Friday, February 24, 2012

Novel N-Benzoyl-2-hydroxybenzamide Disrupts Unique Parasite Secretory Pathway

Antimicrob Agents Chemother. 2012 Feb 21. [Epub ahead of print]

Novel N-Benzoyl-2-hydroxybenzamide Disrupts Unique Parasite Secretory Pathway.

Fomovska A, Huang Q, El Bissati K, Mui EJ, Witola WH, Cheng G, Zhou Y, Sommerville C, Roberts CW, Bettis S, Prigge ST, Afanador GA, Hickman MR, Lee PJ, Leed SE, Auschwitz JM, Pieroni M, Stec J, Muench SP, Rice DW, Kozikowski AP, McLeod R.

Department of Ophthalmology and Visual Sciences, Pediatrics (Infectious Diseases), Committees on Genetics, Immunology, and Molecular Medicine, Institute of Genomics and Systems Biology, and The College, The University of Chicago, Chicago, Illinois 60637, United States.

Toxoplasma gondii is a protozoan parasite that can damage the human brain and eyes. There are no curative medicines. Herein, we describe our discovery of N-benzoyl-2-hydroxybenzamides as a class of compounds effective in low nanomolar range against T. gondii in vitro and in vivo. Our lead compound QQ-437 displays robust activity against the parasite, useful as a new scaffold for development of novel and improved inhibitors of T. gondii. Our genome-wide investigations reveal a specific mechanism of resistance to N-benzoyl-2-hydroxybenzamides mediated by Adaptin-3β, a large protein from the secretory protein complex. N-benzoyl-2-hydroxybenzamide -resistant clones have alterations of their secretory pathway which traffics proteins to micronemes, rhoptries, dense granules and acidocalcisome/Plant-Like Vacuole (PLV). N-benzoyl-2-hydroxybenzamide treatment also alters micronemes, rhoptries, the contents of dense granules and most markedly acidocalcisomes/PLV. Furthermore, QQ-437 is active against chloroquine-resistant Plasmodium falciparum. Our studies reveal a novel class of compounds that disrupts a unique secretory pathway of T. gondii, with potential to be used as scaffolds to discover improved compounds to treat the devastating diseases caused by apicomplexan parasites.

PMID: 22354304 [PubMed - as supplied by publisher]

Wednesday, February 22, 2012

Transcriptomic analysis of toxoplasma development reveals many novel functions and structures specific to sporozoites and oocysts

PLoS One. 2012;7(2):e29998. Epub 2012 Feb 13.

Transcriptomic analysis of toxoplasma development reveals many novel functions and structures specific to sporozoites and oocysts.

Fritz HM, Buchholz KR, Chen X, Durbin-Johnson B, Rocke DM, Conrad PA, Boothroyd JC.

Department of Pathology, Microbiology and Immunology, University of California Davis, School of Veterinary Medicine, Davis, California, United States of America.

Sexual reproduction of Toxoplasma gondii occurs exclusively within enterocytes of the definitive felid host. The resulting immature oocysts are excreted into the environment during defecation, where in the days following, they undergo a complex developmental process. Within each oocyst, this culminates in the generation of two sporocysts, each containing 4 sporozoites. A single felid host is capable of shedding millions of oocysts, which can survive for years in the environment, are resistant to most methods of microbial inactivation during water-treatment and are capable of producing infection in warm-blooded hosts at doses as low as 1-10 ingested oocysts. Despite its extremely interesting developmental biology and crucial role in initiating an infection, almost nothing is known about the oocyst stage beyond morphological descriptions. Here, we present a complete transcriptomic analysis of the oocyst from beginning to end of its development. In addition, and to identify genes whose expression is unique to this developmental form, we compared the transcriptomes of developing oocysts with those of in vitro-derived tachyzoites and in vivo-derived bradyzoites. Our results reveal many genes whose expression is specifically up- or down-regulated in different developmental stages, including many genes that are likely critical to oocyst development, wall formation, resistance to environmental destruction and sporozoite infectivity. Of special note is the up-regulation of genes that appear "off" in tachyzoites and bradyzoites but that encode homologues of proteins known to serve key functions in those asexual stages, including a novel pairing of sporozoite-specific paralogues of AMA1 and RON2, two proteins that have recently been shown to form a crucial bridge during tachyzoite invasion of host cells. This work provides the first in-depth insight into the development and functioning of one of the most important but least studied stages in the Toxoplasma life cycle.

