scholarly journals Interleukin-17A-Deficient Mice Are Highly Susceptible to Toxoplasma gondii Infection Due to Excessively Induced T. gondii HSP70 and Interferon Gamma Production

2017 ◽  
Vol 85 (12) ◽  
Author(s):  
Masataka Moroda ◽  
Masaya Takamoto ◽  
Yoichiro Iwakura ◽  
Jun Nakayama ◽  
Fumie Aosai
Keyword(s):  
Toxoplasma Gondii ◽  
Interferon Gamma ◽  
Acute Phase ◽  
Host Defense ◽  
Hsp70 Expression ◽  
Mesenteric Lymph Nodes ◽  
Content Type ◽  
Ifn Γ ◽  
Toxoplasma Gondii Infection ◽  
Deficient Mice

ABSTRACT Interleukin17A (IL-17A) is known to be involved in the host defense against pathogens and the pathogenesis of autoimmune diseases. Previously, we showed that excessive amounts of interferon gamma (IFN-γ) play an important role in the pathogenesis of the lethal effects of Toxoplasma gondii by inducing anaphylactic responses. In the study described in this report, we examined the effects of IL-17A deficiency on murine host defense against oral T. gondii infection. IL-17A-deficient C57BL/6 (B6) mice exhibited higher rates of mortality than wild-type (WT) mice during the acute phase of T. gondii infection. CD4+ T cells in the mesenteric lymph nodes (mLNs) and ileum of T. gondii-infected IL-17A-deficient mice produced higher levels of IFN-γ than did those of WT mice. In addition, the level of T. gondii HSP70 (T.g.HSP70) expression was also significantly increased in the ileum, mLNs, liver, and spleen of infected IL-17A-deficient mice compared with that in WT mice. These elevated levels of expression of T.g.HSP70 and IFN-γ in infected IL-17A-deficient mice were presumably linked to the IL-17A defect since they decreased to WT levels after treatment with recombinant IL-17A. Furthermore, IL-17A-deficient mice were highly susceptible to the anaphylactic effect of T.g.HSP70, and the survival of IL-17A-deficient mice during the acute phase was improved by treatment with an anti-T.g.HSP70 monoclonal antibody. These results suggest that IL-17A plays an important role in host survival against T. gondii infection by protecting the host from an anaphylactic reaction via the downregulation of T.g.HSP70 and IFN-γ production.

scholarly journals Essential Role of mGBP7 for Survival of Toxoplasma gondii Infection

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Nora Steffens ◽  
Cornelia Beuter-Gunia ◽  
Elisabeth Kravets ◽  
Artur Reich ◽  
Larissa Legewie ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Interferon Gamma ◽  
Parasitophorous Vacuole ◽  
Acute Infection ◽  
Intracellular Pathogen ◽  
Content Type ◽  
Replication Control ◽  
Complete Failure ◽  
Ifn Γ ◽  
Toxoplasma Gondii Infection

ABSTRACT Members of the murine guanylate-binding protein family (mGBP) are induced by interferon gamma (IFN-γ) and have been shown to be important factors in cell-autonomous immunity toward the intracellular pathogen Toxoplasma gondii. Previously, we identified that mGBP2 mediates disruption of the parasitophorous vacuole membrane (PVM) and directly assaults the plasma membrane of the parasite. Here, we show that mGBP7-deficient mice are highly susceptible to T. gondii infection. This is demonstrated by the loss of parasite replication control, pronounced development of ascites, and death of the animals in the acute infection phase. Interestingly, live-cell microscopy revealed that mGBP7 recruitment to the PVM occurs after mGBP2 recruitment, followed by disruption of the PVM and T. gondii integrity and accumulation of mGBP7 inside the parasite. This study defines mGBP7 as a crucial effector protein in resistance to intracellular T. gondii. IMPORTANCE Guanylate-binding proteins (GBPs) are induced by the inflammatory cytokine interferon gamma (IFN-γ) and have been shown to be important factors in the defense of the intracellular pathogen Toxoplasma gondii. In previous studies, we showed that members of the mouse GBP family, such as mGBP2 and mGBP7, accumulate at the parasitophorous vacuole of T. gondii, which is the replicatory niche of the parasite. In this study, we show that mice deficient in mGBP7 succumb early after infection with T. gondii, showing a complete failure of resistance to the pathogen. On a molecular level, mGBP7 is found directly at the parasite, likely mediating its destruction.

