Thursday, March 29, 2007

Fatal disseminated toxoplasmosis during primary HIV infection

Curr HIV Res. 2007 Mar;5(2):273-4.

Fatal disseminated toxoplasmosis during primary HIV infection.

Signorini L, Gulletta M, Coppini D, Donzelli C, Stellini R, Manca N, Carosi G, Matteelli A.

Istituto di Malattie Infettive e Tropicali, Universita degli Studi di Brescia, Italy.

Toxoplasmosis is a well recognized manifestation of AIDS, but the disseminated disease is a rare condition and it has not been associated to HIV seroconversion to our knowledge. We describe a fatal episode of disseminated T. gondii acute infection with massive organ involvement during primary HIV infection. The serological data demonstrate primary T. gondii infection. The avidity index for HIV antibodies supports recent HIV-1 infection.

Publication Types:
Case Reports

PMID: 17346141 [PubMed - indexed for MEDLINE]

A Controlled Prospective Study of Toxo Infection in Individuals With Schizophrenia: Beyond Seroprevalence

Schizophr Bull. 2007 Mar 26; [Epub ahead of print]

A Controlled Prospective Study of Toxoplasma gondii Infection in Individuals With Schizophrenia: Beyond Seroprevalence.

Hinze-Selch D, Daubener W, Eggert L, Erdag S, Stoltenberg R, Wilms S.

2The Center for Integrative Psychiatry, Department of Psychiatry and Psychotherapy, Christian-Albrechts-University, Niemannsweg 147, D-24105 Kiel, Germany.

Toxoplasma gondii (TG) infection has been reported to be more frequent in schizophrenia. The interaction of the lifelong persisting parasite with the host's immune system involves T-cell/interferon-gamma-induced degradation of tryptophan and provides a challenge to the host well beyond a possible role in the etiology of schizophrenia. The hypothesis we tested in this study was that TG infection may be more frequent (serofrequency) and/or more intense (serointensity) in patients with schizophrenia or major depression compared with psychiatrically healthy controls. In addition, these measures are associated with the clinical course. We did a cross-sectional, prospective investigation of individuals with schizophrenia (n = 277) and major depression (n = 465) admitted to our department (2002-2005) and of healthy controls (n = 214), with all groups adjusted for age and geographic home region. Serofrequency was comparable between the groups, but serointensity was significantly higher in the patients. In individuals with schizophrenia, serointensity was significantly positively associated with C-reactive protein levels and leukocyte counts, and first-episode patients yielded significantly higher serotiters. Immunomodulatory medication was associated with decreased serotiters. In addition, the route of infection appears to differ between patients and controls. Thus, our results support increased host responses to TG infection in the patients, as well as increased titers in first-episode patients with schizophrenia; this may relate to the shifted T-helper 1/2 status described in these patients. Therefore, we suggest that TG infection, particularly in individuals with schizophrenia, is an important environmental factor in the interaction between psychiatric vulnerability, genetic background, immunomodulation, and the neurotransmitter systems.

PMID: 17387159 [PubMed - as supplied by publisher]

Toxo reduces GPI-induced TNF{alpha} production through inhibition of NF-{kappa}B pathway

Infect Immun. 2007 Mar 26; [Epub ahead of print]

Fatty acids isolated from Toxoplasma gondii reduce GPI-induced TNF{alpha} production through inhibition of NF-{kappa}B signaling pathway.

Debierre-Grockiego F, Rabi K, Schmidt J, Geyer H, Geyer R, Schwarz RT.

Institut fur Virologie, AG Parasitologie, Hans-Meerwein-Str. 2, D-35043 Marburg, Germany, and Institut fur Biochemie, Friedrichstrasse 24, D-35392 Giessen, Germany, and Unite de Glycobiologie Structurale et Fonctionnelle UMR CNRS/USTL n degrees 8576 - IFR 118, F-59655 Villeneuve D'Ascq, France.

Glycosylphosphatidylinositols (GPIs) are involved in the pathogenicity of protozoan parasites and are known to induce inflammatory cytokines. However, we have previously shown that the family of six GPIs of Toxoplasma gondii extracted together from tachyzoites could not induce TNF-alpha secretion by macrophages, whereas GPIs individually separated from this extract by thin-layer chromatography (TLC) were able to stimulate the cells. In the present study we show that the TLC step permits to eliminate inhibitors extracted together with the T. gondii GPIs. Among the non-GPI molecules we have isolated fatty acids able to inhibit the secretion of TNF-alpha induced by the T. gondii GPIs. Myristic and palmitic acids reduce the production of TNF-alpha through the inhibition of tyrosine phosphorylation of cytoplasmic proteins and the inhibition of NF-kappaB activation in a PPAR-independent pathway and after a rapid entry into the cytoplasm of macrophages. GPIs are considered as toxin inducing irreversible damages in the host, and fatty acids produced in parallel by the parasite could reduce the immune response thus favoring the persistence of parasite infection.