PMID: 22347997 [PubMed - in process]

Identification of potential apicoplast associated therapeutic targets in human and animal pathogen Toxoplasma gondii ME49

Bioinformation. 2011;7(8):379-83. Epub 2011 Dec 21.

Identification of potential apicoplast associated therapeutic targets in human and animal pathogen Toxoplasma gondii ME49.

Saremy S, Boroujeni ME, Bhattacharjee B, Mittal V, Chatterjee J.

Toxoplasma gondii ME49 is an obligatory intracellular apicomplexa parasite that causes toxoplasmosis in humans, domesticated and wild animals. Waterborne outbreaks of acute toxoplasmosis worldwide reinforce the transmission of Toxoplasma gondii ME49 to humans through contaminated water and may have a greater epidemiological impact than previously believed. In the quest for drug and vaccine target identification subtractive genomics involving subtraction between the host and pathogen genome has been implemented for enlisting essential pathogen specific proteins. Using this approach, our analysis on both human and Toxoplasma gondii ME49 reveals that out of 7987 protein coding sequences of the pathogen, 950 represent essential non human-homologous proteins. Subcellular localization prediction & comparative-biochemical pathway analysis of these essential proteins gives a list of apicoplast-associated proteins having unique pathogen-specific metabolic pathway. These apicoplast-associated enzymes involved in fatty acid biosynthesis pathway of Toxoplasma gondii ME49, may be used as potential drug targets, as the pathway is vital for the protozoan's survival. Structure prediction of drug target proteins was done using fold based recognition method. Screening of the functional inhibitors against these novel targets may result in discovery of novel therapeutic compounds that can be effective against Toxoplasma gondii ME49. ABBREVIATIONS: DEG - Database of Essential Gene, KEGG - Kyoto Encyclopaedia of Genes and Genomes, KAAS - KEGG Automated Annotation Server, PFP - Protein Function Prediction, COG - Cluster of Orthologous Genes.

PMID: 22347778 [PubMed - in process]

A Genetic Screen to Isolate Toxoplasma gondii Host-cell Egress Mutants

J Vis Exp. 2012 Feb 8;(60). pii: 3807. doi: 10.3791/3807.

A Genetic Screen to Isolate Toxoplasma gondii Host-cell Egress Mutants.

Coleman BI, Gubbels MJ.

Department of Biology, Boston College.

The widespread, obligate intracellular, protozoan parasite Toxoplasma gondii causes opportunistic disease in immuno-compromised patients and causes birth defects upon congenital infection. The lytic replication cycle is characterized by three stages: 1. active invasion of a nucleated host cell; 2. replication inside the host cell; 3. active egress from the host cell. The mechanism of egress is increasingly being appreciated as a unique, highly regulated process, which is still poorly understood at the molecular level. The signaling pathways underlying egress have been characterized through the use of pharmacological agents acting on different aspects of the pathways(1-5). As such, several independent triggers of egress have been identified which all converge on the release of intracellular Ca(2+), a signal that is also critical for host cell invasion(6-8). This insight informed a candidate gene approach which led to the identification of plant like calcium dependent protein kinase (CDPK) involved in egress(9). In addition, several recent breakthroughs in understanding egress have been made using (chemical) genetic approaches(10-12). To combine the wealth of pharmacological information with the increasing genetic accessibility of Toxoplasma we recently established a screen permitting the enrichment for parasite mutants with a defect in host cell egress(13). Although chemical mutagenesis using N-ethyl-N-nitrosourea (ENU) or ethyl methanesulfonate (EMS) has been used for decades in the study of Toxoplasma biology(11,14,15), only recently has genetic mapping of mutations underlying the phenotypes become routine(16-18). Furthermore, by generating temperature-sensitive mutants, essential processes can be dissected and the underlying genes directly identified. These mutants behave as wild-type under the permissive temperature (35 °C), but fail to proliferate at the restrictive temperature (40 °C) as a result of the mutation in question. Here we illustrate a new phenotypic screening method to isolate mutants with a temperature-sensitive egress phenotype(13). The challenge for egress screens is to separate egressed from non-egressed parasites, which is complicated by fast re-invasion and general stickiness of the parasites to host cells. A previously established egress screen was based on a cumbersome series of biotinylation steps to separate intracellular from extracellular parasites(11). This method also did not generate conditional mutants resulting in weak phenotypes. The method described here overcomes the strong attachment of egressing parasites by including a glycan competitor, dextran sulfate (DS), that prevents parasites from sticking to the host cell(19). Moreover, extracellular parasites are specifically killed off by pyrrolidine dithiocarbamate (PDTC), which leaves intracellular parasites unharmed(20). Therefore, with a new phenotypic screen to specifically isolate parasite mutants with defects in induced egress, the power of genetics can now be fully deployed to unravel the molecular mechanisms underlying host cell egress.