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 Involvement of Host Defense Mechanisms against Toxoplasma gondii Infection in Anhedonic and Despair-Like Behaviors in Mice

2017 ◽  
Vol 85 (4) ◽  
Author(s):  
Motamed Elsayed Mahmoud ◽  
Ragab Fereig ◽  
Yoshifumi Nishikawa
Keyword(s):  
Toxoplasma Gondii ◽  
Host Defense ◽  
Defense Mechanisms ◽  
Defense Mechanism ◽  
Acute Infection ◽  
Sickness Behavior ◽  
Wild Type ◽  
Chronic Infections ◽  
Content Type ◽  
Ifn Γ

ABSTRACT Toxoplasma gondii is a pathogen relevant to psychiatric disorders. We recently showed that reactivation of chronic T. gondii infection induced depression-like behaviors in mice. Furthermore, it has been hypothesized that depression-like behaviors are mediated via a host defense mechanism against invading pathogens; proximate mechanisms of this behavioral hypothesis remain unclear. In the present study, we investigate the contribution of indoleamine 2,3-dioxygenase (IDO), inflammation, and interferon gamma (IFN-γ) to anhedonic and despair-related behaviors in T. gondii-infected mice by using sucrose preference and forced-swim tests, respectively. First, we confirmed that BALB/c mice exhibited both sickness and depression-like behaviors during acute infection. Treatment of infected wild-type mice with minocycline (anti-inflammatory drug) abated sickness and anhedonic and despair-like behaviors, whereas in T. gondii-infected mice, treatment normalized kynurenine/tryptophan (Kyn/Trp) ratios in both plasma and brain tissue. Additionally, T. gondii infection failed to induce anhedonic and despair-like behaviors or increase the Kyn/Trp ratio in immunocompromised (IFN-γ−/−) mice, whereas sickness behavior was observed in both immunocompetent and IFN-γ−/− mice following infection. Furthermore, treatment with 1-methyl tryptophan (an IDO inhibitor) did not affect locomotor activity, attenuated clinical scores and anhedonic and despair-like behaviors, and resulted in normal Kyn/Trp ratios in T. gondii-infected wild-type mice. Although low levels of serotonin and dopamine were observed in the brain during acute and chronic infections, anhedonic and despair-like behaviors were not detected in the chronic stage of infection. Collectively, our results demonstrated that immune enhancement in response to infection with T. gondii resulted in IFN-γ production, IDO activation, and inflammation associated with anhedonic and despair-like behaviors.

scholarly journals Cell Death of Gamma Interferon-Stimulated Human Fibroblasts upon Toxoplasma gondii Infection Induces Early Parasite Egress and Limits Parasite Replication

2013 ◽  
Vol 81 (12) ◽  
pp. 4341-4349 ◽  
Author(s):  
Wendy Niedelman ◽  
Joris K. Sprokholt ◽  
Barbara Clough ◽  
Eva-Maria Frickel ◽  
Jeroen P. J. Saeij
Keyword(s):  
Cell Death ◽  
Toxoplasma Gondii ◽  
Human Fibroblasts ◽  
Protozoan Parasite ◽  
Resistance Mechanisms ◽  
Gamma Interferon ◽  
Content Type ◽  
Food Borne Illness ◽  
Ifn Γ ◽  
Toxoplasma Gondii Infection

ABSTRACTThe intracellular protozoan parasiteToxoplasma gondiiis a major food-borne illness and opportunistic infection for the immunosuppressed. Resistance toToxoplasmais dependent on gamma interferon (IFN-γ) activation of both hematopoietic and nonhematopoietic cells. Although IFN-γ-induced innate immunity in nonhematopoietic cells has been extensively studied in mice, it remains unclear what resistance mechanisms are relied on in nonhematopoietic human cells. Here, we report an IFN-γ-induced mechanism of resistance toToxoplasmain primary human foreskin fibroblasts (HFFs) that does not depend on the deprivation of tryptophan or iron. In addition, infection is still controlled in HFFs deficient in the p65 guanylate binding proteins GBP1 or GBP2 and the autophagic protein ATG5. Resistance is coincident with host cell death that is not dependent on the necroptosis mediator RIPK3 or caspases and is correlated with early egress of the parasite before replication. This IFN-γ-induced cell death and early egress limits replication in HFFs and could promote clearance of the parasite by immune cells.

scholarly journals Toxoplasma gondii Upregulates Interleukin-12 To Prevent Plasmodium berghei-Induced Experimental Cerebral Malaria

