scholarly journals NADPH Oxidase and Guanylate Binding Protein 5 Restrict Survival of Avirulent Type III Strains of Toxoplasma gondii in Naive Macrophages

mBio ◽  
2018 ◽  
Vol 9 (4) ◽  
Author(s):  
Sumit K. Matta ◽  
Kelley Patten ◽  
Quiling Wang ◽  
Bae-Hoon Kim ◽  
John D. MacMicking ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Nadph Oxidase ◽  
Binding Protein ◽  
Parasitic Infections ◽  
Type I ◽  
Content Type ◽  
Innate Defense ◽  
Type Iii ◽  
Ifn Γ ◽  
Guanylate Binding Protein

ABSTRACT Phagocytic cells are the first line of innate defense against intracellular pathogens, and yet Toxoplasma gondii is renowned for its ability to survive in macrophages, although this paradigm is based on virulent type I parasites. Surprisingly, we find that avirulent type III parasites are preferentially cleared in naive macrophages, independent of gamma interferon (IFN-γ) activation. The ability of naive macrophages to clear type III parasites was dependent on enhanced activity of NADPH oxidase (Nox)-generated reactive oxygen species (ROS) and induction of guanylate binding protein 5 (Gbp5). Macrophages infected with type III parasites (CTG strain) showed a time-dependent increase in intracellular ROS generation that was higher than that induced by type I parasites (GT1 strain). The absence of Nox1 or Nox2, gp91 subunit isoforms of the Nox complex, reversed ROS-mediated clearance of CTG parasites. Consistent with this finding, both Nox1−/− and Nox2−/− mice showed higher susceptibility to CTG infection than wild-type mice. Additionally, Gbp5 expression was induced upon infection and the enhanced clearance of CTG strain parasites was reversed in Gbp5−/− macrophages. Expression of a type I ROP18 allele in CTG prevented clearance in naive macrophages, suggesting that it plays a role counteracting Gbp5. Although ROS and Gbp5 have been linked to activation of the NLRP3 inflammasome, clearance of CTG parasites did not rely on induction of pyroptosis. Collectively, these findings reveal that not all strains of T. gondii are adept at avoiding clearance in macrophages and define new roles for ROS and Gbps in controlling this important intracellular pathogen. IMPORTANCE Toxoplasma infections in humans and other mammals are largely controlled by IFN-γ produced by the activated adaptive immune system. However, we still do not completely understand the role of cell-intrinsic functions in controlling Toxoplasma or other apicomplexan infections. The present work identifies intrinsic activities in naive macrophages in counteracting T. gondii infection. Using an avirulent strain of T. gondii, we highlight the importance of Nox complexes in conferring protection against parasite infection both in vitro and in vivo. We also identify Gbp5 as a novel macrophage factor involved in limiting intracellular infection by avirulent strains of T. gondii. The rarity of human infections caused by type III strains suggests that these mechanisms may also be important in controlling human toxoplasmosis. These findings further extend our understanding of host responses and defense mechanisms that act to control parasitic infections at the cellular level.

scholarly journals Comprehensive Characterization of Toxoplasma Acyl Coenzyme A-Binding Protein TgACBP2 and Its Critical Role in Parasite Cardiolipin Metabolism

mBio ◽  
2018 ◽  
Vol 9 (5) ◽  
Author(s):  
Yong Fu ◽  
Xia Cui ◽  
Sai Fan ◽  
Jing Liu ◽  
Xiao Zhang ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Lipid Metabolism ◽  
Toxoplasma Gondii ◽  
Binding Protein ◽  
Ankyrin Repeat ◽  
Type I ◽  
Type Ii ◽  
Content Type ◽  
High K ◽  
Acyl Coenzyme A