PMID: 22349295 [PubMed - in process]

Thursday, February 16, 2012

The Relationship Between Toxoplasma gondii Infection and Mood Disorders in the Third National Health and Nutrition Survey

Biol Psychiatry. 2012 Feb 9. [Epub ahead of print]

The Relationship Between Toxoplasma gondii Infection and Mood Disorders in the Third National Health and Nutrition Survey.

Pearce BD, Kruszon-Moran D, Jones JL.

Department of Epidemiology, Emory University, Atlanta, Georgia.

Toxoplasma gondii (T. gondii) is a neurotropic protozoan parasite that causes persistent infection in humans. A substantial literature suggests that schizophrenia is associated with increased seroprevalence of T. gondii, but a possible link of the parasite with mood disorders has not been as thoroughly investigated.

We examined the association of Toxoplasma-specific immunoglobulin G results with mood disorder outcomes in 7440 respondents from the third National Health and Nutrition Survey, which is a nationally representative sample of the United States noninstitutionalized civilian population. Regression models were adjusted for numerous potential confounders, including tobacco smoking and C-reactive protein levels.

No statistically significant associations were found between T. gondii seroprevalence and a history of major depression (n = 574; adjusted odds ratio [OR]: .8; 95% confidence interval [CI]: .5-1.2), severe major depression (n = 515; adjusted OR: .8; 95% CI: .6-1.2), dysthymia (n = 548; adjusted OR: 1.1; 95% CI: .7-1.8), or dysthymia with comorbid major depression (n = 242, adjusted OR: 1.2; 95% CI: .6-2.4), all p values were > .05, including analysis stratified by gender. However, there was a significant relationship between T. gondii seroprevalence and bipolar disorder type I for respondents in which both manic and major depression symptoms were reported (n = 41; adjusted OR: 2.4; 95% CI: 1.2-4.8; p < .05).

In a population-based sample, T. gondii seroprevalence is not elevated in unipolar mood disorders but is higher in a subset of respondents with a history of bipolar disorder type 1.

Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

PMID: 22325983 [PubMed - as supplied by publisher]

Sunday, February 12, 2012

The Use and Abuse of Haem in Apicomplexan Parasites

Antioxid Redox Signal. 2012 Feb 9. [Epub ahead of print]

The Use and Abuse of Haem in Apicomplexan Parasites.

van Dooren G, Kennedy A, McFadden G.

Australian National University, Research School of Biology, Building 134, Linnaeus Way, Canberra, Australian Capital Territory, Australia, 0200, +61-2-61250665, +61-2-61250313;