2014 ◽  
Vol 82 (3) ◽  
pp. 1343-1353 ◽  
Author(s):  
Erik W. Settles ◽  
Lindsey A. Moser ◽  
Tajie H. Harris ◽  
Laura J. Knoll
Keyword(s):  
Toxoplasma Gondii ◽  
Cerebral Malaria ◽  
Plasmodium Berghei ◽  
Serum Levels ◽  
Interleukin 12 ◽  
Experimental Cerebral Malaria ◽  
Content Type ◽  
T Cell Infiltration ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACTA chronic infection with the parasiteToxoplasma gondiihas previously been shown to protect mice against subsequent viral, bacterial, or protozoal infections. Here we have shown that a chronicT. gondiiinfection can preventPlasmodium bergheiANKA-induced experimental cerebral malaria (ECM) in C57BL/6 mice. Treatment with solubleT. gondiiantigens (STAg) reduced parasite sequestration and T cell infiltration in the brains ofP. berghei-infected mice. Administration of STAg also preserved blood-brain barrier function, reduced ECM symptoms, and significantly decreased mortality. STAg treatment 24 h post-P. bergheiinfection led to a rapid increase in serum levels of interleukin 12 (IL-12) and gamma interferon (IFN-γ). By 5 days afterP. bergheiinfection, STAg-treated mice had reduced IFN-γ levels compared to those of mock-treated mice, suggesting that reductions in IFN-γ at the time of ECM onset protected against lethality. Using IL-10- and IL-12βR-deficient mice, we found that STAg-induced protection from ECM is IL-10 independent but IL-12 dependent. Treatment ofP. berghei-infected mice with recombinant IL-12 significantly decreased parasitemia and mortality. These data suggest that IL-12, either induced by STAg or injected as a recombinant protein, mediates protection from ECM-associated pathology potentially through early induction of IFN-γ and reduction in parasitemia. These results highlight the importance of early IL-12 induction in protection against ECM.

Abstract 116: Detrimental Role of Toll-Like Receptor 4 in Cardiovirus-Induced Myocarditis

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Fumitaka Sato ◽  
Seiichi Omura ◽  
Nicholas E Martinez ◽  
Eiichiro Kawai ◽  
Ganta V Chaitanya ◽  
...  
Keyword(s):  
Immune Responses ◽  
Acute Phase ◽  
Viral Entry ◽  
Viral Myocarditis ◽  
Chronic Phase ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tlr4 Ligand ◽  
Ifn Γ ◽  
Deficient Mice

Picornavirus infections have been known as a leading cause of viral myocarditis in humans. Theiler’s murine encephalomyelitis virus (TMEV) belongs to the genus Cardiovirus, the family Picornaviridae and was reported to cause inflammation in the heart in one manuscript, while its pathomechanism is unclear. In viral myocarditis, viral replication in the heart and/or immune responses against virus as well as heart-antigen (autoimmunity) can contribute to the pathogenesis. Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) that are important for recognizing pathogens as well as triggering innate immunity. Among TLRs, TLR4 has been demonstrated to play important roles in virus-mediated pathology: 1) TLR4 can contribute to viral entry in some viruses, 2) TLR4 may mediate tissue damage by anti-virus immune responses (immunopathology), 3) high levels of TLR4 expression were observed in the heart of patients with dilated cardiomyopathy following acute viral myocarditis, and 4) some viruses can bind to lipopolysaccharide (LPS), which is a TLR4 ligand. To determine the role of TLR4 in TMEV-induced myocarditis, we infected male C3H/HeJ (TLR4-deficient) and C3H/HeNtac (control TLR4+) mice with the DA strain of TMEV. We harvested the hearts and spleens on days 6 and 7 (acute phase) or days 63 and 64 (chronic phase) post-infection. Cardiac pathology was evaluated by hematoxylin and eosin staining and production of pro-inflammatory cytokines, interleukin (IL)-17A and interferon (IFN)-γ, from spleen cells was measured by an enzyme-linked immunosorbent assay (ELISA). In both mice, mild myocarditis was observed during the acute phase of TMEV infection. During the chronic phase, both mice developed severe pathology in the heart, including basophilic degeneration and calcification. However, the incidence of myocarditis was higher in control mice than TLR4-deficient mice. IL-17A and IFN-γ production was higher in control mice than in TLR4-deficient mice (control vs. TLR4-deficient mice, acute phase: IL-17A, 196 vs. 146 pg/ml; IFN-γ, 72 vs. 39 ng/ml; chronic phase: IL-17A, 290 vs. 229 pg/ml; IFN- γ, 142 vs. 88 ng/ml). These results suggest that TLR4 may be detrimental in TMEV-induced myocarditis by increasing pro-inflammatory cytokine production.