ABSTRACT Acyl coenzyme A (CoA)-binding protein (ACBP) can bind acyl-CoAs with high specificity and affinity, thus playing multiple roles in cellular functions. Mitochondria of the apicomplexan parasite Toxoplasma gondii have emerged as key organelles for lipid metabolism and signaling transduction. However, the rationale for how this parasite utilizes acyl-CoA-binding protein to regulate mitochondrial lipid metabolism remains unclear. Here, we show that an ankyrin repeat-containing protein, TgACBP2, is localized to mitochondria and displays active acyl-CoA-binding activities. Dephosphorylation of TgACBP2 is associated with relocation from the plasma membrane to the mitochondria under conditions of regulation of environmental [K+]. Under high [K+] conditions, loss of ACBP2 induced mitochondrial dysfunction and apoptosis-like cell death. Disruption of ACBP2 caused growth and virulence defects in the type II strain but not in type I parasites. Interestingly, mitochondrial association factor-1 (MAF1)-mediated host mitochondrial association (HMA) restored the growth ability of ACBP2-deficient type II parasites. Lipidomics analysis indicated that ACBP2 plays key roles in the cardiolipin metabolism of type II parasites and that MAF1 expression complemented the lipid metabolism defects of ACBP2-deficient type II parasites. In addition, disruption of ACBP2 caused attenuated virulence of Prugniuad (Pru) parasites for mice. Taking the results collectively, these data indicate that ACBP2 is critical for the growth and virulence of type II parasites and for the growth of type I parasites under high [K+] conditions. IMPORTANCE Toxoplasma gondii is one of the most successful human parasites, infecting nearly one-third of the total world population. T. gondii tachyzoites residing within parasitophorous vacuoles (PVs) can acquire fatty acids both via salvage from host cells and via de novo synthesis pathways for membrane biogenesis. However, although fatty acid fluxes are known to exist in this parasite, how fatty acids flow through Toxoplasma lipid metabolic organelles, especially mitochondria, remains unknown. In this study, we demonstrated that Toxoplasma expresses an active ankyrin repeat containing protein TgACBP2 to coordinate cardiolipin metabolism. Specifically, HMA acquisition resulting from heterologous functional expression of MAF1 rescued growth and lipid metabolism defects in ACBP2-deficient type II parasites, manifesting the complementary role of host mitochondria in parasite cardiolipin metabolism. This work highlights the importance of TgACBP2 in parasite cardiolipin metabolism and provides evidence for metabolic association of host mitochondria with T. gondii.

scholarly journals ROP16-Mediated Activation of STAT6 Suppresses Host Cell Reactive Oxygen Species Production, Facilitating Type III Toxoplasma gondii Growth and Survival

mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Joshua A. Kochanowsky ◽  
Kaitlin K. Thomas ◽  
Anita A. Koshy
Keyword(s):  
Reactive Oxygen Species ◽  
Toxoplasma Gondii ◽  
Host Cell ◽  
Parasite Growth ◽  
Effector Proteins ◽  
Oxygen Species ◽  
Content Type ◽  
Growth And Survival ◽  
Type Iii ◽  
Ifn Γ

ABSTRACT Polymorphic effector proteins determine the susceptibility of Toxoplasma gondii strains to IFN-γ-mediated clearance mechanisms deployed by murine host cells. However, less is known about the influence of these polymorphic effector proteins on IFN-γ-independent clearance mechanisms. Here, we show that deletion of one such polymorphic effector protein, ROP16, from a type III background leads to a defect in parasite growth and survival in unstimulated human fibroblasts and murine macrophages. Rescue of these defects requires a ROP16 with a functional kinase domain and the ability to activate a specific family of host cell transcription factors (STAT3, 5a, and 6). The growth and survival defects correlate with an accumulation of host cell reactive oxygen species (ROS) and are prevented by treatment with an ROS inhibitor. Exogenous activation of STAT3 and 6 suppresses host cell ROS production during infection with ROP16-deficient parasites and depletion of STAT6, but not STAT3 or 5a, causes an accumulation of ROS in cells infected with wild-type parasites. Pharmacological inhibition of NOX2 and mitochondrially derived ROS also rescues growth and survival of ROP16-deficient parasites. Collectively, these findings reveal an IFN-γ-independent mechanism of parasite restriction in human cells that is subverted by injection of ROP16 by type III parasites. IMPORTANCE Toxoplasma gondii is an obligate intracellular parasite that infects up to one-third of the world’s population. Control of the parasite is largely accomplished by IFN-γ-dependent mechanisms that stimulate innate and adaptive immune responses. Parasite suppression of IFN-γ-stimulated responses has been linked to proteins that the parasite secretes into its host cell. These secreted proteins vary by T. gondii strain and determine strain-specific lethality in mice. How these strain-specific polymorphic effector proteins affect IFN-γ-independent parasite control mechanisms in human and murine cells is not well known. This study shows that one such secreted protein, ROP16, enables efficient parasite growth and survival by suppressing IFN-γ-independent production of ROS by human and mouse cells.