Significance. Haem is an essential prosthetic group for most life on Earth. It functions in numerous cellular redox reactions, including in antioxidant defences and at several stages of the electron transport chain in prokaryotes and eukaryotic mitochondria. Haem also functions as a sensor and transport molecule for gases such as oxygen. Haem is a complex organic molecule and can only be synthesised through a multi-enzyme pathway from simpler precursors. Most free-living organisms synthesise their own haem by a broadly conserved metabolic pathway. Parasites are adept at scavenging molecules from their hosts, and haem is no exception. Recent Advances. In this review we examine recent advances in understanding haem usage and acquisition in Apicomplexa, a group of parasites that include the causative agents of malaria, toxoplasmosis and several major parasites of livestock. Critical Issues. Haem is critical to the survival of Apicomplexa, although the functions of haem in these organisms remain poorly understood. Some Apicomplexa likely scavenge haem from their host organisms, while others retain the ability to synthesise haem. Surprisingly, some Apicomplexa may be able to both synthesise and scavenge haem. Several Apicomplexa live in intracellular environments that contain high levels of haem. Since haem is toxic at high concentrations, parasites must carefully regulate intracellular haem levels and develop mechanisms to detoxify excess haem. Indeed, drugs interfering with haem detoxification serve as major antimalarials. Future Directions. Understanding haem requirements and regulation in apicomplexan parasites promises to reveal multiple targets for much-needed therapeutic intervention against these parasites.

PMID: 22320355 [PubMed - as supplied by publisher]

Development of Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitors with Potent Anti-Toxoplasma Activity

J Med Chem. 2012 Feb 9. [Epub ahead of print]

Development of Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitors with Potent Anti-Toxoplasma Activity.

Johnson SM, Murphy RC, Geiger JA, Derocher A, Zhang Z, Ojo K, Larson E, Perera BG, Dale E, He P, Fox A, Mueller N, Merritt EA, Fan E, Reid M, Parsons M, Van Voorhis WC, Maly DJ.

Toxoplasmosis is a disease of prominent health concern that is caused by the protozoan parasite, Toxoplasma gondii. Proliferation of T. gondii is dependent on its ability to invade host cells, which is mediated, in part, by calcium-dependent protein kinase 1 (CDPK1). We have developed ATP competitive inhibitors of TgCDPK1 that block invasion of parasites into host cells, preventing their proliferation. The presence of a unique glycine gatekeeper residue in TgCDPK1 permits selective inhibition of the parasite enzyme over human kinases. These potent TgCDPK1 inhibitors do not inhibit the growth of human cell lines and represent promising candidates as toxoplasmosis therapeutics.

PMID: 22320388 [PubMed - as supplied by publisher]

Thursday, February 09, 2012

Animal Models for Toxoplasma gondii Infection

Curr Protoc Immunol. 2012 Feb;Chapter 19:Unit19.3.

Animal Models for Toxoplasma gondii Infection.

Subauste C.

Case Western Reserve University School of Medicine, Cleveland, Ohio.

Toxoplasma gondii is a protozoan of worldwide distribution. This unit describes murine models of acute T. gondii infection, toxoplasmic encephalitis, and Toxoplasma retinochoroiditis. T. gondii infection in SCID mice allows the study of T cell-independent mechanisms of defense. The uracil auxotroph strain cps1-1 and temperature-sensitive mutant strains of T. gondii allow studies of immunization and adoptive transfer. In vivo study of parasite host-interaction is possible with the use of parasites that express fluorescent proteins and model antigens, plus the use of transgenic mice that express the appropriate T cell receptor and fluorescently labeled leukocytes. Parasites that express bioluminescent markers make it possible to study the dynamics of infection in real time using bioluminescence imaging. Support protocols present methodology for evaluation of progression of infection and immune response to the parasite, the maintenance of T. gondii tissue cysts and tachyzoites, as well as preparation of T. gondii lysate antigens. Curr. Protoc. Immunol. 96:19.3.1-19.3.23. © 2012 by John Wiley & Sons, Inc.

PMID: 22314833 [PubMed - in process]

Toxoplasma gondii invasion and replication in astrocyte primary cultures and astrocytoma cell lines: systematic review of the literature

Parasitol Res. 2012 Feb 8. [Epub ahead of print]

Toxoplasma gondii invasion and replication in astrocyte primary cultures and astrocytoma cell lines: systematic review of the literature.

Contreras-Ochoa CO, Lagunas-Martínez A, Belkind-Gerson J, Correa D.