scholarly journals Overlapping Roles for Interleukin-36 Cytokines in Protective Host Defense against MurineLegionella pneumophilaPneumonia

2018 ◽  
Vol 87 (1) ◽  
Author(s):  
Yuta Nanjo ◽  
Michael W. Newstead ◽  
Tetsuji Aoyagi ◽  
Xianying Zeng ◽  
Kazuhisa Takahashi ◽  
...  
Keyword(s):  
Host Defense ◽  
Legionella Pneumophila ◽  
Ex Vivo ◽  
Inflammatory Cells ◽  
Bacterial Clearance ◽  
Content Type ◽  
Cytokines And Chemokines ◽  
M1 Polarization ◽  
Life Threatening ◽  
Deficient Mice

ABSTRACTLegionella pneumophilacauses life-threatening pneumonia culminating in acute lung injury. Innate and adaptive cytokines play an important role in host defense againstL. pneumophilainfection. Interleukin-36 (IL-36) cytokines are recently described members of the larger IL-1 cytokine family known to exert potent inflammatory effects. In this study, we elucidated the role for IL-36 cytokines in experimental pneumonia caused byL. pneumophila. Intratracheal (i.t.) administration ofL. pneumophilainduced the upregulation of both IL-36α and IL-36γ mRNA and protein production in the lung. Compared to the findings forL. pneumophila-infected wild-type (WT) mice, the i.t. administration ofL. pneumophilato IL-36 receptor-deficient (IL-36R−/−) mice resulted in increased mortality, a delay in lung bacterial clearance, increasedL. pneumophiladissemination to extrapulmonary organs, and impaired glucose homeostasis. Impaired lung bacterial clearance in IL-36R−/−mice was associated with a significantly reduced accumulation of inflammatory cells and the decreased production of proinflammatory cytokines and chemokines.Ex vivo, reduced expression of costimulatory molecules and impaired M1 polarization were observed in alveolar macrophages isolated from infected IL-36R−/−mice compared to macrophages from WT mice. WhileL. pneumophila-induced mortality in IL-36α- or IL-36γ-deficient mice was not different from that in WT animals, antibody-mediated neutralization of IL-36γ in IL-36α−/−mice resulted in mortality similar to that observed in IL-36R−/−mice, indicating redundant and overlapping roles for these cytokines in experimental murineL. pneumophilapneumonia.

scholarly journals Pulmonary Interleukin-17-Positive Lymphocytes Increase during Pneumocystis murina Infection but Are Not Required for Clearance of Pneumocystis

2017 ◽  
Vol 85 (7) ◽  
Author(s):  
Chiara Ripamonti ◽  
Lisa R. Bishop ◽  
Joseph A. Kovacs
Keyword(s):  
T Cells ◽  
Fungal Infections ◽  
Intracellular Cytokine Staining ◽  
Γδ T Cells ◽  
Interleukin 17 ◽  
Content Type ◽  
Immunosuppressed Patients ◽  
Ifn Γ ◽  
Immunocompetent Mice ◽  
Deficient Mice

ABSTRACT Pneumocystis remains an important pathogen of immunosuppressed patients, causing a potentially life-threatening pneumonia. Despite its medical importance, the immune responses required to control infection, including the role of interleukin-17 (IL-17), which is important in controlling other fungal infections, have not been clearly defined. Using flow cytometry and intracellular cytokine staining after stimulation with phorbol myristate acetate and ionomycin, we examined gamma interferon (IFN-γ), IL-4, IL-5, and IL-17 production by lung lymphocytes in immunocompetent C57BL/6 mice over time following infection with Pneumocystis murina. We also examined the clearance of Pneumocystis infection in IL-17A-deficient mice. The production of both IFN-γ and IL-17 by pulmonary lymphocytes increased during infection, with maximum production at approximately days 35 to 40, coinciding with peak Pneumocystis levels in the lungs, while minimal changes were seen in IL-4- and IL-5-positive cells. The proportion of cells producing IFN-γ was consistently higher than for cells producing IL-17, with peak levels of ∼25 to 30% of CD3+ T cells for the former compared to ∼15% for the latter. Both CD4+ T cells and γδ T cells produced IL-17. Administration of anti-IFN-γ antibody led to a decrease in IFN-γ-positive cells, and an increase in IL-5-positive cells, but did not impact clearance of Pneumocystis infection. Despite the increases in IL-17 production during infection, IL-17A-deficient mice cleared Pneumocystis infection with kinetics similar to C57BL/6 mice. Thus, while IL-17 production in the lungs is increased during Pneumocystis infection in immunocompetent mice, IL-17A is not required for control of Pneumocystis infection.

