scholarly journals CD73-Generated Adenosine Is Critical for Immune Regulation during Toxoplasma gondii Infection

2014 ◽  
Vol 83 (2) ◽  
pp. 721-729 ◽  
Author(s):  
Deeqa A. Mahamed ◽  
Leon E. Toussaint ◽  
Margaret S. Bynoe
Keyword(s):  
Toxoplasma Gondii ◽  
Adenosine Receptor ◽  
Oral Infection ◽  
Intracellular Pathogen ◽  
Necrosis Factor Alpha ◽  
Extracellular Adenosine ◽  
Content Type ◽  
Adenosine Receptor Agonist ◽  
Obligate Intracellular Pathogen ◽  
Toxoplasma Gondii Infection

As an obligate intracellular pathogen, the apicomplexan parasiteToxoplasma gondiievades immune system-mediated clearance by undergoing stage differentiation to persist indefinitely in susceptible hosts. Previously, we found that mice deficient in the ectoenzyme CD73, which generates adenosine in the extracellular matrix, were resistant to chronic toxoplasmosis after oral infection withT. gondii. Resistance in CD73 knockout mice was due to a delay in parasite differentiation in the central nervous system (CNS). To further clarify the role of CD73 and extracellular adenosine inT. gondiipathogenesis, we infected wild-type (WT) and CD73−/−mice withT. gondiicysts systemically by the intraperitoneal (i.p.) route. In contrast to oral infection, i.p. infected CD73−/−mice were highly susceptible to immune-mediated pathology, with significantly increased infiltration of neutrophils and T cells into the peritoneal cavity. Administration of the broad-spectrum adenosine receptor agonist 5′-N-ethylcarboxamidoadenosine (NECA) protected CD73−/−mice againstT. gondii-induced immunopathology, suggesting that the absence of CD73-generated adenosine led to the increased susceptibility in these mice. Peritoneal exudate cells from infected CD73−/−mice produced higher levels of the inflammatory mediators nitric oxide, tumor necrosis factor alpha (TNF-α), and interleukin-1β (IL-1β), without enhanced parasite killing or clearance. Bone marrow chimeras established that CD73 expression in both hematopoietic and nonhematopoietic compartments contributes to limitingT. gondii-induced immunopathology. In addition, mice deficient in the adenosine receptor A2Awere more susceptible to immunopathology during intraperitoneal infection withT. gondiithan WT mice. Thus, extracellular adenosine is a key immune regulator that limits collateral tissue damage due to an intracellular pathogen and promotes host survival.

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 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 Differential Gamma Interferon- and Tumor Necrosis Factor Alpha-Driven Cytokine Response Distinguishes Acute Infection of a Metatherian Host with Toxoplasma gondii and Neospora caninum

2017 ◽  
Vol 85 (6) ◽  
Author(s):  
Shannon L. Donahoe ◽  
David N. Phalen ◽  
Bronwyn M. McAllan ◽  
Denis O'Meally ◽  
Milton M. McAllister ◽  
...  
Keyword(s):  
Immune Response ◽  
Toxoplasma Gondii ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Neospora Caninum ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Toxoplasma gondii and Neospora caninum (both Apicomplexa) are closely related cyst-forming coccidian parasites that differ significantly in their host ranges and ability to cause disease. Unlike eutherian mammals, Australian marsupials (metatherian mammals) have long been thought to be highly susceptible to toxoplasmosis and neosporosis because of their historical isolation from the parasites. In this study, the carnivorous fat-tailed dunnart (Sminthopsis crassicaudata) was used as a disease model to investigate the immune response and susceptibility to infection of an Australian marsupial to T. gondii and N. caninum. The disease outcome was more severe in N. caninum-infected dunnarts than in T. gondii-infected dunnarts, as shown by the severity of clinical and histopathological features of disease and higher tissue parasite burdens in the tissues evaluated. Transcriptome sequencing (RNA-seq) of spleens from infected dunnarts and mitogen-stimulated dunnart splenocytes was used to define the cytokine repertoires. Changes in mRNA expression during the time course of infection were measured using quantitative reverse transcription-PCR (qRT-PCR) for key Th1 (gamma interferon [IFN-γ] and tumor necrosis factor alpha [TNF-α]), Th2 (interleukin 4 [IL-4] and IL-6), and Th17 (IL-17A) cytokines. The results show qualitative differences in cytokine responses by the fat-tailed dunnart to infection with N. caninum and T. gondii. Dunnarts infected with T. gondii were capable of mounting a more effective Th1 immune response than those infected with N. caninum, indicating the role of the immune response in the outcome scenarios of parasite infection in this marsupial mammal.