Centro de Investigación sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública, Av. Universidad no. 655, Colonia Santa María Ahuacatitlán, cerrada los Pinos y Caminera, Cuernavaca, Morelos, CP 62100, Mexico,

Toxoplasma gondii is a cosmopolitan protozoan which infects all homoeothermic species, including humans. This parasite may cause severe neurological problems in congenitally infected newborns or immunocompromised individuals, but it also provokes psychiatric and neurological disorders as well as behavioural and sensory deficit. There is controversy regarding the effect of T. gondii upon astrocytes, which may serve as parasite proliferation recipients or protective immune response activators within the central nervous system. This apparent contradiction could partially be due to the infection degree obtained in the different experiments reported. Thus, we decided to systematically review the in vitro models used to study these phenomena. Fifteen articles from which direct invasion and replication data could be gathered were found. Very heterogeneous results emerged, mainly due to diversity of models in relation to parasite strain (virulence), host species, parasite dose and evaluation times after infection. Also, the results were measured in diverse ways, i.e. some reported percent infected cells, while others informed parasites per vacuole or cell, or parasitic vacuoles per cell. Very few conclusions could be drawn, among them that human astrocytoma cell lines and mouse astrocytes seem more susceptible to infection and less resistant to tachyzoite proliferation than human primary culture astrocytes. The present study supports the need to reanalyse T. gondii astrocyte invasion and replication processes, especially with the use of actual technology, which allows detailed mechanistic studies.

PMID: 22314782 [PubMed - as supplied by publisher]

Toxoplasma gondii immune mapped protein-1 (TgIMP1) is a novel vaccine candidate against toxoplasmosis

Vaccine. 2012 Feb 3. [Epub ahead of print]

Toxoplasma gondii immune mapped protein-1 (TgIMP1) is a novel vaccine candidate against toxoplasmosis.

Cui X, Lei T, Yang D, Hao P, Li B, Liu Q.

Key Laboratory of Animal Epidemiology and Zoonosis, Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.

Immune mapped protein1 (IMP1) is a new protective protein in apicomplexan parasites, and exists in Toxoplasma gondii. In the present study, a DNA vaccine expressing IMP1 of T. gondii was constructed and the immune response induced in BALB/c mice was evaluated. The coding sequence of IMP1 was inserted into the eukaryotic expression vector pcDNA 3.1(+), resulting a recombinant plasmid pcDNA-IMP1, which was used to immunize BALB/c mice intramuscularly. After immunization, the immune response was evaluated using lymphoproliferative assay, and cytokine and antibody measurements. The mice were challenged with tachyzoites of the virulent T. gondii RH strain 14th day after the last immunization to observe the survival time. The results showed that the group immunized with pcDNA-IMP1 developed a high level of specific antibody responses against Escherichia coli expressed recombinant TgIMP1, with high IgG antibody titers, predominance of IgG2a production, a strong lymphoproliferative response, and significant levels of IFN-γ, IL-2, IL-4 and IL-10 production compared with the control groups. These results demonstrate that pcDNA-IMP1 could elicit strong humoral and Th1 immune responses. Immunized mice showed a significantly (15.8±6 days) prolonged survival time compared with control mice, which died within 7 days of challenge infection. These results suggest that IMP1 is a promising vaccine candidate against toxoplasmosis.

Copyright © 2012. Published by Elsevier Ltd.

PMID: 22310204 [PubMed - as supplied by publisher]

PRMT1 methylates the single Argonaute of Toxoplasma gondii and is important for the recruitment of Tudor nuclease for target RNA cleavage

Cell Microbiol. 2012 Feb 6. doi: 10.1111/j.1462-5822.2012.01763.x. [Epub ahead of print]

PRMT1 methylates the single Argonaute of Toxoplasma gondii and is important for the recruitment of Tudor nuclease for target RNA cleavage by antisense guide RNA.

Musiyenko A, Majumdar T, Andrews J, Adams B, Barik S.

Department of Biochemistry and Molecular Biology, University of South Alabama, College of Medicine, 307 University Blvd., Mobile, Alabama, USA. Center for Gene Regulation in Health and Disease, and Department of Biological, Geological and Environmental Sciences, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, Ohio 44115, USA.

