The centrosome serves as a central hub coordinating multiple cellular events in eukaryotes. A recent study in Toxoplasma gondii revealed a unique bipartite structure of the centrosome, which coordinates the nuclear cycle (S-phase and mitosis) and budding cycle (cytokinesis) of the parasite, and deciphers the principle behind flexible apicomplexan cell division modes.
The rise of the AIDS epidemic made the requirement for T cells in our continuous protection from pathogens critically apparent. The striking frequency with which AIDS patients exhibited profound neurological pathologies brought attention to many chronic infections that are latent within the immune-privileged CNS. One of the most common lethal opportunistic infections of these patients was with the protozoan parasite, Toxoplasma gondii. Reactivation of Toxoplasma cysts within the brain causes massive tissue destruction evidenced as multiple ring-enhancing lesions on MRI and is called toxoplasmic encephalitis (TE). TE is not limited to AIDS patients, but rather is a risk for all severely immunocompromised patients, including recipients of chemotherapy or transplant recipients. The lessons learned from these patient populations are supported by T cell depletion studies in mice. Such experiments have demonstrated that CD4+ and CD8+ T cells are required for protection against TE. Although it is clear that these T cell subsets work synergistically to fight infection, much evidence has been generated that suggests CD8+ T cells play a dominant role in protection during chronic toxoplasmosis. In other models of CNS inflammation, such as intracerebral infection with LCMV and experimental autoimmune encephalomyelitis (EAE), infiltration of T cells into the brain is harmful and even fatal. In the brain of the immunocompetent host, the well-regulated T cell response to T. gondii is therefore an ideal model to understand a controlled inflammatory response to CNS infection. This review will examine our current understanding of CD8+ T cells in the CNS during T. gondii infection in regards to the (1) mechanisms governing entry into the brain, (2) cues that dictate behavior within the brain, and (3) the functional and phenotypic properties exhibited by these cells.
Infection of C57BL/6J mice with the parasite Toxoplasma gondii triggers a powerful Th1 immune response that is detrimental to the host. During acute infection, a reduction in CD4+Foxp3+ regulatory T cells (Treg) has been reported. We studied the role of Treg during T. gondii infection by adoptive transfer of cells purified from transgenic Foxp3EGFP mice to infected wild type animals. We found a less severe weight loss, a significant delayed mortality in infected Treg-transferred mice, and reduced pathology of the small intestine that were associated with lower IFN-γ and TNF-α levels. Nevertheless, higher cyst number and parasite load in brain were observed in these mice. Treg-transferred infected mice showed reduced levels of both IFN-γ and TNF-α in sera. A reduced number of CD4+ T cells producing IFN-γ was detected in these mice, while IL-2 producing CD4+ T cells were restored to levels nearly similar to uninfected mice. CD25 and CD69 expression of CD4+ T cells were also down modulated. Our data show that the low Treg cell number are insufficient to modulate the activation of CD4+ T cells and the production of high levels of IFN-γ. Thus, a delicate balance between an optimal immune response and its modulation by Treg cells must exist.
In this issue of Molecular Microbiology Rugarabamu and colleagues (Rugarabamu et al., 2015) investigate the role of rhomboid proteases responsible for adhesin shedding during invasion of the Apicomplexan parasite Toxoplasma gondii. This study, together with several other recent publications, raises new questions about the function of these rhomboids in Toxoplasma, whilst also strongly arguing against other recently proposed roles for these proteases.
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Apicomplexan parasites include some of the most prevalent and deadly human pathogens. Novel antiparasitic drugs are urgently needed. Synthesis and metabolism of isoprenoids may present multiple targets for therapeutic intervention. The apicoplast-localized methylerythritol phosphate (MEP) pathway for isoprenoid precursor biosynthesis is distinct from the mevalonate (MVA) pathway used by the mammalian host, and this pathway is apparently essential in most Apicomplexa. In this review, we discuss the current field of research on production and metabolic fates of isoprenoids in apicomplexan parasites, including the acquisition of host isoprenoid precursors and downstream products. We describe recent work identifying the first MEP pathway regulator in apicomplexan parasites, and introduce several promising areas for ongoing research into this well-validated antiparasitic target.