scholarly journals Pathogenic Effects of IFIT2 and Interferon-β during Fatal SystemicCandida albicansInfection

mBio ◽  
2018 ◽  
Vol 9 (2) ◽  
pp. e00365-18 ◽  
Author(s):  
Marcin Stawowczyk ◽  
Shamoon Naseem ◽  
Valeria Montoya ◽  
Darren P. Baker ◽  
James Konopka ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Immune Response ◽  
Nadph Oxidase ◽  
Murine Model ◽  
Viral Infections ◽  
Attributable Mortality ◽  
Type I ◽  
Content Type ◽  
Innate Defense ◽  
Gene Coding

ABSTRACTA balanced immune response to infection is essential to prevent the pathology and tissue damage that can occur from an unregulated or hyperactive host defense. Interferons (IFNs) are critical mediators of the innate defense to infection, and in this study we evaluated the contribution of a specific gene coding for IFIT2 induced by type I IFNs in a murine model of disseminatedCandida albicans. Invasive candidiasis is a frequent challenge during immunosuppression or surgical medical interventions, andC. albicansis a common culprit that leads to high rates of mortality. When IFIT2 knockout mice were infected systemically withC. albicans, they were found to have improved survival and reduced fungal burden compared to wild-type mice. One of the mechanisms by which IFIT2 increases the pathological effects of invasiveC. albicansappears to be suppression of NADPH oxidase activation. Loss of IFIT2 increases production of reactive oxygen species by leukocytes, and we demonstrate that IFIT2 is a binding partner of a critical regulatory subunit of NADPH oxidase, p67phox. Since the administration of IFN has been used therapeutically to combat viral infections, cancer, and multiple sclerosis, we evaluated administration of IFN-β to mice prior toC. albicansinfection. IFN-β treatment promoted pathology and death fromC. albicansinfection. We provide evidence that IFIT2 increases the pathological effects of invasiveC. albicansand that administration of IFN-β has deleterious effects during infection.IMPORTANCEThe attributable mortality associated with systemicC. albicansinfections in health care settings is significant, with estimates greater than 40%. This life-threatening disease is common in patients with weakened immune systems, either due to disease or as a result of therapies. Type I interferons (IFN) are cytokines of the innate defense response that are used as immune modulators in the treatment of specific cancers, viral infections, and multiple sclerosis. In this study, we show using a murine model that the loss of a specific IFN-stimulated gene coding for IFIT2 improves survival following systemicC. albicansinfection. This result infers a harmful effect of IFN duringC. albicansinfection and is supported by our finding that administration of IFN-β prior to invasive infection promotes fatal pathology. The findings contribute to our understanding of the innate immune response toC. albicans, and they suggest that IFN therapies present a risk factor for disseminated candidiasis.

scholarly journals Toxoplasma gondii Inhibits Gamma Interferon (IFN-γ)- and IFN-β-Induced Host Cell STAT1 Transcriptional Activity by Increasing the Association of STAT1 with DNA

2013 ◽  
Vol 82 (2) ◽  
pp. 706-719 ◽  
Author(s):  
Emily E. Rosowski ◽  
Quynh P. Nguyen ◽  
Ana Camejo ◽  
Eric Spooner ◽  
Jeroen P. J. Saeij
Keyword(s):  
Toxoplasma Gondii ◽  
Host Cell ◽  
Transcriptional Activation ◽  
Histone Deacetylases ◽  
Gamma Interferon ◽  
Host Cells ◽  
Secondary Response ◽  
Type I ◽  
Content Type ◽  
Ifn Γ

ABSTRACTThe gamma interferon (IFN-γ) response, mediated by the STAT1 transcription factor, is crucial for host defense against the intracellular pathogenToxoplasma gondii, but prior infection withToxoplasmacan inhibit this response. Recently, it was reported that theToxoplasmatype II NTE strain prevents the recruitment of chromatin remodeling complexes containing Brahma-related gene 1 (BRG-1) to promoters of IFN-γ-induced secondary response genes such asCiitaand major histocompatibility complex class II genes in murine macrophages, thereby inhibiting their expression. We report here that a type I strain ofToxoplasmainhibits the expression of primary IFN-γ response genes such asIRF1through a distinct mechanism not dependent on the activity of histone deacetylases. Instead, infection with a type I, II, or III strain ofToxoplasmainhibits the dissociation of STAT1 from DNA, preventing its recycling and further rounds of STAT1-mediated transcriptional activation. This leads to increased IFN-γ-induced binding of STAT1 at theIRF1promoter in host cells and increased global IFN-γ-induced association of STAT1 with chromatin.Toxoplasmatype I infection also inhibits IFN-β-induced interferon-stimulated gene factor 3-mediated gene expression, and this inhibition is also linked to increased association of STAT1 with chromatin. The secretion of proteins into the host cell by a type I strain ofToxoplasmawithout complete parasite invasion is not sufficient to block STAT1-mediated expression, suggesting that the effector protein responsible for this inhibition is not derived from the rhoptries.