Argonaute (Ago) plays a central role in RNA interference in metazoans, but its status in lower organisms remains ill-defined. We report on the Ago complex of the unicellular protozoan, Toxoplasma gondii (Tg), an obligatory pathogen of mammalian hosts. The PIWI-like domain of TgAgo lacked the canonical DDE/H catalytic triad, explaining its weak target RNA cleavage activity. However, TgAgo associated with a stronger RNA slicer, a Tudor staphylococcal nuclease (TSN), and with a protein Arg methyl transferase, PRMT1. Mutational analysis suggested that the N-terminal RGG-repeat domain of TgAgo was methylated by PRMT1, correlating with the recruitment of TSN. The slicer activity of TgAgo was Mg(+2) -dependent and required perfect complementarity between the guide RNA and the target. In contrast, the TSN activity was Ca(+2) -dependent and required an imperfectly paired guide RNA. Ago knockout parasites showed essentially normal growth, but in contrast, the PRMT1 knockouts grew abnormally. Chemical inhibition of Arg methylation also had an anti-parasitic effect. These results suggest that the parasitic PRMT1 plays multiple roles, and its loss affects the recruitment of a more potent second slicer to the paras. © 2012 Blackwell Publishing Ltd.

© 2012 Blackwell Publishing Ltd.

PMID: 22309152 [PubMed - as supplied by publisher]

Wednesday, February 01, 2012

Brain cancer mortality rates increase with Toxoplasma gondii seroprevalence in France

Infect Genet Evol. 2012 Jan 25. [Epub ahead of print]

Brain cancer mortality rates increase with Toxoplasma gondii seroprevalence in France.

Vittecoq M, Elguero E, Lafferty K, Roche B, Brodeur J, Gauthier-Clerc M, Missé D, Thomas F.

IRD, MIVEGEC (UMR CNRS/IRD/UM1), 911 Ave. Agropolis, BP 64501, FR-34394 Montpellier Cedex 5, France; Centre de Recherche de la Tour du Valat, Le Sambuc, 13200 Arles, France.

The incidence of adult brain cancer was shown to be higher in countries where the parasite Toxoplasma gondii is common, suggesting that this brain protozoan could potentially increase the risk of tumor formation. Using countries as replicates has, however, several potential confounding factors, particularly because detection rates vary with country wealth. Using an independent dataset entirely within France, we further establish the significance of the association between T. gondii and brain cancer and find additional demographic resolution. In adult age classes 55years and older, regional mortality rates due to brain cancer correlated positively with the local seroprevalence of T. gondii. This effect was particularly strong for men. While this novel evidence of a significant statistical association between T. gondii infection and brain cancer does not demonstrate causation, these results suggest that investigations at the scale of the individual are merited.

Copyright © 2012. Published by Elsevier B.V.

PMID: 22285308 [PubMed - as supplied by publisher

Apicoplast targeting of a T. gondii transmembrane protein requires a cytosolic tyrosine-based motif

Traffic. 2012 Jan 30. doi: 10.1111/j.1600-0854.2012.01335.x. [Epub ahead of print]

Apicoplast targeting of a T. gondii transmembrane protein requires a cytosolic tyrosine-based motif.

Derocher AE, Karnataki A, Vaney P, Parsons M.

Seattle Biomedical Research Institute, 307 Westlake Ave N, Seattle Washington 98109-5219 University of Washington, Department of Global Health, Seattle Washington 98195-5065.

Toxoplasma gondii, like most apicomplexan parasites, possesses an essential relict chloroplast, the apicoplast. Several apicoplast membrane proteins lack the bipartite targeting sequences of luminal proteins. Vesicles bearing these membrane proteins are detected during apicoplast enlargement, but the means of cargo selection remains obscure. We used a combination of deletion mutagenesis, point mutations, and protein chimeras to identify a short motif prior to the first transmembrane domain of the T. gondii apicoplast phosphate transporter 1 (APT1) that is necessary for apicoplast trafficking. Tyrosine 16 was essential for proper localization; any substitution resulted in misdirection of APT1 to the Golgi body. Glycine 17 was also important, with significant Golgi body accumulation in the alanine mutant. Separation of at least eight amino acids from the transmembrane domain was required for full motif function. Similarly placed YG motifs are present in apicomplexan APT1 orthologues and the corresponding N-terminal domain from Plasmodium vivax was able to route T. gondii APT1 to the apicoplast. Differential permeabilization demonstrated that both the N- and C- termini of APT1 are exposed to the cytosol. We propose that this YG motif facilitates APT1 trafficking via interactions that occur on the cytosolic face of nascent vesicles destined for the apicoplast.