POSTDOCTORAL POSITION available to
investigate host-pathogen interactions using the protozoan parasite Toxoplasma gondii as a model system. Related
to the malaria parasite, Plasmodium, Toxoplasma causes life-threatening
infection in immunocompromised patients and has been linked to altering the behavior
of its host. We are investigating cellular changes that occur in both the parasite
and its host that are critical to pathogenesis.
requires a Ph.D., expertise in molecular biology, neuroscience, or cell signaling,
and excellent communication skills (speaking and writing English). Experience
in microbiology/parasitology is a plus, but not required. Submit CV, project
plan (half page), and contact information for three references to Dr. Bill
Sullivan (email@example.com). Applicants that
fail to include a brief description of project ideas will not be considered.
lab is part of the Intracellular Pathogens Group at IU, which meets regularly
to foster innovation and collaboration. Visit www.sullivanlab.com for more information.
in downtown Indianapolis, Indiana University School of Medicine (IUSM) is the second largest medical school in the US and boasts an outstanding intellectual atmosphere
and core facilities. IUSM was nationally ranked in the Top 30 Best Places to
Work for Postdocs. IUSM is an equal opportunity employer.
The atypical IκB family member Bcl-3 associates with p50/NF-κB1 or p52/NF-κB2 homodimers in nuclei, thereby either positively or negatively modulating transcription in a context-dependent manner. Previously we reported that Bcl-3 was critical for host resistance to Toxoplasma gondii. Bcl-3-deficient mice succumbed within 3-5 weeks after infection, correlating with an apparently impaired Th1-type adaptive immune response. However in which cell type(s) Bcl-3 functioned to assure resistance remained unknown. We now show that Bcl-3 expression in dendritic cells is required to generate a protective Th1-type immune response and confer resistance to T.gondii. Surprisingly, mice lacking Bcl-3 in dendritic cells were as susceptible as mice globally deficient for Bcl-3. Furthermore, early innate defenses were not compromised by the absence of Bcl-3, as initial production of IL-12 by dendritic cells and IFN-γ by NK cells were preserved. However, subsequent production of IFN-γ by CD4+ and CD8+ T cells was compromised when dendritic cells lacked Bcl-3, and these mice succumbed at a time when T cell-mediated IFN-γ production was essential for host resistance. These findings demonstrate that Bcl-3 is required in dendritic cells to prime protective T-cell-mediated immunity to T.gondii. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Adaptive Immunity, Bcl-3; Dendritic Cells; IFN-γ; T cells; T.gondii
Toxoplasma gondii infection has been associated with psychiatric diseases. However, there is no information about the link between this infection and patients with mental and behavioral disorders due to psychoactive substance use.
We performed a case-control study with 149 psychiatric patients suffering from mental and behavioral disorders due to psychoactive substance use and 149 age- and gender-matched control subjects of the general population. We searched for anti-T. gondii IgG and IgM antibodies in the sera of participants by means of commercially available enzyme-linked immunoassays. Seroprevalence association with socio-demographic, clinical and behavioral characteristics in psychiatric patients was also investigated.
Anti-T. gondii IgG antibodies were present in 15 (10.1%) of 149 cases and in 14 (9.4%) of 149 controls (P = 1.0). Anti-T. gondii IgM antibodies were found in 11 (7.4%) of the 149 cases and in 16 (10.7%) of the 149 controls (P = 0.31). No association of T. gondii exposure with socio-demographic characteristics of patients was found. Multivariate analysis of clinical and behavioral characteristics of cases showed that T. gondii seropositivity was positively associated with consumption of opossum meat (OR = 10.78; 95% CI: 2.16-53.81; P = 0.003) and soil flooring at home (OR = 11.15; 95% CI: 1.58-78.92; P = 0.01), and negatively associated with suicidal ideation (OR = 0.17; 95% CI: 0.05-0.64; P = 0.008).
Mental and behavioral disorders due to psychoactive substance use do not appear to represent an increased risk for T. gondii exposure. This is the first report of a positive association of T. gondii exposure with consumption of opossum meat. Further studies to elucidate the role of T. gondii infection in suicidal ideation and behavior are needed to develop optimal strategies for the prevention of infection with T. gondii.
To perform a meta-analysis on studies reporting prevalence of Toxoplasma gondii (T. gondii) infection in any psychiatric disorder compared with healthy controls. Our secondary objective was to analyze factors possibly moderating heterogeneity.
A systematic search was performed to identify studies into T. gondii infection for all major psychiatric disorders versus healthy controls. Methodological quality, publication bias, and possible moderators were assessed.
A total of 2866 citations were retrieved and 50 studies finally included. Significant odds ratios (ORs) with IgG antibodies were found in schizophrenia (OR 1.81, P < 0.00001), bipolar disorder (OR 1.52, P = 0.02), obsessive-compulsive disorder (OR 3.4, P < 0.001), and addiction (OR 1.91, P < 0.00001), but not for major depression (OR 1.21, P = 0.28). Exploration of the association between T. gondii and schizophrenia yielded a significant effect of seropositivity before onset and serointensity, but not IgM antibodies or gender. The amplitude of the OR was influenced by region and general seroprevalence. Moderators together accounted for 56% of the observed variance in study effects. After controlling for publication bias, the adjusted OR (1.43) in schizophrenia remained significant.
