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.

scholarly journals Counter-Protective Role for Interleukin-5 during Acute Toxoplasma gondii Infection

2001 ◽  
Vol 69 (2) ◽  
pp. 1044-1052 ◽  
Author(s):  
M. B. Nickdel ◽  
F. Roberts ◽  
F. Brombacher ◽  
J. Alexander ◽  
C. W. Roberts
Keyword(s):  
Nitric Oxide ◽  
Toxoplasma Gondii ◽  
Early Stage ◽  
Mortality Rates ◽  
Interferon Γ ◽  
Protective Role ◽  
Oral Infection ◽  
Interleukin 5 ◽  
Ifn Γ ◽  
Toxoplasma Gondii Infection

ABSTRACT The role of interleukin-5 (IL-5) during Toxoplasma gondii infection was investigated by comparing disease progression in IL-5 gene deficient (IL-5−/−) mice and their wild-type (WT) counterparts on a C57BL/6 background. IL-5−/− mice infected orally with T. gondii were less susceptible to infection than WT mice as demonstrated by reduced mortality rates. Consistent with this data, orally infected IL-5−/− mice had less severe pathological changes in their small intestines than WT mice at 8 days postinfection. At this time, splenocytes and mesenteric lymph node cells derived from IL-5−/− mice produced levels of IL-12, interferon-γ (IFN-γ), IL-4, IL-10, and nitric oxide (measured as nitrite) similar to those derived from WT mice when stimulated withToxoplasma lysate antigen. However, peak serum IL-12 and IFN-γ levels (at days 6 and 8, respectively) were significantly higher in IL-5−/− mice than in WT mice. In addition, WT mice but not IL-5−/− mice had raised levels of eosinophils in their peripheral blood between days 5 and 8 following infection. Oral administration ofNω-nitro-l-arginine methyl (from day 4 postinfection) increased mortality rates in both IL-5−/− and WT mice, indicating a protective role for nitric oxide during the early stages of oral T. gondii infection. In comparison with oral infection, no difference in mortality was observed between IL-5−/− and WT mice following intraperitoneal infection with T. gondii, with all mice surviving until 35 days postinfection. Similarly, no significant differences were observed in the severity of the meningitis, perivascular cuffing, or number of microglial nodules or parasites in the brains of intraperitoneally infected mice. Together, these results demonstrate a detrimental role for IL-5 during the early stage of oral infection with T. gondii which is associated with increased small-intestine pathology, eosinophilia, and reduced plasma IL-12 and IFN-γ levels.

scholarly journals Lack of Interleukin-6 Affects IFN-γ and TNF-α Production and Early In Vivo Control of Brucella abortus Infection

Pathogens ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1040
Author(s):  
Erika S. Guimarães ◽  
Jéssica M. Martins ◽  
Marco Túlio R. Gomes ◽  
Daiane M. Cerqueira ◽  
Sergio C. Oliveira
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Brucella Abortus ◽  
Interleukin 6 ◽  
Early Phase ◽  
Protective Role ◽  
Myeloperoxidase Activity ◽  
Tnf Α ◽  
Ifn Γ

Interleukin-6 (IL-6) is a pleiotropic cytokine promptly produced in response to infections, which contributes to host defense through the stimulation of acute phase immune responses. Brucella abortus is an intracellular bacterium that causes chronic disease in humans and domestic animals and triggers a robust immune response, characterized by the production of inflammatory cytokines. However, the mechanisms of IL-6-related immune responses in the context of Brucella infections are not completely understood. In this report, we describe an increased susceptibility of IL-6 knockout (KO) mice in the early phase of Brucella infection. Furthermore, we demonstrate that IL-6 is required for interferon (IFN)-γ and tumor necrosis factor (TNF)-α induction by infected splenocytes, indicating a protective role for IL-6 against B. abortus that parallels with Th1 type of immune response. Additionally, IL-6 KO mice exhibited reduced splenomegaly during the early phase of the infection. Corroborating this result, IL-6 KO mice displayed reduced numbers of macrophages, dendritic cells, and neutrophils in the spleen and reduced myeloperoxidase activity in the liver compared to wild-type infected mice. However, we demonstrate that IL-6 is not involved in B. abortus intracellular restriction in mouse macrophages. Taken together, our findings demonstrate that IL-6 contributes to host resistance during the early phase of B. abortus infection in vivo, and suggest that its protective role maybe partially mediated by proinflammatory immune responses and immune cell recruitment.

scholarly journals Toxoplasma gondii TgIST co-opts host chromatin repressors dampening STAT1-dependent gene regulation and IFN-γ–mediated host defenses

