scholarly journals IL-33 promotes innate lymphoid cell-dependent IFN-γ production required for innate immunity to Toxoplasma gondii

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Joseph T Clark ◽  
David A Christian ◽  
Jodi A Gullicksrud ◽  
Joseph A Perry ◽  
Jeongho Park ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Nk Cells ◽  
Parasite Burden ◽  
Lymphoid Cells ◽  
Protective Effects ◽  
Innate Resistance ◽  
Inflammatory Monocytes ◽  
Parasite Replication ◽  
Ifn Γ ◽  
Cell Expression

IL-33 is an alarmin required for resistance to the parasite Toxoplasma gondii, but its role in innate resistance to this organism is unclear. Infection with T. gondii promotes increased stromal cell expression of IL-33 and levels of parasite replication correlate with release of IL-33 in affected tissues. In response to infection, a subset of innate lymphoid cells (ILC) emerges composed of IL-33R+ NK cells and ILC1s. In Rag1-/- mice, where NK cells and ILC1 production of IFN-g mediates innate resistance to T. gondii, the loss of the IL-33R resulted in reduced ILC responses and increased parasite replication. Furthermore, administration of IL-33 to Rag1-/- mice resulted in a marked decrease in parasite burden, increased production of IFN-g and the recruitment and expansion of inflammatory monocytes associated with parasite control. These protective effects of exogenous IL-33 were dependent on endogenous IL-12p40 and the ability of IL-33 to enhance ILC production of IFN-g. These results highlight that IL-33 synergizes with IL-12 to promote ILC-mediated resistance to T. gondii.

scholarly journals IL-33 promotes innate lymphoid cell-dependent IFN-γ production required for innate immunity to Toxoplasma gondii

2021 ◽  
Author(s):  
Joseph T. Clark ◽  
David A. Christian ◽  
Jodi A. Gullicksrud ◽  
Joseph A. Perry ◽  
Jeongho Park ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Nk Cells ◽  
Parasite Burden ◽  
Lymphoid Cells ◽  
Protective Effects ◽  
Parasite Control ◽  
Inflammatory Monocytes ◽  
Parasite Replication ◽  
Ifn Γ ◽  
Cell Expression

AbstractIL-33 is an alarmin required for resistance to the parasite Toxoplasma gondii, but its role in innate resistance to this infection is unclear. T. gondii infection promotes increased stromal cell expression of IL-33 and levels of parasite replication correlate with IL-33 release. In response to infection, a subset of innate lymphoid cells (ILC) emerges composed of IL-33R+ NK cells and ILC1s. In Rag-/- mice, where NK cells and ILC1 provide an innate mechanism of resistance to T. gondii, the loss of IL-33R reduced ILC responses and increased parasite replication. Furthermore, administration of IL-33 to Rag-/- mice resulted in a marked decrease in parasite burden, increased production of IFN-γ and the recruitment and expansion of inflammatory monocytes associated with parasite control. These protective effects of exogenous IL-33 were dependent on endogenous IL-12p40 and the ability of IL-33 to enhance ILC production of IFN-γ. These results highlight that IL-33 synergizes with IL-12 to promote ILC-mediated resistance to T. gondii.

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 Role of NK Cells and Gamma Interferon in Transplacental Passage of Toxoplasma gondii in a Mouse Model of Primary Infection

2004 ◽  
Vol 72 (3) ◽  
pp. 1397-1401 ◽  
Author(s):  
Ahmed Abou-Bacar ◽  
Alexander W. Pfaff ◽  
Sophie Georges ◽  
Valérie Letscher-Bru ◽  
Denis Filisetti ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Nk Cells ◽  
Protective Immunity ◽  
Nk Cell ◽  
Congenital Toxoplasmosis ◽  
Parasite Burden ◽  
Blood Parasite ◽  
Gamma Interferon ◽  
Recombination Activating Gene ◽  
Ifn Γ

ABSTRACT Protective immunity in mice infected with Toxoplasma gondii is mainly mediated by NK cells, CD4 and CD8 T cells, and type 1 cytokines, such as gamma interferon (IFN-γ). To clarify the roles of NK cells and IFN-γ in protection against primary congenital toxoplasmosis, we used recombination activating gene 2 knockout (RAG-2−/−) mice, which lack T and B lymphocytes, in comparison with the wild-type BALB/c model. RAG-2−/− mice had a significantly lower risk of fetal toxoplasmosis than BALB/c mice (25 versus 63.9%; P = 0.003). This protection was associated with an increased number of maternal NK cells, IFN-γ secretion by spleen cells, and decreased parasitemia. In the RAG-2−/− mice, NK cell depletion increased both the rate of fetal infection, to 56.5% (P = 0.02), and the blood parasite burden. Conversely, in the BALB/c mice, this treatment did not modify maternofetal transmission or the blood parasite burden. Neutralization of IFN-γ in both infected RAG-2−/− and BALB/c mice decreased congenital Toxoplasma transmission, contrasting with an exacerbation of maternal infection. These data suggest that a partially protective immunity against congenital toxoplasmosis is achieved due to the increased number of NK cells in RAG-2−/− mice. However, it seems that IFN-γ enhances, directly or indirectly, the transplacental transmission.