scholarly journals CCR5 Is Involved in Interruption of Pregnancy in Mice Infected with Toxoplasma gondii during Early Pregnancy

2017 ◽  
Vol 85 (9) ◽  
Author(s):  
Maki Nishimura ◽  
Kousuke Umeda ◽  
Masayuki Suwa ◽  
Hidefumi Furuoka ◽  
Yoshifumi Nishikawa
Keyword(s):  
Toxoplasma Gondii ◽  
Early Pregnancy ◽  
Parasite Burden ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Pregnant Mice ◽  
Implantation Sites ◽  
Factor Alpha ◽  
Embryo Loss

ABSTRACT Toxoplasmosis can cause abortion in pregnant humans and other animals; however, the mechanism of abortion remains unknown. C-C chemokine receptor type 5 (CCR5) is essential for host defense against Toxoplasma gondii infection. To investigate the relationship between CCR5 and abortion in toxoplasmosis, we inoculated wild-type and CCR5-deficient (CCR5−/−) mice with T. gondii tachyzoites intraperitoneally on day 3 of pregnancy (embryonic day 3 [E3]). The pregnancy rate decreased as pregnancy progressed in infected wild-type mice. Histopathologically, no inflammatory lesions were observed in the fetoplacental tissues. Although wild-type mice showed a higher parasite burden at the implantation sites than did CCR5−/− mice at E6 (3 days postinfection [dpi]), T. gondii antigen was detected only in the uterine tissue and not in the fetoplacental tissues. At E8 (5 dpi), the embryos in infected wild-type mice showed poor development compared with those of infected CCR5−/− mice, and apoptosis was observed in poorly developed embryos. Compared to uninfected mice, infected wild-type mice showed increased CCR5 expression at the implantation site at E6 and E8. Furthermore, analyses of mRNA expression in the uterus of nonpregnant and pregnant mice suggested that a lack of the CCR5 gene and the downregulation of tumor necrosis factor alpha (TNF-α) and CCL3 expression at E6 (3 dpi) are important factors for the maintenance of pregnancy following T. gondii infection. These results suggested that CCR5 signaling is involved in embryo loss in T. gondii infection during early pregnancy and that apoptosis is associated with embryo loss rather than direct damage to the fetoplacental tissues.

scholarly journals Brucella canis Is an Intracellular Pathogen That Induces a Lower Proinflammatory Response than Smooth Zoonotic Counterparts

2015 ◽  
Vol 83 (12) ◽  
pp. 4861-4870 ◽  
Author(s):  
Carlos Chacón-Díaz ◽  
Pamela Altamirano-Silva ◽  
Gabriela González-Espinoza ◽  
María-Concepción Medina ◽  
Alejandro Alfaro-Alarcón ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Clinical Signs ◽  
Intracellular Pathogen ◽  
Virulence Determinants ◽  
Proinflammatory Response ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Type Iv ◽  
Brucella Canis ◽  
Zoonotic Risk