© 2012 John Wiley & Sons A/S.

PMID: 22288938 [PubMed - as supplied by publisher]

Inhibition of ATF6β-dependent host adaptive immune response by a Toxoplasma virulence factor ROP18

Virulence. 2012 Jan 1;3(1). [Epub ahead of print]

Inhibition of ATF6β-dependent host adaptive immune response by a Toxoplasma virulence factor ROP18.

Yamamoto M, Takeda K.

Department of Microbiology and Immunology; Graduate School of Medicine; and Laboratory of Mucosal Immunology; WPI Immunology Frontier Research Center; Osaka University; Suita, Osaka Japan.

Toxoplasma gondii (T. gondii) secretes various effector molecules, which co-opt host cells and enable parasite proliferation. Of these, the rhoptry protein, ROP18, is a parasite-derived factor that determines acute virulence. ROP18 is injected into the host cytoplasm during infection and, eventually, localizes to parasitophorous vacuole (PV) membranes. ROP18 is predicted to be a serine/threonine kinase; however, the molecular mechanism by which ROP18 mediates its pathological effects remains unclear. At the end of 2010, two groups reported that ROP18 targets and phosphorylates interferon-inducible p47 small GTPases (IRGs), demonstrating the parasite's strategy for disarming the innate defense system. Recently, we described a mechanism by which ROP18 mediates degradation of the host endoplasmic reticulum-localizing transcription factor, ATF6β, to downregulate CD8 T cell-mediated type I adaptive immune responses. Taken together, these results suggest that T. gondii inactivates host innate and adaptive immune responses by targeting different host immunity-related molecules: IRGs and ATF6β.

PMID: 22286708 [PubMed - as supplied by publisher]

Toxoplasma gondii infection inhibits Th17-mediated spontaneous development of arthritis in IL-1 receptor antagonist-deficient mice

Infect Immun. 2012 Jan 30. [Epub ahead of print]

Toxoplasma gondii infection inhibits Th17-mediated spontaneous development of arthritis in IL-1 receptor antagonist-deficient mice.

Washino T, Moroda M, Iwakura Y, Aosai F.

Department of Infection and Host Defense, Chiba University Graduate School of Medicine, 1-8-1 Inohana Chuo-ku, Chiba 260-8670, Japan.

IL-1 receptor antagonist (IL-1Ra)-deficient BALB/c mice develop spontaneous arthritis resembling human rheumatoid arthritis. We herein report that infection with Toxoplasma gondii, an intracellular protozoan, is capable of ameliorating the spontaneous development of arthritis in IL-1Ra-deficient mice. The onset of arthritis development was delayed and the severity score of arthritis was significantly suppressed in T. gondii-infected mice. Expression of IL-12p40 mRNA from CD11c(+) cells of mesenteric lymph nodes (mLN) and spleen markedly increased at 1 week after peroral infection. While CD11c(+) cells also produced IL-10, IL-1β and IL-6, CD4(+) T cells from T. gondii-infected mice expressed significantly high levels of T-bet and IFN- γ mRNA at both mLN and spleen. Levels of GATA-3/IL-4 mRNA or RORγt/IL-17 mRNA decreased in the infected mice, indicating Th1 polarization and the reduction of Th2 and Th17 polarization. The severity of arthritis was related to Th1 polarization accompanied with Th17 reduction, demonstrating the protective role of T. gondii-derived Th1 response against Th17-mediated arthritis in IL-1Ra-deficient mice.

PMID: 22290145 [PubMed - as supplied by publisher]