PMID: 17387164 [PubMed - as supplied by publisher]

Tuesday, March 27, 2007

Toxoplasma gondii: DNA vaccination

Exp Parasitol. 2007 Feb 1; [Epub ahead of print]

Toxoplasma gondii: DNA vaccination with genes encoding antigens MIC2, M2AP, AMA1 and BAG1 and evaluation of their immunogenic potential.

Dautu G, Munyaka B, Carmen G, Zhang G, Omata Y, Xuenan X, Igarashi M.

National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido 080-8555, Japan.

A combination of antigenic regions of microneme proteins have been previously reported as being protective against chronic toxoplasmosis. In this work, we evaluated immune responses induced by immunizing BALB/c and C57BL/6 mice intradermally with plasmid DNA encoding the protein sequences of Toxoplasma gondii AMA1, MIC2, M2AP and BAG1. Mice immunized with the AMA1 gene developed high levels of serum IgG2a and c antibodies as well as cellular immune responses associated with IFN-gamma synthesis suggesting a modulated Th1 type of response. Immunization with the AMA1 gene resulted in a partial but significant protection against the acute phase of toxoplasmosis compared to MIC2, M2AP and BAG1 genes. Therefore, the AMA1 gene appears to generate a strong specific immune response and also provides effective protection against toxoplasmosis more than the MIC2, M2AP and BAG1 genes.

PMID: 17379212 [PubMed - as supplied by publisher]

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Divergent polyamine metabolism in the Apicomplexa

Microbiology. 2007 Apr;153(Pt 4):1123-30.

Divergent polyamine metabolism in the Apicomplexa.

Cook T, Roos D, Morada M, Zhu G, Keithly JS, Feagin JE, Wu G, Yarlett N.

Haskins Laboratories, Pace University, New York, NY 10038, USA.

The lead enzymes of polyamine biosynthesis, i.e. ornithine decarboxylase (ODC) and arginine decarboxylase (ADC), were not detected in Toxoplasma gondii [the limit of detection for ODC and ADC was 5 pmol min(-1) (mg protein)(-1)], indicating that T. gondii lacks a forward-directed polyamine biosynthetic pathway, and is therefore a polyamine auxotroph. The biochemical results were supported by results obtained from data-mining the T. gondii genome. However, it was possible to demonstrate the presence of a highly active backconversion pathway that formed spermidine from spermine, and putrescine from spermidine, via the combined action of spermidine/spermine N(1)-acetyltransferase (SSAT) or spermidine N(1)-acetyltransferase (SAT) and polyamine oxidase (PAO). With spermine as the substrate, T. gondii SSAT had a specific activity of 1.84 nmol min(-1) (mg protein)(-1), and an apparent K(m) for spermine of 180 mM; with spermidine as the substrate, the SAT had a specific activity of 3.95 nmol min(-1) (mg protein)(-1), and a K(m) for spermidine of 240 mM. T. gondii PAO had a specific activity of 10.6 nmol min(-1) (mg protein)(-1), and a K(m) for acetylspermine of 36 mM. Furthermore, the results demonstrated that T. gondii SSAT was 50 % inhibited by 30 mM di(ethyl)norspermine. The parasite actively transported arginine and ornithine, which were converted via the arginine dihydrolase pathway to citrulline and carbamoyl phosphate, resulting in the formation of ATP via carbamate kinase. The lack of polyamine biosynthesis by T. gondii is contrasted with polyamine metabolism by other apicomplexans.

PMID: 17379721 [PubMed - in process]

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Saturday, March 24, 2007

Toxo antibodies in cancer patients

Cancer Lett. 2007 Mar 19; [Epub ahead of print]

Toxoplasma gondii antibodies in cancer patients.

Yuan Z, Gao S, Liu Q, Xia X, Liu X, Liu B, Hu R.

Laboratory of Parasitology, Veterinary Institute, Academy of Military Medical Sciences, 1068 Qinglong Road, Changchun 130062, China.

To determine Toxoplasma gondii antibodies in cancer patients, 267 cancer patients were studied using ELISA and higher positivity rates of T. gondii IgG were detected than the control. The positivity rates of T. gondii IgG in nasopharyngeal carcinoma, rectal cancer groups were significantly higher than the other cancer groups, but the differences in IgM positivity rates were not significant, demonstrating that there is a likely association between T. gondii infection and some kinds of cancer, especially nasopharyngeal carcinoma and rectal cancer.