Canine brucellosis caused byBrucella canisis a disease of dogs and a zoonotic risk.B. canisharbors most of the virulence determinants defined for the genus, but its pathogenic strategy remains unclear since it has not been demonstrated that this natural rough bacterium is an intracellular pathogen. Studies ofB. canisoutbreaks in kennel facilities indicated that infected dogs displaying clinical signs did not present hematological alterations. A virulentB. canisstrain isolated from those outbreaks readily replicated in different organs of mice for a protracted period. However, the levels of tumor necrosis factor alpha, interleukin-6 (IL-6), and IL-12 in serum were close to background levels. Furthermore,B. canisinduced lower levels of gamma interferon, less inflammation of the spleen, and a reduced number of granulomas in the liver in mice than didB. abortus. When the interaction ofB. caniswith cells was studiedex vivo, two patterns were observed, a predominant scattered cell-associated pattern of nonviable bacteria and an infrequent intracellular replicative pattern of viable bacteria in a perinuclear location. The second pattern, responsible for the increase in intracellular multiplication, was dependent on the type IV secretion system VirB and was seen only if the inoculum used for cell infections was in early exponential phase. Intracellular replicativeB. canisfollowed an intracellular trafficking route undistinguishable from that ofB. abortus. AlthoughB. canisinduces a lower proinflammatory response and has a stealthier replication cycle, it still displays the pathogenic properties of the genus and the ability to persist in infected organs based on the ability to multiply intracellularly.

scholarly journals Chronic Toxoplasma gondii Infection Induces Anti-N-Methyl-D-Aspartate Receptor Autoantibodies and Associated Behavioral Changes and Neuropathology

2018 ◽  
Vol 86 (10) ◽  
Author(s):  
Ye Li ◽  
Raphael P. Viscidi ◽  
Geetha Kannan ◽  
Ross McFarland ◽  
Mikhail V. Pletnikov ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Cyst Formation ◽  
Synaptic Proteins ◽  
Psychotic Symptoms ◽  
Temporal Association ◽  
Autoantibody Production ◽  
Content Type ◽  
Serologic Marker ◽  
Behavioral Abnormalities ◽  
Toxoplasma Gondii Infection

ABSTRACT Anti-NMDA receptor (NMDAR) autoantibodies have been postulated to play a role in the pathogenesis of NMDAR hypofunction, which contributes to the etiology of psychotic symptoms. Toxoplasma gondii is a pathogen implicated in psychiatric disorders and associated with elevation of NMDAR autoantibodies. However, it remains unclear whether parasite infection is the cause of NMDAR autoantibodies. By using mouse models, we found that NMDAR autoantibody generation had a strong temporal association with tissue cyst formation, as determined by MAG1 antibody seroreactivity (r = 0.96; P < 0.0001), which is a serologic marker for the cyst burden. The presence of MAG1 antibody response, but not T. gondii IgG response, was required for NMDAR autoantibody production. The pathogenic relevance of NMDAR autoantibodies to behavioral abnormalities (blunted response to amphetamine-triggered activity and decreased locomotor activity and exploration) and reduced expression of synaptic proteins (the GLUN2B subtype of NMDAR and PSD-95) has been demonstrated in infected mice. Our study suggests that NMDAR autoantibodies are specifically induced by persistent T. gondii infection and are most likely triggered by tissue cysts. NMDAR autoantibody seroreactivity may be a novel pathological hallmark of chronic toxoplasmosis, which raises questions about NMDAR hypofunction and neurodegeneration in the infected brain.

scholarly journals Bumped Kinase Inhibitor 1294 Treats Established Toxoplasma gondii Infection

2014 ◽  
Vol 58 (6) ◽  
pp. 3547-3549 ◽  
Author(s):  
J. Stone Doggett ◽  
Kayode K. Ojo ◽  
Erkang Fan ◽  
Dustin J. Maly ◽  
Wesley C. Van Voorhis
Keyword(s):  
Toxoplasma Gondii ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Content Type ◽  
Calcium Dependent ◽  
Dependent Protein ◽  
Orally Bioavailable ◽  
Toxoplasma Gondii Infection ◽  
Bumped Kinase Inhibitor

ABSTRACTToxoplasma gondiiis a unicellular parasite that causes severe brain and eye disease. Current drugs forT. gondiiare limited by toxicity. Bumped kinase inhibitors (BKIs) selectively inhibit calcium-dependent protein kinases of the apicomplexan pathogensT. gondii, cryptosporidia, and plasmodia. A lead anti-ToxoplasmaBKI, 1294, has been developed to be metabolically stable and orally bioavailable. Herein, we demonstrate the oral efficacy of 1294 against toxoplasmosisin vivo.

scholarly journals Active Escape of Orientia tsutsugamushi from Cellular Autophagy