Toxoplasma gondii is an important protozoan parasite that infects all warm-blooded animals and causes opportunistic infections in immuno-compromised humans. Its closest relative, Neospora caninum, is an important veterinary pathogen that causes spontaneous abortion in livestock. Comparative genomics of these two closely related coccidians has been of particular interest to identify genes that contribute to varied host cell specificity and disease. Here, we describe a manual evaluation of these genomes based on strand-specific RNA sequencing and shotgun proteomics from the invasive tachyzoite stages of these two parasites. We have corrected predicted structures of over one third of the previously annotated gene models and have annotated untranslated regions (UTRs) in over half of the predicted protein-coding genes. We observe distinctly long UTRs in both the organisms, almost four times longer than other model eukaryotes. We have also identified a putative set of cis-natural antisense transcripts (cis-NATs) and long intergenic non-coding RNAs (lincRNAs). We have significantly improved the annotation quality in these genomes that would serve as a manually curated dataset for Toxoplasma and Neospora research communities.
Toxoplasma gondii induces polarization of mouse macrophages, including both classically activated macrophage (M1) and alternatively activated macrophage (M2) in a genotype-related manner. Here we presented a novel result that the Wh6 strain with type Chinese 1, which is predominantly prevalent in China, induced Arg1 expression in a STAT6 dependent manner in primary rat peritoneal macrophages, compared to the PRU stain with typeⅡ that elicited a high expression of Arg1 in a C/EBPβ dependent manner. Additional experiment revealed that dexamethasone inhibited Arg1 expression in rat macrophage in both contexts. Our data suggested that Arg1 expression, which is abundant in polarized M2 cells, is associated with strain/genotype difference in varying pathways.
are currently looking for four postdoctoral scholars to work on three different
NIH-funded projects investigating host-parasite interactions. We are studying
the innate and adaptive immune response to Toxoplasma and, in turn, how Toxoplasma
modulates the host cell. We are particularly interested in individual differences
in host susceptibility to Toxoplasma and Toxoplasma strain
differences in interacting with the host. The Vet School at UC Davis is ranked
as the best in the country and our location in the Vet School will allow us to
investigate Toxoplasma proteins that play a role in its sexual cycle in
cats and to perform genetic crosses to identify the molecular basis for
phenotypic strain differences. More information can be found on our
are looking for team players that are excited about studying host-parasite
interactions and have excellent communication skills. Previous experience with
molecular biology, biochemistry, immunology, genetics or computational skills
is a plus.
Davis is located in the town of Davis, which is ranked as one of the best towns
to live in in the nation. Davis is close to San Francisco, Sacramento, the
Napa/Sonoma wine country and the Lake Tahoe ski area. UC Davis offers excellent
benefits and multiple opportunities for professional development for postdocs
candidates can submit a current C.V. and names of three references to: Dr.
Jeroen Saeij (firstname.lastname@example.org), Associate
Professor of Biology.
Proteomics data can supplement genome annotation efforts, for example being used to confirm gene models or correct gene annotation errors. Here we present a large scale proteogenomics study of two important apicomplexan pathogens: Toxoplasma gondii and Neospora caninum. We queried proteomics data against a panel of official and alternate gene models generated directly from RNASeq data, using several newly generated and some previously published MS data sets for this meta-analysis. We identified a total of 201996 and 39953 peptide-spectrum matches (PSMs) for T. gondii and N. caninum respectively at a 1% peptide false discovery rate threshold. This equated to the identification of 30494 distinct peptide sequences and 2921 proteins (matches to official gene models) for T. gondii, and 8911 peptides / 1273 proteins for N. caninum following stringent protein-level thresholding. We have also identified 289 and 140 loci for T. gondii and N. caninum respectively which mapped to RNA-Seq derived gene models used in our analysis and apparently absent from the official annotation (release 10 from EuPathDB) of these species. We present several examples in our study where the RNA-Seq evidence can help in correction of the current gene model and can help in discovery of potential new genes. The findings of this study have been integrated into the EuPathDB. The data have been deposited to the ProteomeXchange with identifiers PXD000297and PXD000298. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Gene annotation; MS/MS; N. caninum; OMSSA; Open-source; Proteogenomics; T. gondii; X!Tandem
Toxoplasma gondii, the causative agent of toxoplasmosis, is an obligate intracellular protozoan pathogen. The parasite invades and replicates within virtually any warm blooded vertebrate cell type. During parasite invasion of a host cell, the parasite creates a parasitophorous vacuole (PV) that originates from the host cell membrane independent of phagocytosis within which the parasite replicates. While IFN-dependent-innate and cell mediated immunity is important for eventual control of infection, innate immune cells, including neutrophils, monocytes and dendritic cells, can also serve as vehicles for systemic dissemination of the parasite early in infection. An approach is described that utilizes the host innate immune response, in this case macrophages, in a forward genetic screen to identify parasite mutants with a fitness defect in infected macrophages following activation but normal invasion and replication in naïve macrophages. Thus, the screen isolates parasite mutants that have a specific defect in their ability to resist the effects of macrophage activation. The paper describes two broad phenotypes of mutant parasites following activation of infected macrophages: parasite stasis versus parasite degradation, often in amorphous vacuoles. The parasite mutants are then analyzed to identify the responsible parasite genes specifically important for resistance to induced mediators of cell autonomous immunity. The paper presents a general approach for the forward genetics screen that, in theory, can be modified to target parasite genes important for resistance to specific antimicrobial mediators. It also describes an approach to evaluate the specific macrophage antimicrobial mediators to which the parasite mutant is susceptible. Activation of infected macrophages can also promote parasite differentiation from the tachyzoite to bradyzoite stage that maintains chronic infection. Therefore, methodology is presented to evaluate the importance of the identified parasite gene to establishment of chronic infection.