PMID: 17376590 [PubMed - as supplied by publisher]

Toxo membrane skeleton protein IMC2A

Toxoplasma gondii membrane skeleton protein IMC2A (IMC2A) mRNA, complete cds

Thursday, March 22, 2007

BSR4, SRS9, and the P36 antibody

Int J Parasitol. 2007 Feb 14; [Epub ahead of print]

The BSR4 protein is up-regulated in Toxoplasma gondii bradyzoites, however the dominant surface antigen recognised by the P36 monoclonal antibody is SRS9.

Van TT, Kim SK, Camps M, Boothroyd JC, Knoll LJ.

Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, 1300 University Avenue, Madison, WI 53706, USA.

The protozoan parasite, Toxoplasma gondii, interconverts between fast-growing tachyzoites and slow-growing bradyzoites within intermediate hosts. The surface of T. gondii is covered by the SAG1-related sequence (SRS) superfamily of glycosyl phosphatidyl inositol-anchored proteins, many of which are stage-specific. Previous transient transfection of BSR4, a member of the SRS superfamily, showed reactivity with the bradyzoite-specific P36 mAb by immunofluorescene assay. BSR4 mRNA levels were equally abundant in tachyzoites and bradyzoites, suggesting post-transcriptional regulation of the protein. In this study, we show that BSR4 protein is present in both tachyzoites and bradyzoites, but up-regulated in bradyzoites. However, stable expression of BSR4 in two BSR4-negative T. gondii strains shows minimal reactivity to the P36 mAb by Western immunoblotting, even though the BSR4 protein is abundant. We discovered that the SRS9 protein, a bradyzoite-specific member of the SRS superfamily and encoded immediately downstream of BSR4, was also ablated in the BSR4-negative strains, suggesting that SRS9 is the surface antigen recognised by the P36 mAb. Stable expression of SRS9 in the BSR4 mutant strains shows robust reactivity to the P36 mAb. Immunoprecipitation experiments confirm that the P36 mAb interacts with the SRS9 protein. These data indicate that while the BSR4 protein is up-regulated in bradyzoites, the dominant antigen that the P36 mAb recognises is SRS9.

PMID: 17368655 [PubMed - as supplied by publisher]

Apicomplexan UCHL3 retains dual specificity for ubiquitin and Nedd8 throughout evolution

Cell Microbiol. 2007 Feb 15; [Epub ahead of print]

Apicomplexan UCHL3 retains dual specificity for ubiquitin and Nedd8 throughout evolution.

Frickel EM, Quesada V, Muething L, Gubbels MJ, Spooner E, Ploegh H, Artavanis-Tsakonas K.

Whitehead Institute, 9 Cambridge Center, Cambridge, MA 02142, USA.

Post-translational modification of proteins by ubiquitin or ubiquitin-like polypeptides such as Nedd8 controls cellular functions including protein degradation, the cell cycle and transcription. Here we have used an activity-based chemical probe that covalently labels ubiquitin hydrolases. We identify four such enzymes from Toxoplasma gondii by mass spectrometry. The homologue of mammalian UCHL3 was cloned from both T. gondii and Plasmodium falciparum and we show that both enzymes possess deubiquitinating as well as deNeddylating activity. A phylogenetic analysis of the UCHL3 amino acid sequences from several eukaryotes suggests that dual specificity for ubiquitin and Nedd8 was present in the ancestral eukaryotic UCHL3 and has been conserved throughout evolution. Finally, the structural characterization of UCHL3 from T. gondii shows a unique insertion at the surface of this enzyme, which may be involved in novel interactions with other proteins. The characterization of these apicomplexan UCHL3s adds to our understanding of the ubiquitin and Nedd8 pathways in these parasites.

PMID: 17371404 [PubMed - as supplied by publisher]

Diacylglycerol kinase {zeta} regulates microbial recognition and host resistance to Toxo

J Exp Med. 2007 Mar 19; [Epub ahead of print]

Diacylglycerol kinase {zeta} regulates microbial recognition and host resistance to Toxoplasma gondii.

Liu CH, Machado FS, Guo R, Nichols KE, Burks AW, Aliberti JC, Zhong XP.

Department of Pediatrics-Allergy and Immunology and 2Department of Immunology, Duke University Medical Center, Durham, NC 27710.