scholarly journals Infection-Induced Intestinal Dysbiosis Is Mediated by Macrophage Activation and Nitrate Production

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Shuai Wang ◽  
Ayah El-Fahmawi ◽  
David A. Christian ◽  
Qun Fang ◽  
Enrico Radaelli ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Oral Infection ◽  
Nitrate Respiration ◽  
Characteristic Change ◽  
Intestinal Immunity ◽  
Parasite Control ◽  
Shotgun Metagenomics ◽  
Content Type ◽  
Distal Small Intestine ◽  
Ifn Γ

ABSTRACT Oral infection of C57BL/6J mice with Toxoplasma gondii results in a marked bacterial dysbiosis and the development of severe pathology in the distal small intestine that is dependent on CD4+ T cells and interferon gamma (IFN-γ). This dysbiosis and bacterial translocation contribute to the development of ileal pathology, but the factors that support the bloom of bacterial pathobionts are unclear. The use of microbial community profiling and shotgun metagenomics revealed that Toxoplasma infection induces a dysbiosis dominated by Enterobacteriaceae and an increased potential for nitrate respiration. In vivo experiments using bacterial metabolic mutants revealed that during this infection, host-derived nitrate supports the expansion of Enterobacteriaceae in the ileum via nitrate respiration. Additional experiments with infected mice indicate that the IFN-γ/STAT1/iNOS axis, while essential for parasite control, also supplies a pool of nitrate that serves as a source for anaerobic respiration and supports overgrowth of Enterobacteriaceae. Together, these data reveal a trade-off in intestinal immunity after oral infection of C57BL/6J mice with T. gondii, in which inducible nitric oxide synthase (iNOS) is required for parasite control, while this host enzyme is responsible for specific modification of the composition of the microbiome that contributes to pathology. IMPORTANCE Toxoplasma gondii is a protozoan parasite and a leading cause of foodborne illness. Infection is initiated when the parasite invades the intestinal epithelium, and in many host species, this leads to intense inflammation and a dramatic disruption of the normal microbial ecosystem that resides in the healthy gut (the so-called microbiome). One characteristic change in the microbiome during infection with Toxoplasma—as well as numerous other pathogens—is the overgrowth of Escherichia coli or similar bacteria and a breakdown of commensal containment leading to seeding of peripheral organs with gut bacteria and subsequent sepsis. Our findings provide one clear explanation for how this process is regulated, thereby improving our understanding of the relationship between parasite infection, inflammation, and disease. Furthermore, our results could serve as the basis for the development of novel therapeutics to reduce the potential for harmful bacteria to bloom in the gut during infection.

scholarly journals Innate, adaptive, and cell-autonomous immunity against Toxoplasma gondii infection

2019 ◽  
Vol 51 (12) ◽  
pp. 1-10 ◽  
Author(s):  
Miwa Sasai ◽  
Masahiro Yamamoto
Keyword(s):  
Immune Response ◽  
Toxoplasma Gondii ◽  
Immune Responses ◽  
Parasitophorous Vacuole ◽  
Interferon Γ ◽  
Protective Role ◽  
Ifn Γ ◽  
Acquired Immune Responses ◽  
Toxoplasma Gondii Infection ◽  
Antimicrobial Immunity

AbstractHosts have been fighting pathogens throughout the evolution of all infectious diseases. Toxoplasma gondii is one of the most common infectious agents in humans but causes only opportunistic infection in healthy individuals. Similar to antimicrobial immunity against other organisms, the immune response against T. gondii activates innate immunity and in turn induces acquired immune responses. After activation of acquired immunity, host immune cells robustly produce the proinflammatory cytokine interferon-γ (IFN-γ), which activates a set of IFN-γ-inducible proteins, including GTPases. IFN-inducible GTPases are essential for cell-autonomous immunity and are specialized for effective clearance and growth inhibition of T. gondii by accumulating in parasitophorous vacuole membranes. Recent studies suggest that the cell-autonomous immune response plays a protective role in host defense against not only T. gondii but also various intracellular bacteria. Moreover, the negative regulatory mechanisms of such strong immune responses are also important for host survival after infection. In this review, we will discuss in detail recent advances in the understanding of host defenses against T. gondii and the roles played by cell-autonomous immune responses.

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