Nobody doubts that infections have imposed specialisations on the mammalian genome. However sufficient information is usually missing to attribute a specific genomic modification to pressure from a specific pathogen. Recent studies on mechanisms of mammalian resistance against the ubiquitous protozoan parasite, Toxoplasma gondii, have shown that the small rodents presumed to be largely responsible for transmission of the parasite to its definitive host, the domestic cat, possess distinctive recognition proteins, and interferon-inducible effector proteins (IRG proteins) that limit the potential virulence of the parasite. The phylogenetic association of the recognition proteins, TLR11 and TLR12, with T. gondii resistance is weak, but there is evidence for reciprocal polymorphism between parasite virulence proteins and host IRG proteins that strongly suggests current or recent coevolution.
The apicomplexan protozoan Toxoplasma gondii has a striking predilection for infecting the central nervous system and has been suggested as a risk factor for schizophrenia. Here, we address some of the mechanisms by which T. gondii achieves this by manipulating signaling pathways of the host brain cells.
Recent years have brought notable progress in the understanding of how the opportunistic parasite T. gondii establishes a successful infection in mammalian brain by secreting effector molecules that manipulate multiple cell functions. Many pathways involved in this inter-kingdom signaling, such as dopaminergic, GABAergic and kynurenine pathways, also have key roles in the development of schizophrenia. More understanding of T. gondii-brain cell interaction holds the key to unlocking the mystery of T. gondii-mediated schizophrenia pathogenesis.
T. gondii usurps a variety of host signaling pathways to ensure physiological adaptation, evasion of host immune defense systems, and efficient replication. A detailed knowledge of T. gondii signaling molecules involved in this cross-kingdom communication with host brain cells will probably provide novel means of pharmacologically manipulating host cellular pathways to promote efficient elimination of the parasite and may permit the development of new schizophrenia-modifying therapeutics.
There is marked variation in the human response to Toxoplasma gondii infection. Epidemiological studies indicate associations between strain virulence and severity of toxoplasmosis. Animal studies on the pathogenic effect of chronic infection focused on relatively avirulent strains (e.g. type II) because they can easily establish latent infections in mice, defined by the presence of bradyzoite-containing cysts. To provide insight into virulent strain-related severity of human toxoplasmosis, we established a chronic model of the virulent type I strain using outbred mice. We found that type I-exposed mice displayed variable outcomes ranging from aborted to severe infections. According to antibody profiles, we found that most of mice generated antibodies against T. gondii organism but varied greatly in the production of antibodies against matrix antigen MAG1. There was a strong correlation between MAG1 antibody level and brain cyst burden in chronically infected mice (r = 0.82, p = 0.0021). We found that mice with high MAG1 antibody level displayed lower weight, behavioral changes, altered levels of gene expression and immune activation. The most striking change in behavior we discovered was a blunted response to amphetamine-trigged locomotor activity. The extent of most changes was directly correlated with levels of MAG1 antibody. These changes were not found in mice with less cyst burden or mice that were acutely but not chronically infected. Our finding highlights the critical role of cyst burden in a range of disease severity during chronic infection, the predictive value of MAG1 antibody level to brain cyst burden and to changes in behavior or other pathology in chronically infected mice. Our finding may have important implications for understanding the heterogeneous effects of T. gondii infections in human.
Alzheimer is a progressive neurological disease that results in irreversible loss of neurons and includes about two thirds of all cases of dementia. Toxoplasma gondii may be an important infectious agent involved in neurodegenerative diseases. The aim of this study was to investigate the correlation between Toxoplasma as an etiologic agent in the progress of Alzheimer's disease. This case control study was conducted on 75 Alzheimer's patients and 75 healthy volunteers. Blood samples were obtained and anti-Toxoplasma IgG and IgM tests were done by using ELISA technique. DNA was extracted from buffy coat and then GRA6 gene and SAG2 loci were amplified by PCR and nested PCR, respectively. Chi-square, Fisher's test, and binary logistic regression were used for data analysis. A percentage of 61.3 % of Alzheimer's patients and 62.6 % of healthy volunteers were positive for anti-Toxoplasma IgG but all participants were negative for anti-Toxoplasma IgM. There were no significant differences between Alzheimer's patients with their controls in terms of anti-Toxoplasma IgG antibody (P = 0.5). Due to lack of positive IgM sample, results of the molecular methods were negative by GRA6 and SAG2 fragments amplification. This result shows that, infection with T. gondii cannot be considered as a risk factor for etiology and developing Alzheimer's disease.