2012 ◽  
Vol 81 (2) ◽  
pp. 552-559 ◽  
Author(s):  
Youngho Ko ◽  
Ji-Hye Choi ◽  
Na-Young Ha ◽  
Ik-Sang Kim ◽  
Nam-Hyuk Cho ◽  
...  
Keyword(s):  
Defense Mechanism ◽  
Host Cells ◽  
Intracellular Pathogen ◽  
Orientia Tsutsugamushi ◽  
Content Type ◽  
Cellular Autophagy ◽  
A Cell ◽  
Infected Cells ◽  
Obligate Intracellular Pathogen

ABSTRACTOrientia tsutsugamushi, the causative agent of scrub typhus, is an obligate intracellular pathogen. After entry into host cells, the bacterium rapidly escapes from the endosomal pathway and replicates in the cytosol of eukaryotic host cells. Here we show thatO. tsutsugamushiinfection efficiently promotes cellular autophagy, a cell-autonomous defense mechanism of innate immunity. However, most of the internalized bacteria barely colocalized with the induced autophagosomes, even when stimulated with rapamycin, a chemical inducer of autophagy. Treatment of infected cells with tetracycline suppressed bacterial evasion from autophagy and facilitatedO. tsutsugamushitargeting to autophagosomes, suggesting that the intracellular pathogen may be equipped with a bacterial factor or factors that block autophagic recognition. Finally, we also found that chemical modulators of cellular autophagy or genetic knockout of theatg3gene does not significantly affect the intracellular growth ofO. tsutsugamushiin vitro. These results suggest thatO. tsutsugamushihas evolved to block autophagic microbicidal defense by evading autophagic recognition even though it activates the autophagy pathway during the early phase of infection.

scholarly journals Host-derived glucose and its transporter in the obligate intracellular pathogen Toxoplasma gondii are dispensable by glutaminolysis

2009 ◽  
Vol 106 (31) ◽  
pp. 12998-13003 ◽  
Author(s):  
M. Blume ◽  
D. Rodriguez-Contreras ◽  
S. Landfear ◽  
T. Fleige ◽  
D. Soldati-Favre ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Intracellular Pathogen ◽  
Obligate Intracellular ◽  
Obligate Intracellular Pathogen

scholarly journals RIPK3 Facilitates Host Resistance to Oral Toxoplasma gondii Infection

2021 ◽  
Vol 89 (5) ◽  
Author(s):  
Patrick W. Cervantes ◽  
Bruno Martorelli Di Genova ◽  
Billy Joel Erazo Flores ◽  
Laura J. Knoll
Keyword(s):  
Cell Death ◽  
Toxoplasma Gondii ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Parasite Burden ◽  
Kinase Domain ◽  
Content Type ◽  
Protection Mechanism ◽  
Cell Death Pathway ◽  
Toxoplasma Gondii Infection

ABSTRACT Toxoplasma gondii infection activates pattern recognition receptor (PRR) pathways that drive innate inflammatory responses to control infection. Necroptosis is a proinflammatory cell death pathway apart from the innate immune response that has evolved to control pathogenic infection. In this study, we further defined the role of Z-DNA binding protein 1 (ZBP1) as a PRR and assessed its contribution to necroptosis as a host protection mechanism to T. gondii infection. We found that ZBP1 does not induce proinflammatory necroptosis cell death, and ZBP1 null mice have reduced survival after oral T. gondii infection. In contrast, mice deleted in receptor-interacting serine/threonine-protein kinase 3 (RIPK3−/−), a central mediator of necroptosis, have significantly improved survival after oral T. gondii infection without a reduction in parasite burden. The physiological consequences of RIPK3 activity did not show any differences in intestine villus immunopathology, but RIPK3−/− mice showed higher immune cell infiltration and edema in the lamina propria. The contribution of necroptosis to host survival was clarified with mixed-lineage kinase domain-like pseudokinase null (MLKL−/−) mice. We found MLKL−/− mice succumbed to oral T. gondii infection the same as wild-type mice, indicating necroptosis-independent RIPK3 activity impacts host survival. These results provide new insights on the impacts of proinflammatory cell death pathways as a mechanism of host defense to oral T. gondii infection.

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