2016 ◽  
Vol 213 (9) ◽  
pp. 1779-1798 ◽  
Author(s):  
Gabrielle Gay ◽  
Laurence Braun ◽  
Marie-Pierre Brenier-Pinchart ◽  
Julien Vollaire ◽  
Véronique Josserand ◽  
...  
Keyword(s):  
Gene Expression ◽  
Toxoplasma Gondii ◽  
Acute Infection ◽  
Protective Role ◽  
Immune Gene ◽  
Nucleosome Remodeling ◽  
Inflammatory Monocytes ◽  
Ifn Γ ◽  
Immune Pathology ◽  
Toxoplasma Gondii Infection

An early hallmark of Toxoplasma gondii infection is the rapid control of the parasite population by a potent multifaceted innate immune response that engages resident and homing immune cells along with pro- and counter-inflammatory cytokines. In this context, IFN-γ activates a variety of T. gondii–targeting activities in immune and nonimmune cells but can also contribute to host immune pathology. T. gondii has evolved mechanisms to timely counteract the host IFN-γ defenses by interfering with the transcription of IFN-γ–stimulated genes. We now have identified TgIST (T. gondii inhibitor of STAT1 transcriptional activity) as a critical molecular switch that is secreted by intracellular parasites and traffics to the host cell nucleus where it inhibits STAT1-dependent proinflammatory gene expression. We show that TgIST not only sequesters STAT1 on dedicated loci but also promotes shaping of a nonpermissive chromatin through its capacity to recruit the nucleosome remodeling deacetylase (NuRD) transcriptional repressor. We found that during mice acute infection, TgIST-deficient parasites are rapidly eliminated by the homing Gr1+ inflammatory monocytes, thus highlighting the protective role of TgIST against IFN-γ–mediated killing. By uncovering TgIST functions, this study brings novel evidence on how T. gondii has devised a molecular weapon of choice to take control over a ubiquitous immune gene expression mechanism in metazoans, as a way to promote long-term parasitism.

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 ISG15 Connects Autophagy and IFN-γ-Dependent Control of Toxoplasma gondii Infection in Human Cells

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Jaya Bhushan ◽  
Joshua B. Radke ◽  
Yi-Chieh Perng ◽  
Michael Mcallaster ◽  
Deborah J. Lenschow ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Parasitophorous Vacuole ◽  
Interferon Γ ◽  
Parasite Growth ◽  
Human Cells ◽  
Growth Restriction ◽  
Intracellular Pathogens ◽  
Functional Link ◽  
Content Type ◽  
Ifn Γ

ABSTRACT The intracellular protozoan parasite Toxoplasma gondii is capable of infecting most nucleated cells, where it survives in a specially modified compartment called the parasitophorous vacuole (PV). Interferon gamma (IFN-γ) is the major cytokine involved in activating cell-autonomous immune responses to inhibit parasite growth within this intracellular niche. In HeLa cells, IFN-γ treatment leads to ubiquitination of susceptible parasite strains, recruitment of the adaptors p62 and NDP52, and engulfment in microtubule-associated protein 1 light chain 3 (LC3)-positive membranes that restrict parasite growth. IFN-γ-mediated growth restriction depends on core members of the autophagy (ATG) pathway but not the initiation or degradative steps in the process. To explore the connection between these different pathways, we used permissive biotin ligation to identify proteins that interact with ATG5 in an IFN-γ-dependent fashion. Network analysis of the ATG5 interactome identified interferon-stimulated gene 15 (ISG15), which is highly upregulated by IFN treatment, as a hub connecting the ATG complex with other IFN-γ-induced genes, suggesting that it forms a functional link between the pathways. Deletion of ISG15 resulted in impaired recruitment of p62, NDP52, and LC3 to the PV and loss of IFN-γ-restricted parasite growth. The function of ISG15 required conjugation, and a number of ISGylated targets overlapped with the IFN-γ-dependent ATG5 interactome, including the adapter p62. Collectively, our findings establish a role for ISG15 in connecting the ATG pathway with IFN-γ-dependent restriction of T. gondii in human cells. IMPORTANCE Interferon(s) provide the primary defense against intracellular pathogens, a property ascribed to their ability to upregulate interferon-stimulated genes. Due to the sequestered niche occupied by Toxoplasma gondii, the host has elaborated intricate ways to target the parasite within its vacuole. One such mechanism is the recognition by a noncanonical autophagy pathway that envelops the parasite-containing vacuole and stunts growth in human cells. Remarkably, autophagy-dependent growth restriction requires interferon-γ, yet none of the classical components of autophagy are induced by interferon. Our studies draw a connection between these pathways by demonstrating that the antiviral protein ISG15, which is normally upregulated by interferons, links the autophagy-mediated control to ubiquitination of the vacuole. These findings suggest a similar link between interferon-γ signaling and autophagy that may underlie defense against other intracellular pathogens.