This study aimed to investigate the effects of diphenyl diselenide (PhSe)2to treat mice experimentally infected by Toxoplasma gondii on seric biomarkers of cardiac function (creatine kinase, creatine kinase MB, troponin, and myoglobin), and lactate dehydrogenase, as well as to evaluate the enzymatic activity of creatine kinase (CK) and adenylate kinase (AK) in heart tissue. For the study, 40 female mice were divided into four groups of 10 animals each: the group A (uninfected and untreated), the group B (uninfected and treated), the group C (infected and untreated) and the group D (infected and treated). The inoculation was performed with 50 cysts of T. gondii (ME-49 strain). Mice from groups B and D were treated at days 1 and 20 post-infection (PI) with 5 μmol kg-1of (PhSe)2subcutaneously. On day 30 PI, the mice were anesthetized and euthanized for blood and heart collection. As a result, it was observed a decrease in AK activity (P < 0.01) in the heart samples of groups C and D compared to the group A. Cardiac CK increased in the group C compared to the group A (P < 0.01). CK levels increased in infected mice (the group C) compared to other groups (A and D). Regarding CK-MB level, there was a decrease in the group D compared to the group B, without statistical difference compared to control groups (A and C). It was observed an increase on myoglobin in groups C and D, differently of troponin, which did not show statistical difference (P < 0.05) between groups. Mice from the group C showed an increase in lactate dehydrogenase (LDH) levels compared to other groups (A, B, and D). Histopathological evaluation of heart samples revealed necrosis, hemorrhagic regions and inflammatory infiltrates in mice from the Group C, differently from the group D where animals showed only inflammatory infiltrates. Based on these results we conclude that the (PhSe)2had a protective effect on the heart in experimental toxoplasmosis by modulating tissue and seric CK activity, and avoiding an increase on seric LDH levels, probably due to the antioxidant effect of this compound.
Exposure to the neurotropic parasite, Toxoplasma gondii, causes significant brain and behavioral anomalies in humans and other mammals. Understanding the cellular mechanisms of T. gondii-generated brain pathologies would aid the advancement of novel strategies to reduce disease. Complement factor C1q is part of a classic immune pathway that functions peripherally to tag and remove infectious agents and cellular debris from circulation. In the developing and adult brain, C1q modifies neuronal architecture through synapse marking and pruning. T. gondii exposure and complement activation have both been implicated in the development of complex brain disorders such as schizophrenia. Thus, it seems logical that mechanistically, the physiological pathways associated with these two factors are connected. We employed a rodent model of chronic infection to investigate the extent to which cyst presence in the brain triggers activation of cerebral C1q. Compared to uninfected mice, cortical C1q was highly expressed at both the RNA and protein levels in infected animals bearing a high cyst burden. In these mice, C1q protein localized to cytoplasm, adjacent to GFAP-labeled astrocytes, near degenerating cysts, and in punctate patterns along processes. In summary,our results demonstrated an upregulation of cerebral C1q in response to latent T. gondii infection. Our data preliminarily suggest that this complement activity may aid in the clearance of this parasite from the CNS and in so doing, have consequences for the connectivity of neighboring cells and synapses.
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 NTPase I and II were not essential for tachyzoite growthin vitroor virulence in mice. Our study reveals that whileT. gondiiNTPases are not essential for immune evasion, they can affect ATP-dependent reporters. Importantly, this limitation was overcome using an ATP independent Gaussia luciferase (GLUC), which provides a more appropriate reporter for use withT. gondiiinfection studies.