scholarly journals Type II Toxoplasma gondii Induction of CD40 on Infected Macrophages Enhances Interleukin-12 Responses

2014 ◽  
Vol 82 (10) ◽  
pp. 4047-4055 ◽  
Author(s):  
Pedro Morgado ◽  
Dattanand M. Sudarshana ◽  
Lanny Gov ◽  
Katherine S. Harker ◽  
Tonika Lam ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Transcript Level ◽  
Forward Genetics ◽  
Interleukin 12 ◽  
Type I ◽  
Dependent Manner ◽  
Type Ii ◽  
Content Type ◽  
Type Iii ◽  
Infected Cells

ABSTRACTToxoplasma gondiiis an obligate intracellular parasite that can cause severe neurological disease in infected humans. CD40 is a receptor on macrophages that plays a critical role in controllingT. gondiiinfection. We examined the regulation of CD40 on the surface ofT. gondii-infected bone marrow-derived macrophages (BMdMs).T. gondiiinduced CD40 expression both at the transcript level and on the cell surface, and interestingly, the effect was parasite strain specific: CD40 levels were dramatically increased in type IIT. gondii-infected BMdMs compared to type I- or type III-infected cells. Type II induction of CD40 was specific to cells harboring intracellular parasites and detectable as early as 6 h postinfection (hpi) at the transcript level. CD40 protein expression peaked at 18 hpi. Using forward genetics with progeny from a type II × type III cross, we found that CD40 induction mapped to a region of chromosome X that included the gene encoding the dense granule protein 15 (GRA15). Using type I parasites stably expressing the type II allele ofGRA15(GRA15II), we found that type I GRA15IIparasites induced the expression of CD40 on infected cells in an NF-κB-dependent manner. In addition, stable expression of hemagglutinin-tagged GRA15IIin THP-1 cells resulted in CD40 upregulation in the absence of infection. Since CD40 signaling contributes to interleukin-12 (IL-12) production, we examined IL-12 from infected macrophages and found that CD40L engagement of CD40 amplified the IL-12 response in type II-infected cells. These data indicate that GRA15IIinduction of CD40 promotes parasite immunity through the production of IL-12.

scholarly journals Functional Analysis of the Role of Toxoplasma gondii Nucleoside Triphosphate Hydrolases I and II in Acute Mouse Virulence and Immune Suppression

2016 ◽  
Vol 84 (7) ◽  
pp. 1994-2001 ◽  
Author(s):  
Philipp Olias ◽  
L. David Sibley
Keyword(s):  
Toxoplasma Gondii ◽  
Specific Effect ◽  
Nucleoside Triphosphate ◽  
Type I ◽  
Type Ii ◽  
Content Type ◽  
Raw264.7 Macrophages ◽  
Ifn Γ ◽  
Fluc Activity ◽  
Strain Dependent

Bioluminescent reporter assays have been widely used to study the effect ofToxoplasma gondiion host gene expression. In the present study, we extend these studies by engineering novel reporter cell lines containing a gamma-activated sequence (GAS) element driving firefly luciferase (FLUC). In RAW264.7 macrophages,T. gondiitype I strain (GT1) infection blocked interferon gamma (IFN-γ)-induced FLUC activity to a significantly greater extent than infection by type II (ME49) and type III (CTG) strains. Quantitative trait locus (QTL) analysis of progeny from a prior genetic cross identified a genomic region on chromosome XII that correlated with the observed strain-dependent phenotype. This QTL region contains two isoforms of theT. gondiienzyme nucleoside triphosphate hydrolase (NTPase) that were the prime candidates for mediating the observed strain-specific effect. Using reverse genetic analysis we show that deletion of NTPase I from a type I strain (RH) background restored the higher luciferase levels seen in the type II (ME49) strain. Rather than an effect on IFN-γ-dependent transcription, our data suggest that NTPase I was responsible for the strain-dependent difference in FLUC activity due to hydrolysis of ATP. We further show that NTPases I and II were not essential for tachyzoite growthin vitroor virulence in mice. Our study reveals that althoughT. gondiiNTPases are not essential for immune evasion, they can affect ATP-dependent reporters. Importantly, this limitation was overcome using an ATP-independentGaussialuciferase, which provides a more appropriate reporter for use withT. gondiiinfection studies.