Toxoplasma gondii is an intracellular parasite widely distributed in nature. Infection is asymptomatic in immunocompetent individuals; however, various clinical manifestations may occur in immunocompromised individuals. Although there are medications for the treatment of toxoplasmosis, such as pyrimethamine and sulfonamide, they cannot always be used due to adverse reactions or to therapeutic failures related to intolerance or malabsorption of drugs and to parasite drug resistance. In recent years, the search for new antimicrobial agents derived from plants has intensified because a quarter of synthetic drugs that are currently prescribed have been isolated from a plant source, demonstrating that natural products are important in the development of new drugs. A systematic literature search was conducted to evaluate the use of natural products as an alternative for the treatment of T. gondii infection. The search was conducted for the 2000-2014 period in Science Direct, Scopus, PubMed, EMBASE, and SciELO databases, using the following MeSH terms: anti-Toxoplasma activity, toxoplasma AND natural products, toxoplasma AND plant extracts. Ethnobotanical and experimental evidence (in vitro/in vivo) was found supporting the use of natural products as a source for the discovery of new therapies against T. gondii.
Latent infection with Toxoplasma gondii is common in humans (approximately 30% of the global population) and is a significant risk factor for schizophrenia. Since prevalence of T. gondii infection is far greater than prevalence of schizophrenia (0.5-1%), genetic risk factors are likely also necessary to contribute to schizophrenia. To test this concept in an animal model, Nurr1-null heterozygous (+/-) mice and wild-type (+/+) mice were evaluate using an emergence test, activity in an open field and with a novel object, response to bobcat urine and prepulse inhibition of the acoustic startle response (PPI) prior to and 6 weeks after infection with T. gondii. In the emergence test, T. gondii infection significantly decreased the amount of time spent in the cylinder. Toxoplasma gondii infection significantly elevated open field activity in both +/+ and +/- mice but this increase was significantly exacerbated in +/- mice. T. gondii infection reduced PPI in male +/- mice but this was not statistically significant. Aversion to bobcat urine was abolished by T. gondii infection in +/+ mice. In female +/- mice, aversion to bobcat urine remained after T. gondii infection while the male +/- mice showed no aversion to bobcat urine. Antibody titers of infected mice were a critical variable associated with changes in open field activity, such that an inverted U shaped relationship existed between antibody titers and the percent change in open field activity with a significant increase in activity at low and medium antibody titers but no effect at high antibody titers. These data demonstrate that the Nurr1 +/- genotype predisposes mice to T. gondii-induced alterations in behaviors that involve dopamine neurotransmission and are associated with symptoms of schizophrenia. We propose that these alterations in murine behavior were due to further exacerbation of the altered dopamine neurotransmission in Nurr1 +/- mice.
Uninfected female rats (Rattus novergicus) exhibit greater attraction to the males infected with protozoan parasite Toxoplasma gondii. This phenomenon is contrary to the aversion towards infected males observed in multitude of other host-parasite associations. In this report, we describe a proximate mechanism for this anomaly. We demonstrate that T. gondii infection enhances hepatic production and urinary excretion of α2u-globulins in rats. We further demonstrate that α2u-globulins are sufficient to recapitulate male sexual attractiveness akin to effects of the infection. This manipulation possibly results in greater horizontal transmission of this parasite between the infected male and the uninfected female. It supports the notion that in some evolutionary niches parasites can alter host sexual signaling, likely leading to an increased rate of sexual transmission.