scholarly journals STAT1 Signaling in Astrocytes Is Essential for Control of Infection in the Central Nervous System

mBio ◽  
2016 ◽  
Vol 7 (6) ◽  
Author(s):  
Shinya Hidano ◽  
Louise M. Randall ◽  
Lucas Dawson ◽  
Hans K. Dietrich ◽  
Christoph Konradt ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Toxoplasma Gondii ◽  
Critical Role ◽  
Opportunistic Pathogen ◽  
Protective Effects ◽  
The Central Nervous System ◽  
Parasite Replication ◽  
Ifn Γ ◽  
The Brain

ABSTRACTThe local production of gamma interferon (IFN-γ) is important to controlToxoplasma gondiiin the brain, but the basis for these protective effects is not fully understood. The studies presented here reveal that the ability of IFN-γ to inhibit parasite replication in astrocytesin vitrois dependent on signal transducer and activator of transcription 1 (STAT1) and that mice that specifically lack STAT1 in astrocytes are unable to limit parasite replication in the central nervous system (CNS). This susceptibility is associated with a loss of antimicrobial pathways and increased cyst formation in astrocytes. These results identify a critical role for astrocytes in limiting the replication of an important opportunistic pathogen.IMPORTANCEAstrocytes are the most numerous cell type in the brain, and they are activated in response to many types of neuroinflammation, but their function in the control of CNS-specific infection is unclear. The parasiteToxoplasma gondiiis one of the few clinically relevant microorganisms that naturally infects astrocytes, and the studies presented here establish that the ability of astrocytes to inhibit parasite replication is essential for the local control of this opportunistic pathogen. Together, these studies establish a key role for astrocytes as effector cells and in the coordination of many aspects of the protective immune response that operates in the brain.

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 Toxoplasma gondiiInfection Drives Conversion of NK Cells into ILC1s

2019 ◽  
Author(s):  
Eugene Park ◽  
Swapneel J. Patel ◽  
Qiuling Wang ◽  
Prabhakar S. Andhey ◽  
Konstantin Zaitsev ◽  
...  
Keyword(s):  
Steady State ◽  
Tumor Microenvironment ◽  
Toxoplasma Gondii ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Cell Conversion ◽  
Ongoing Infection

AbstractInnate lymphoid cells (ILCs) were originally classified based on their cytokine profiles, placing natural killer (NK) cells and ILC1s together, but recent studies support their separation into different lineages at steady-state. However, tumors may induce NK cell conversion into ILC1-like cells that are limited to the tumor microenvironment and whether this conversion occurs beyond this environment remains unknown. Here we describeToxoplasma gondiiinfection converts NK cells into cells resembling steady-state ILC1s that are heterogeneous and distinct from both steady-state NK cells and ILC1s in uninfected mice. Most toxoplasma-induced ILC1s were Eomes-dependent, indicating that NK cells can give rise to Eomes−Tbet-dependent ILC1-like cells that circulate widely and persist independent of ongoing infection. Moreover, these changes appear permanent, as supported by epigenetic analyses. Thus, these studies markedly expand current concepts of NK cells, ILCs, and their potential conversion.

scholarly journals Treatment of mice with IL2-complex enhances inflammasome-driven IFN-γ production and prevents lethal toxoplasmosis

2019 ◽  
Author(s):  
Andreas Kupz ◽  
Saparna Pai ◽  
Paul R. Giacomin ◽  
Jennifer A. Whan ◽  
Robert A. Walker ◽  
...  
Keyword(s):  
T Cells ◽  
Toxoplasma Gondii ◽  
Nk Cells ◽  
Immune Cell ◽  
Nk Cell ◽  
Severe Disease ◽  
Toxoplasmic Encephalitis ◽  
Parasite Invasion ◽  
Ifn Γ

AbstractToxoplasmic encephalitis is an AIDS-defining condition in HIV+individuals. The decline of IFN-γ-producing CD4+T cells in AIDS is a major contributing factor in reactivation of quiescentToxoplasma gondiito an actively replicating stage of infection. Hence, it is important to identify CD4-independent mechanisms to control acuteT. gondiiinfection. Here we have investigated the targeted expansion and regulation of IFN-γ production by CD8+T cells, DN T cells and NK cells in response toT. gondiiinfection using IL-2 complex (IL2C) pre-treatment in an acutein vivomouse model. Our results show that expansion of CD8+T cells, DN T cells and NK cell by S4B6 IL2C treatment increases survival rates of mice infected withT. gondiiand this increased survival is dependent on both IL-12- and IL-18-driven IFN-γ production. Processing and secretion of IFN-γ-inducing, bioactive IL-18 is dependent on the sensing of active parasite invasion by multiple redundant inflammasome sensors in multiple hematopoietic cell types but independent fromT. gondii-derived dense granule (GRA) proteins. Our results provide evidence for a protective role of IL2C-mediated expansion of CD8+T cells, DN T cells and NK cells in murine toxoplasmosis and may represent a promising adjunct therapy for acute toxoplasmosis.Author SummaryA third of the world’s population is chronically infected with the parasiteToxoplasma gondii. In most cases the infection is asymptomatic, but in individuals suffering from AIDS, reactivation of brain and muscle cysts containingT. gondiiis a significant cause of death. The gradual decline of CD4 T cells, the hallmark of AIDS, is believed to be a major contributing factor in reactivation ofT. gondiiinfection and the development of acute disease. In this study, we show that targeted expansion of non-CD4 immune cell subsets can prevent severe disease and premature death via increased availability of interferon gamma-producing immune cells. We also demonstrate that the upstream signaling molecule interleukin-18 is required for the protective immune response by non-CD4 cells and show that the sensing of active parasite invasion by danger recognition molecules is crucial. Our findings reveal that targeted cell expansion may be a promising therapy in toxoplasmosis and suggests that the development of novel intervention strategies targeting danger recognition pathways may be useful against toxoplasmosis, particularly in the context of AIDS.