Nonidentical Induction of the Guanylate Binding Protein and the 56K Protein by Type I and Type II Interferons

1986 ◽  
Vol 6 (4) ◽  
pp. 417-427 ◽  
Author(s):  
YIH-SHYUN E. CHENG ◽  
MARY F. BECKER-MANLEY ◽  
THAI D. NGUYEN ◽  
WILLIAM F. DEGRADO ◽  
GERALD J. JONAK
Keyword(s):  
Binding Protein ◽  
Type I ◽  
Type Ii ◽  
Guanylate Binding Protein

scholarly journals Bacterial Enzymes Catalyzing the Synthesis of 1,8-Dihydroxynaphthalene, a Key Precursor of Dihydroxynaphthalene Melanin, fromSorangium cellulosum

2018 ◽  
Vol 84 (9) ◽  
Author(s):  
Yusuke Sone ◽  
Shuto Nakamura ◽  
Makoto Sasaki ◽  
Fumihito Hasebe ◽  
Seung-Young Kim ◽  
...  
Keyword(s):  
Pathogenic Bacteria ◽  
Optical Purity ◽  
Brown Pigment ◽  
Type I ◽  
Enzymatic System ◽  
Type Iii Polyketide Synthase ◽  
Content Type ◽  
Type Iii ◽  
Bacterial Origin

ABSTRACT1,8-Dihydroxynaphthalene (1,8-DHN) is a key intermediate in the biosynthesis of DHN melanin, which is specific to fungi. In this study, we characterized the enzymatic properties of the gene products of an operon consisting ofsoceCHS1,bdsA, andbdsBfrom the Gram-negative bacteriumSorangium cellulosum. Heterologous expression ofsoceCHS1,bdsA, andbdsBinStreptomyces coelicolorcaused secretion of a dark-brown pigment into the broth. High-performance liquid chromatography (HPLC) analysis of the broth revealed that the recombinant strain produced 1,8-DHN, indicating that the operon encoded a novel enzymatic system for the synthesis of 1,8-DHN. Simultaneous incubation of the recombinant SoceCHS1, BdsA, and BdsB with malonyl-coenzyme A (malonyl-CoA) and NADPH resulted in the synthesis of 1,8-DHN. SoceCHS1, a type III polyketide synthase (PKS), catalyzed the synthesis of 1,3,6,8-tetrahydroxynaphthalene (T4HN)in vitro. T4HN was in turn converted to 1,8-DHN by successive steps of reduction and dehydration, which were catalyzed by BdsA and BdsB. BdsA, which is a member of the aldo-keto reductase (AKR) superfamily, catalyzed the reduction of T4HN and 1,3,8-tetrahydroxynaphthalene (T3HN) to scytalone and vermelone, respectively. The stereoselectivity of T4HN reduction by BdsA occurred on thesi-face to give (R)-scytalone with more than 99% optical purity. BdsB, a SnoaL2-like protein, catalyzed the dehydration of scytalone and vermelone to T3HN and 1,8-DHN, respectively. The fungal pathway for the synthesis of 1,8-DHN is composed of a type I PKS, naphthol reductases of the short-chain dehydrogenase/reductase (SDR) superfamily, and scytalone dehydratase (SD). These findings demonstrated 1,8-DHN synthesis by novel enzymes of bacterial origin.IMPORTANCEAlthough the DHN biosynthetic pathway was thought to be specific to fungi, we discovered novel DHN synthesis enzymes of bacterial origin. The biosynthesis of bacterial DHN utilized a type III PKS for polyketide synthesis, an AKR superfamily for reduction, and a SnoaL2-like NTF2 superfamily for dehydration, whereas the biosynthesis of fungal DHN utilized a type I PKS, SDR superfamily enzyme, and SD-like NTF2 superfamily. Surprisingly, the enzyme systems comprising the pathway were significantly different from each other, suggesting independent, parallel evolution leading to the same biosynthesis. DHN melanin plays roles in host invasion and adaptation to stress in pathogenic fungi and is therefore important to study. However, it is unclear whether DHN biosynthesis occurs in bacteria. Importantly, we did find that bacterial DHN biosynthetic enzymes were conserved among pathogenic bacteria.

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 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.

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