scholarly journals ILC1-derived IFN-γ mediates cDC1-dependent host resistance against Toxoplasma gondii

2020 ◽  
Author(s):  
Américo H. López-Yglesias ◽  
Elise Burger ◽  
Ellie Camanzo ◽  
Andrew T. Martin ◽  
Alessandra M. Araujo ◽  
...  
Keyword(s):  
Immune Response ◽  
Transcription Factor ◽  
Toxoplasma Gondii ◽  
Host Resistance ◽  
Protozoan Parasite ◽  
Protective Role ◽  
Type I ◽  
Intracellular Pathogens ◽  
Ifn Γ ◽  
Parasitic Pathogens

ABSTRACTHost resistance against intracellular pathogens requires a rapid IFN-γ mediated immune response. We reveal that T-bet-dependent production of IFN-γ is essential for the maintenance of inflammatory DCs at the site of infection with a common protozoan parasite, Toxoplasma gondii. A detailed analysis of the cellular sources for T-bet-dependent IFN-γ identified that ILC1s, but not NK or TH1 cells, were involved in the regulation of inflammatory DCs via IFN-γ. Mechanistically, we established that T-bet dependent ILC1-derived IFN-γ is critical for the induction of IRF8, an essential transcription factor for cDC1s. Failure to upregulate IRF8 in DCs resulted in acute susceptibility to T. gondii infection. Our data identifies that ILC1-derived IFN-γ is indispensable for host resistance against intracellular infection via maintaining IRF8+ inflammatory DCs at the site of infection.Author SummaryMounting a robust type I innate immune response is essential for resistance against numerous intracellular pathogens. The type I immune response is characterized by the production of IFN-γ, a central cytokine required for multiple non-redundant effector functions against bacterial, viral, and parasitic pathogens. Previous work has shown that group 1 innate lymphocyte cells (ILC1s) together with NK and CD4+ T cells play an indispensable IFN-γ mediated protective role against Toxoplasma gondii infection; yet, the pathway of how IFN-γ produced by ILC1s defend against T. gondii remains unknown. In this work we identified that early production of IFN-γ by ILC1 is essential for maintaining dendritic cells (DCs) during infection. Mechanistically, we reveal that ILC1-derived IFN-γ is indispensable for inducing the transcription factor IRF8 that is critical for sustaining inflammatory DCs. Finally, we demonstrate that IRF8+ DCs are critical for parasite elimination.

scholarly journals Toxoplasma gondii Type-I ROP18 Targeting Human E3 Ligase TRIM21 for Immune Escape

2021 ◽  
Vol 9 ◽  
Author(s):  
Lijie Yao ◽  
Liqing Xu ◽  
Lijuan Zhou ◽  
Shuizhen Wu ◽  
Weihao Zou ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Immune Responses ◽  
Immune Escape ◽  
Parasitophorous Vacuole ◽  
E3 Ligase ◽  
Innate Immune ◽  
Intracellular Pathogen ◽  
Type I ◽  
Innate Immune Responses ◽  
Ifn Γ

Toxoplasma gondii is an intracellular pathogen that exerts its virulence through inhibiting host’s innate immune responses, which is mainly related to the type II interferon (IFN-γ) response. IFN-γ inducible tripartite motif 21 (TRIM21), an E3 ligase, plays an important role in anti-infection responses against the intracellular pathogens including bacteria, virus, and parasite. We found that T. gondii virulence factor ROP18 of the type I RH strain (TgROP18I) interacted with human TRIM21, and promoted the latter’s phosphorylation, which subsequently accelerated TRIM21 degradation through lysosomal pathway. Furthermore, TRIM21 protein level was found to be upregulated during RH and CEP strains of T. gondii infection. TRIM21 knocking down reduced the ubiquitin labeling on the parasitophorous vacuole membrane (PVM) [which led to parasitophorous vacuole (PV) acidification and death of CEP tachyzoites], and relieved the inhibition of CEP proliferation induced by IFN-γ in human foreskin fibroblast (HFF) cells which was consistent with the result of TRIM21 overexpression. On the other hand, TRIM21 overexpression enhanced the inhibition of CEP proliferation, and inhibited the binding of IκB-α with p65 to activate the IFN-γ-inducible NF-κB pathway, which might be resulted by TRIM21-IκB-α interaction. In brief, our research identified that in human cells, IFN-γ-inducible TRIM21 functioned in the innate immune responses against type III T. gondii infection; however, TgROP18I promoted TRIM21 phosphorylation, leading to TRIM21 degradation for immune escape in type I strain infection.