scholarly journals CpG Oligodeoxynucleotide Treatment Enhances Innate Resistance and Acquired Immunity to African Trypanosomes

2007 ◽  
Vol 75 (5) ◽  
pp. 2366-2373 ◽  
Author(s):  
Tajie H. Harris ◽  
John M. Mansfield ◽  
Donna M. Paulnock
Keyword(s):  
Parasite Burden ◽  
Type I ◽  
Dependent Manner ◽  
Cpg Odn ◽  
Relative Resistance ◽  
African Trypanosomes ◽  
Innate Resistance ◽  
Cpg Oligodeoxynucleotide ◽  
Developmental Life Cycle ◽  
Ifn Γ

ABSTRACTRelative resistance to African trypanosomiasis is based on the development of a type I cytokine response, which is partially dependent on innate immune responses generated through MyD88 and Toll-like receptor 9 (TLR9). Therefore, we asked whether enhancement of the immune response by artificial stimulation with CpG oligodeoxynucleotide (ODN), a TLR9 agonist, would result in enhanced protection against trypanosomes. In susceptible BALB/c mice, relative resistance to infection was significantly enhanced by CpG ODN treatment and was associated with decreased parasite burden, increased cytokine production, and elevated parasite-specific B- and T-cell responses. In relatively resistant C57BL/6 mice, survival was not enhanced but early parasitemia levels were reduced 100-fold and the majority of the parasites were nondividing, short stumpy (SS) forms. CpG ODN treatment of lymphocyte-deficient C57BL/6-scidand BALB/cByJ-scidmice also enhanced survival and reduced parasitemia, indicating that innate resistance to trypanosome infection can be enhanced. In C57BL/6-scidand BALB/cByJ-scidmice, the parasites were also predominantly SS forms during the outgrowth of parasitemia. However, the effect of CpG ODN treatment on parasite morphology was not as marked in gamma interferon (IFN-γ)-knockout mice, suggesting that downstream effects of IFN-γ production may play a discrete role in parasite cell differentiation. Overall, these studies provide the first evidence that enhancement of resistance to African trypanosomes can be induced in susceptible animals in a TLR9-dependent manner and that CpG ODN treatment may influence the developmental life cycle of the parasites.

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 NK cells require IL-28R for optimal in vivo activity

2015 ◽  
Vol 112 (18) ◽  
pp. E2376-E2384 ◽  
Author(s):  
Fernando Souza-Fonseca-Guimaraes ◽  
Arabella Young ◽  
Deepak Mittal ◽  
Ludovic Martinet ◽  
Claudia Bruedigam ◽  
...  
Keyword(s):  
Nk Cells ◽  
Tumor Metastasis ◽  
Nk Cell ◽  
Lymphoid Cells ◽  
Type I ◽  
Type Iii ◽  
Ifn Γ ◽  
Type Iii Ifn ◽  
Deficient Mice

Natural killer (NK) cells are naturally circulating innate lymphoid cells that protect against tumor initiation and metastasis and contribute to immunopathology during inflammation. The signals that prime NK cells are not completely understood, and, although the importance of IFN type I is well recognized, the role of type III IFN is comparatively very poorly studied. IL-28R–deficient mice were resistant to LPS and cecal ligation puncture-induced septic shock, and hallmark cytokines in these disease models were dysregulated in the absence of IL-28R. IL-28R–deficient mice were more sensitive to experimental tumor metastasis and carcinogen-induced tumor formation than WT mice, and additional blockade of interferon alpha/beta receptor 1 (IFNAR1), but not IFN-γ, further enhanced metastasis and tumor development. IL-28R–deficient mice were also more susceptible to growth of the NK cell-sensitive lymphoma, RMAs. Specific loss of IL-28R in NK cells transferred into lymphocyte-deficient mice resulted in reduced LPS-induced IFN-γ levels and enhanced tumor metastasis. Therefore, by using IL-28R–deficient mice, which are unable to signal type III IFN-λ, we demonstrate for the first time, to our knowledge, the ability of IFN-λ to directly regulate NK cell effector functions in vivo, alone and in the context of IFN-αβ.

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