-exposed DCs and detected substantial amounts of tumor necrosis factor alpha (TNF-α) and interleukin-12 p40 (IL-12p40). However, nocardia-treated DCs secreted only small amounts of IL-12p70, which were significantly smaller than the amounts of IL-23. Thus,N. farcinicaactivates DCs, but adjuvants based on this bacterium may have only a limited capacity to induce Th1 immune responses.

scholarly journals Evaluation of Immunogenic Effect of Toxoplasma gondii RecombinantSAG-1 Antigen with Propranolol as Adjuvant in BALB/c Mice

2019 ◽  
Vol 9 (4) ◽  
pp. 632-639
Author(s):  
Esmaeil Abasi ◽  
Shahram Shahabi ◽  
Majid Golkar ◽  
Peyman Khezri ◽  
Habib Mohammadzadeh Hajipirloo
Keyword(s):  
Toxoplasma Gondii ◽  
Immune Responses ◽  
Lymphocyte Proliferation ◽  
Challenge Test ◽  
Optimal Dose ◽  
Serum Levels ◽  
Control Group ◽  
Interleukin 5 ◽  
Ifn Γ ◽  
Positive Effect

Purpose: Propranolol as a novel adjuvant, was used to evaluate the immunogenic effect of threedoses of recombinant SAG-1 (rSAG-1) antigen of Toxoplasma gondii in BALB/c mice for findingthe optimal dose, and was compared with efficacy of tachyzoite lysate antigen (TLA).Methods: Eight different groups of 15 BALB/c mice received different volumes of theimmunogenic material (three doses of r SAG-1 and one dose of TLA antigens), with or withoutpropranolol adjuvant, subcutaneously. The control group mice received only PBS. Three weeksafter the last immunization, the serum levels of IgG2a, IgG1 and IgG total antibodies againstTLA, splenic interleukin-5 (IL-5) and Interferon-gamma (IFN-γ) (produced against TLA) and thesplenic lymphocyte proliferation after adding TLA were measured to evaluate humoral andcellular immune responses. Challenge test was performed by subcutaneously injection of 1000alive and active tachyzoites in to five mice per each group and survival days for each group ofmice were recorded.Results: The mice group that received propranolol adjuvant and 20 μg of r SAG-1 antigenper dose of injection showed significantly more IFN-γ production, more proliferation ofsplenic lymphocytes and higher anti-TLA-specific IgG2a production (three main indexes forcell mediated immunity) in comparison with other groups. Moreover, in the challenge test,this group of mice had a significantly increased survival time, indicating the positive effect ofpropranolol in the more stimulating of cellular immunity that is necessary for toxoplasmosisprevention or suppress.Conclusion: Our results showed that T. gondii rSAG-1 antigen in combination with propranololas adjuvant (which can induce Th1 related responses) are good candidates for further study toa vaccine design.<br />

scholarly journals STAT1 Is Essential for Antimicrobial Effector Function but Dispensable for Gamma Interferon Production during Toxoplasma gondii Infection

2004 ◽  
Vol 72 (3) ◽  
pp. 1257-1264 ◽  
Author(s):  
L. Cristina Gavrilescu ◽  
Barbara A. Butcher ◽  
Laura Del Rio ◽  
Gregory A. Taylor ◽  
Eric Y. Denkers
Keyword(s):  
T Cell ◽  
Toxoplasma Gondii ◽  
Intracellular Signaling ◽  
Acute Infection ◽  
Gamma Interferon ◽  
Interleukin 12 ◽  
Ifn Γ ◽  
Toxoplasma Gondii Infection ◽  
Oxide Synthase