The parasite Toxoplasma gondii causes infections all around the world. Infections with T. gondii are systemic and the parasite can persist in the heart muscle. Very little is known about the impact of T. gondii on patients with heart disease. We determined the association between T. gondii exposure and patients suffering from heart diseases attending in a public hospital in Durango, Mexico; the association of T. gondii exposure with socio-demographic, behavioral, and clinical characteristics of these patients was also investigated.
Through a case-control study, we examined the seroprevalence of anti-T. gondii IgG and IgM antibodies in 400 patients with heart diseases and 400 age- and gender-matched controls using enzyme-linked immunoassays. In addition, we analyzed the association of patient characteristics as determined by a standardized questionnaire with T. gondii exposure by bivariate and multivariate analyses.
Fifty-five (13.8%) of 400 patients and 32 (8.0%) of 400 controls had anti-T. gondii IgG antibodies (odds ratio (OR) = 1.83; 95% confidence interval (CI): 1.15 - 2.90; P = 0.01). High anti-T. gondii IgG levels (> 150 IU/mL) were found in 28 (50.9%) of the 55 positive cases and in 14 (43.8%) of the 32 positive controls (P = 0.51). Anti-T. gondii IgM antibodies were found in 13 (23.6%) of the 55 anti-T. gondii IgG positive patients and in 19 (59.4%) of 32 anti-T. gondii IgG positive controls (OR = 0.21; 95% CI: 0.08 - 0.54; P = 0.0008). Multivariate analysis showed that T. gondii exposure was positively associated with being born out of Durango State (OR = 2.93; 95% CI: 1.40 - 6.13; P = 0.004), and with consumption of alcohol (OR = 2.04; 95% CI: 1.01 - 4.12; P = 0.04).
Results obtained in this study indicate that T. gondii infection is associated with heart disease, and suggest that heart disease might be related with a chronic infection. This is the first report of an association of T. gondii exposure with alcohol consumption in this population. Results warrant for further research to determine the epidemiological impact of T. gondii exposure on patients with heart diseases. Risk factors associated with T. gondii exposure are critical to design future prevention strategies against T. gondii exposure.
Toxoplasma gondii is one of the most widespread parasites in humans and can cause severe illness in immunocompromised individuals. However, its role in healthy people is probably under-appreciated. The complex epidemiology of this protozoan recognizes several infection routes but consumption of contaminated food is likely to be the predominant one. Among food, consumption of raw and undercooked meat is a relevant route of transmission, but the role of different meat producing animal species and meats thereof is controversial.
The aim of the present work is to summarize and analyse literature data reporting prevalence estimates of T. gondii in meat animals/meats.
We searched Medline, Web of Science, Science Direct (last update 31/03/2015).
Relevant papers should report data from primary studies dealing with the prevalence of T. gondii in meat from livestock species as obtained through direct detection methods. Meta-analysis and meta-regression were performed.
Of 1915 papers screened, 69 papers were included, dealing mainly with cattle, pigs and sheep. Pooled prevalences, based on random-effect models, were 2.6% (CI95 [0.5-5.8]) for cattle, 12.3% (CI95 [7.6-17.8]) for pigs and 14.7% (CI95 [8.9-21.5]) for sheep. Due to the high heterogeneity observed, univariable and multivariable meta-regression models were fitted showing that the geographic area for cattle (p = 0.032), the farming type for pigs (p = 0.0004) and the sample composition for sheep (p = 0.03) had significant effects on the prevalences of Toxoplasma detected/estimated. Moreover, the role of different animal species was dependent on the geographic location of animals' origin.
Limitations were due mainly to a possible publication bias.
CONCLUSIONS AND IMPLICATIONS:
The present work confirms the role of meat, including beef, as T. gondii sources, and highlights the need for a control system for this parasite to be implemented along the meat production chain. Moreover, consumer knowledge should be strengthened in order to reduce the impact of disease.