A Summary of the Third Global Interferon-γ Release Assay Symposium

2013 ◽  
Vol 34 (6) ◽  
pp. 619-624 ◽  
Author(s):  
Antonino Catanzaro ◽  
Charles Daley
Keyword(s):  
Immune Response ◽  
Tuberculin Skin Test ◽  
Skin Test ◽  
Interferon Γ ◽  
Enzyme Linked Immunosorbent Assay ◽  
In Vitro Tests ◽  
The Third ◽  
Specific Antigens ◽  
Ifn Γ

Studies over the past several decades have dramatically increased our understanding of the immune response to Mycobacterium tuberculosis infection, and advances in proteomics and genomics have led to a new class of immune-diagnostic tests, termed interferon-γ (IFN-γ) release assays (IGRAs), which appear to obviate many of the problems encountered with the tuberculin skin test (TST). Worldwide, 2 IGRAs are currently commercially available. QuantiFERON-TB Gold In-Tube (Cellestis) is a third-generation product that uses an enzyme-linked immunosorbent assay to measure IFN-γ generated in whole blood stimulated with M. tuberculosis–specific antigens. T-Spot-TB (Oxford Immunotec) employs enzyme-linked immunosorbent spot technology to enumerate the number of purified lymphocytes that respond to M. tuberculosis–specific antigens by producing IFN-γ. These in vitro tests measure the host immune response to M. tuberculosis–specific antigens, which virtually eliminates false-positive cross reactions caused by bacillus Calmette-Guérin vaccination and/or exposure to environmental nontuberculous mycobacteria that plague the interpretation and accuracy of the tuberculin skin test (TST). The high specificity of IGRAs, together with sensitivity commensurate with or better than that of the TST, promises an accurate diagnosis and the ability to focus tuberculosis-control activities on those who are actually infected with M. tuberculosis. The Third Global Symposium was held over a 3-day period and was presented by the University of California, San Diego, Continuing Medical Education department; slides and sound recordings of each presentation are available at http://cme.ucsd.edu/igras/syllabus.html. A moderated discussion is also available at http://cme.ucsd.edu/igrasvideo. This document provides a summary of the key findings of the meeting, specifically focusing on the use of IGRAs in screening healthcare worker populations.

scholarly journals Resveratrol-mediated reversal of changes in purinergic signaling and immune response induced by Toxoplasma gondii infection of neural progenitor cells

2018 ◽  
Vol 15 (1) ◽  
pp. 77-84 ◽  
Author(s):  
Nathieli B. Bottari ◽  
Micheli M. Pillat ◽  
Maria R.C. Schetinger ◽  
Karine P. Reichert ◽  
Vanessa Machado ◽  
...  
Keyword(s):  
Immune Response ◽  
Toxoplasma Gondii ◽  
Progenitor Cells ◽  
Neural Progenitor Cells ◽  
Purinergic Signaling ◽  
Neural Progenitor ◽  
Toxoplasma Gondii Infection

scholarly journals Analysis of Structures and Epitopes of Surface Antigen Glycoproteins Expressed in Bradyzoites ofToxoplasma gondii

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Hua Cong ◽  
Min Zhang ◽  
Qingli Zhang ◽  
Jing Gong ◽  
Haizi Cong ◽  
...  
Keyword(s):  
Immune Response ◽  
Toxoplasma Gondii ◽  
Immune Responses ◽  
Surface Antigen ◽  
Protein Sequence ◽  
Protozoan Parasite ◽  
3D Models ◽  
Chronic Infections ◽  
Homologous Proteins ◽  
Protein Sequence Alignment

Toxoplasma gondiiis a protozoan parasite capable of infecting humans and animals. Surface antigen glycoproteins, SAG2C, -2D, -2X, and -2Y, are expressed on the surface of bradyzoites. These antigens have been shown to protect bradyzoites against immune responses during chronic infections. We studied structures of SAG2C, -2D, -2X, and -2Y proteins using bioinformatics methods. The protein sequence alignment was performed by T-Coffee method. Secondary structural and functional domains were predicted using software PSIPRED v3.0 and SMART software, and 3D models of proteins were constructed and compared using the I-TASSER server, VMD, and SWISS-spdbv. Our results showed that SAG2C, -2D, -2X, and -2Y are highly homologous proteins. They share the same conserved peptides and HLA-I restricted epitopes. The similarity in structure and domains indicated putative common functions that might stimulate similar immune response in hosts. The conserved peptides and HLA-restricted epitopes could provide important insights on vaccine study and the diagnosis of this disease.

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