ABSTRACT The opportunistic protozoan Toxoplasma gondii is a prototypic Th1-inducing pathogen inducing strong gamma interferon (IFN-γ) cytokine responses that are required to survive infection. Intracellular signaling intermediate STAT1 mediates many effects of IFN-γ and is implicated in activation of T-bet, a master regulator of Th1 differentiation. Here, we show that T. gondii-infected STAT1-null mice fail to upregulate the IFN-γ-dependent effector molecules inducible nitric oxide synthase (iNOS), IGTP, and LRG-47, which are required for mice to survive infection. Both T-bet and interleukin-12 receptor β2 (IL-12Rβ2) failed to undergo normal upregulation in response to T. gondii. Development of IFN-γ-producing CD4+ and CD8+ T lymphocytes was severely curtailed in the absence of STAT1, but a substantial level of STAT1-independent non-T-cell-derived IFN-γ was induced. Absence of STAT1 also resulted in increased IL-4, Arg1, Ym1, and Fizz1, markers of Th2 differentiation and alternative macrophage activation. Together, the results show that T. gondii induces STAT1-dependent T-lymphocyte and STAT1-independent non-T-cell IFN-γ production, but that effector functions of this type 1 cytokine cannot operate in the absence of STAT1, resulting in extreme susceptibility to acute infection.

scholarly journals Infection with Toxoplasma gondii Increases Atherosclerotic Lesion in ApoE-Deficient Mice

2004 ◽  
Vol 72 (6) ◽  
pp. 3571-3576 ◽  
Author(s):  
Luciane R. Portugal ◽  
Luciana R. Fernandes ◽  
Giovana C. Cesar ◽  
Helton C. Santiago ◽  
Dirce R. Oliveira ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Atherosclerotic Lesion ◽  
Inflammatory Cells ◽  
Serum Levels ◽  
Lesion Size ◽  
Liver Cholesterol ◽  
Proinflammatory Response ◽  
Aortic Lesion ◽  
Monocyte Chemoattractant Protein 1 ◽  
Ifn Γ

ABSTRACT Toxoplasma gondii is an intracellular protozoan that elicits a potent inflammatory response during the acute phase of infection. Herein, we evaluate whether T. gondii infection alters the natural course of aortic lesions. ApoE knockout mice were infected with T. gondii, and at 5 weeks of infection, serum, feces, and liver cholesterol; aortic lesion size, cellularity, and inflammatory cytokines; and levels of serum nitrite and gamma interferon (IFN-γ) were analyzed. Our results showed that serum cholesterol and atherogenic lipoproteins were reduced after T. gondii infection. The reduction of serum levels of total cholesterol and atherogenic lipoproteins was associated with increases in the aortic lesion area, numbers of inflammatory cells, and expression of monocyte chemoattractant protein 1 and inducible nitric oxide synthase mRNA in the site of lesions as well as elevated concentrations of IFN-γ and nitrite in sera of T. gondii-infected animals. These results suggest that infection with T. gondii accelerates atherosclerotic development by stimulating the proinflammatory response and oxidative stress, thereby increasing the area of aortic lesion.

scholarly journals Tpl2 kinase regulates T cell interferon-γ production and host resistance to Toxoplasma gondii

2008 ◽  
Vol 205 (12) ◽  
pp. 2803-2812 ◽  
Author(s):  
Wendy T. Watford ◽  
Bruce D. Hissong ◽  
Lydia R. Durant ◽  
Hidehiro Yamane ◽  
Linda M. Muul ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Toxoplasma Gondii ◽  
Cell Lineage ◽  
Physiological Role ◽  
Parasite Clearance ◽  
Interleukin 12 ◽  
Intrinsic Defect ◽  
Dependent Manner ◽  
Ifn Γ

Tpl2 (Tumor progression locus 2), also known as Cot/MAP3K8, is a hematopoietically expressed serine-threonine kinase. Tpl2 is known to have critical functions in innate immunity in regulating tumor necrosis factor–α, Toll-like receptor, and G protein–coupled receptor signaling; however, our understanding of its physiological role in T cells is limited. We investigated the potential roles of Tpl2 in T cells and found that it was induced by interleukin-12 in human and mouse T cells in a Stat4-dependent manner. Deficiency of Tpl2 was associated with impaired interferon (IFN)-γ production. Accordingly, Tpl2−/− mice had impaired host defense against Toxoplasma gondii with reduced parasite clearance and decreased IFN-γ production. Furthermore, reconstitution of Rag2−/− mice with Tpl2-deficient T cells followed by T. gondii infection recapitulated the IFN-γ defect seen in the Tpl2-deficient mice, confirming a T cell–intrinsic defect. CD4+ T cells isolated from Tpl2−/− mice showed poor induction of T-bet and failure to up-regulate Stat4 protein, which is associated with impaired TCR-dependent extracellular signal-regulated kinase activation. These data underscore the role of Tpl2 as a regulator of T helper cell lineage decisions and demonstrate that Tpl2 has an important functional role in the regulation of Th1 responses.