Membrane trafficking pathways play critical roles in Apicomplexa, a phylum of protozoan parasites that cause life-threatening diseases worldwide. Here we report the first retromer-trafficking interactome in Toxoplasma gondii. This retromer complex includes a trimer Vps35-Vps26-Vps29 core complex that serves as a hub for the endosome-like compartment and parasite-specific proteins. Conditional ablation of TgVps35 reveals that the retromer complex is crucial for the biogenesis of secretory organelles and for maintaining parasite morphology. We identify TgHP12 as a parasite-specific and retromer-associated protein with functions unrelated to secretory organelle formation. Furthermore, the major facilitator superfamily homologue named TgHP03, which is a multiple spanning and ligand transmembrane transporter, is maintained at the parasite membrane by retromer-mediated endocytic recycling. Thus, our findings highlight that both evolutionarily conserved and unconventional proteins act in concert in T. gondii by controlling retrograde transport that is essential for parasite integrity and host infection.
As an obligate intracellular protozoan, Toxoplasma gondii is a successful pathogen infecting a variety of animals, including humans. As an adhesin involving in host invasion, the micronemal protein MIC3 plays important roles in host cell attachment, as well as modulation of host EGFR signaling cascade. However, the specific host proteins that interact with MIC3 are unknown and the identification of such proteins will increase our understanding of how MIC3 exerts its functions. This study was designed to identify host proteins interacting with MIC3 by yeast two-hybrid screens. Using MIC3 as bait, a library expressing mouse proteins was screened, uncovering eight mouse proteins that showed positive interactions with MIC3. Two of which, spermatogenesis-associated protein 3 (Spata3) and dickkopf-related protein 2 (Dkk2), were further confirmed to interact with MIC3 by additional protein-protein interaction tests. The results also revealed that the tandem repeat EGF domains of MIC3 were critical in mediating the interactions with the identified host proteins. This is the first study to show that MIC3 interacts with host proteins that are involved in reproduction, growth, and development. The results will provide a clearer understanding of the functions of adhesion-associated micronemal proteins in T. gondii.
Toxoplasma gondii (T. gondii), a protozoan parasite that persists in host tissues, including brain, has been associated with several psychiatric disorders and with suicidal behavior. We sought to test the hypothesis that latent T. gondii infection, as manifest by circulating immunoglobulin G (IgG) antibodies to T. gondii, is associated with both categorical and dimensional measures of aggression.
IgG antibodies to T. gondii were collected between 1991 and 2008 from 358 adult subjects with DSM-5 intermittent explosive disorder (IED), non-IED psychiatric disorders (psychiatric controls), or no evidence of any psychiatric diagnosis (healthy controls). Assessments of aggression, anger, and impulsivity, as well as state/trait anger, depression, and anxiety were completed. T. gondii seropositive status (IgG > 12 IU) was the primary outcome measure for this study.
T. gondii seropositive status (IgG > 12 IU) was associated with higher aggression (P = .022) and impulsivity (P = .05) scores. When both aggression and impulsivity scores were controlled for, however, only aggression scores were higher in seropositive subjects (P = .011). In addition, T. gondii seropositive status and marginal mean ± SE aggression scores increased from healthy controls (9.1% and -0.66 ± 0.05) to psychiatric controls (16.7% and -0.27 ± 0.05) to subjects with IED (21.8% and 1.15 ± 0.06; P ≤ .05). These findings were not accounted for by the presence of other syndromal/personality disorders or by states or traits related to depressed or anxious moods.
These data are consistent with previous studies suggesting a relationship between T. gondii and self-directed aggression (ie, suicidal behavior) and further add to the biological complexity of impulsive aggression both from a categorical and a dimensional perspective.
Toxoplasma gondii, an intracellular protozoan parasite, has a striking predilection for infecting the Central Nervous System and has been linked to an increased incidence of a number of psychiatric diseases. Several in vitro and in vivo studies have shown that T. gondii infection can affect the structure, bioenergetics and function of brain cells, and alters several host cell processes, including dopaminergic, tryptophan-kynurenine, GABAergic, AKT1, Jak/STAT, and vasopressinergic pathways. These mechanisms underlying the neuropathology of latent toxoplasmosis seem to operate also in schizophrenia, supporting the link between the two disorders. Better understanding of the intricate parasite-neuroglial communications holds the key to unlocking the mystery of T. gondii-mediated schizophrenia and offers substantial prospects for the development of disease-modifying therapies.