scholarly journals Induction of IL-12p40 and type 1 immunity by Toxoplasma gondii in the absence of the TLR-MyD88 signaling cascade

2021 ◽  
Vol 17 (10) ◽  
pp. e1009970
Author(s):  
Lindsay M. Snyder ◽  
Claire M. Doherty ◽  
Heather L. Mercer ◽  
Eric Y. Denkers
Keyword(s):  
T Cells ◽  
T Cell ◽  
Toxoplasma Gondii ◽  
Immune Responses ◽  
Myeloid Cell ◽  
Lymphoid Cells ◽  
Type I ◽  
Compensatory Response ◽  
Ifn Γ

Toxoplasma gondii is an orally acquired pathogen that induces strong IFN-γ based immunity conferring protection but that can also be the cause of immunopathology. The response in mice is driven in part by well-characterized MyD88-dependent signaling pathways. Here we focus on induction of less well understood immune responses that do not involve this Toll-like receptor (TLR)/IL-1 family receptor adaptor molecule, in particular as they occur in the intestinal mucosa. Using eYFP-IL-12p40 reporter mice on an MyD88-/- background, we identified dendritic cells, macrophages, and neutrophils as cellular sources of MyD88-independent IL-12 after peroral T. gondii infection. Infection-induced IL-12 was lower in the absence of MyD88, but was still clearly above noninfected levels. Overall, this carried through to the IFN-γ response, which while generally decreased was still remarkably robust in the absence of MyD88. In the latter mice, IL-12 was strictly required to induce type I immunity. Type 1 and type 3 innate lymphoid cells (ILC), CD4+ T cells, and CD8+ T cells each contributed to the IFN-γ pool. We report that ILC3 were expanded in infected MyD88-/- mice relative to their MyD88+/+ counterparts, suggesting a compensatory response triggered by loss of MyD88. Furthermore, bacterial flagellin and Toxoplasma specific CD4+ T cell populations in the lamina propria expanded in response to infection in both WT and KO mice. Finally, we show that My88-independent IL-12 and T cell mediated IFN-γ production require the presence of the intestinal microbiota. Our results identify MyD88-independent intestinal immune pathways induced by T. gondii including myeloid cell derived IL-12 production, downstream type I immunity and IFN-γ production by ILC1, ILC3, and T lymphocytes. Collectively, our data reveal an underlying network of immune responses that do not involve signaling through MyD88.

scholarly journals Neutrophil Depletion during Toxoplasma gondii Infection Leads to Impaired Immunity and Lethal Systemic Pathology

2001 ◽  
Vol 69 (8) ◽  
pp. 4898-4905 ◽  
Author(s):  
Susan K. Bliss ◽  
L. Cristina Gavrilescu ◽  
Ana Alcaraz ◽  
Eric Y. Denkers
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Toxoplasma Gondii ◽  
Parasite Burden ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Reverse Transcription Pcr ◽  
Neutrophil Depletion ◽  
Toxoplasma Gondii Infection ◽  
Systemic Pathology

ABSTRACT The immunomodulatory role of neutrophils during infection withToxoplasma gondii was investigated. Monoclonal antibody-mediated depletion revealed that neutrophils are essential for survival during the first few days of infection. Moreover, neutrophil depletion was associated with a weaker type 1 immune response as measured by decreased levels of gamma interferon, interleukin-12 (IL-12) and tumor necrosis factor alpha. IL-10 was also decreased in depleted animals. Additionally, splenic populations of CD4+T cells, CD8+ T cells, and NK1.1+ cells were decreased in depleted mice. Neutrophil-depleted mice exhibited lesions of greater severity in tissues examined and a greater parasite burden as determined by histopathology and reverse transcription-PCR. We conclude that neutrophils are critical near the time of infection because they influence the character of the immune response and control tachyzoite replication.

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