Mammalian Toll-like receptors (TLRs) recognize microbial pathogen-associated molecular patterns and are critical for innate immunity against microbial infection. Diacylglycerol (DAG) kinases (DGKs) regulate the intracellular levels of two important second messengers involved in signaling from many surface receptors by converting DAG to phosphatidic acid (PA). We demonstrate that the zeta isoform of the DGK family (DGKzeta) is expressed in macrophages (Mphi) and dendritic cells. DGKzeta deficiency results in impaired interleukin (IL) 12 and tumor necrosis factor alpha production following TLR stimulation in vitro and in vivo, increased resistance to endotoxin shock, and enhanced susceptibility to Toxoplasma gondii infection. We further show that DGKzeta negatively controls the phosphatidylinositol 3-kinase (PI3K)-Akt pathway and that inhibition of PI3K activity or treatment with PA can restore lipopolysaccharide-induced IL-12 production by DGKzeta-deficient Mphi. Collectively, our data provide the first genetic evidence that an enzyme involved in DAG/PA metabolism plays an important role in innate immunity and indicate that DGKzeta promotes TLR responses via a pathway involving inhibition of PI3K.

PMID: 17371930 [PubMed - as supplied by publisher]

Wednesday, March 21, 2007

SAG1 Not Required for Acute Ocular Toxoplasmosis in Mice

The SAG1 Toxoplasma gondii Surface Protein Is Not Required for Acute Ocular
Toxoplasmosis in Mice
Elizabeth Charles, Michelle C. Callegan, and Ira J. Blader
Infect. Immun. 2007;75 2079-2083

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Bradyzoite-Specific Surface Antigen SRS9

Bradyzoite-Specific Surface Antigen SRS9 Plays a Role in Maintaining
Toxoplasma gondii Persistence in the Brain and in Host Control of Parasite
Replication in the Intestine
Seon-Kyeong Kim, Ariela Karasov, and John C. Boothroyd
Infect. Immun. 2007;75 1626-1634

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Thursday, March 15, 2007

Toxo sugar transporters

Toxoplasma gondii sugar transporter (ST3) mRNA, complete cds

Toxoplasma gondii sugar transporter (ST2) mRNA, complete cds

Cell cycle-regulated vesicular trafficking of APT1, a protein localized to multiple apicoplast membranes

Molecular Microbiology - Volume 63 Issue 6 Page 1653 - March 2007

Cell cycle-regulated vesicular trafficking of Toxoplasma APT1, a protein localized to multiple apicoplast membranes

Anuradha Karnataki, Amy DeRocher, Isabelle Coppens, Coral Nash, Jean E. Feagin, Marilyn Parsons

The apicoplast is a relict plastid essential for viability of the apicomplexan parasites Toxoplasma and Plasmodium. It is surrounded by multiple membranes that proteins, substrates and metabolites must traverse. Little is known about apicoplast membrane proteins, much less their sorting mechanisms. We have identified two sets of apicomplexan proteins that are homologous to plastid membrane proteins that transport phosphosugars or their derivatives. Members of the first set bear N-terminal extensions similar to those that target proteins to the apicoplast lumen. While Toxoplasma gondii lacks this type of translocator, the N-terminal extension from the Plasmodium falciparum sequence was shown to be functional in T. gondii. The second set of translocators lacks an N-terminal targeting sequence. This translocator, TgAPT1, when tagged with HA, localized to multiple apicoplast membranes in T. gondii. Contrasting with the constitutive targeting of luminal proteins, the localization of the translocator varied during the cell cycle. Early-stage parasites showed circumplastid distribution, but as the plastid elongated in preparation for division, vesicles bearing TgAPT1 appeared adjacent to the plastid. After plastid division, the protein resumes a circumplastid colocalization. These studies demonstrate for the first time that vesicular trafficking likely plays a role in the apicoplast biogenesis.

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Tuesday, March 13, 2007

Adenosine Metabolism: Potential Targets for Chemotherapy

Curr Pharm Des. 2007;13(6):581-97.

Adenosine Metabolism in Toxoplasma gondii: Potential Targets for Chemotherapy

El Kouni MH

Department of Pharmacology and Toxicology, Center for AIDS Research, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Toxoplasma gondii is an intracellular parasitic protozoan that infects approximately a billion people worldwide. Infection with T. gondii represents a major health problem for immunocompromised individuals, such as AIDS patients, organ transplant recipients, and the unborn children of infected mothers. Currently available drugs usually do not eradicate infection and as many as 50% of the patients do not respond to this therapy. Furthermore, they are ineffective against T. gondii tissue cysts. In addition, prolonged exposure to these drugs induces serious host toxicity forcing the discontinuation of the therapy. Finally, there is no effective vaccine currently available for the treatment of toxoplasmosis. Therefore, it is necessary to develop new and effective drugs for the treatment and management of toxoplasmosis. The rational design of a drug depends on the exploitation of fundamental biochemical or physiological differences between pathogens and their host. Some of the most striking differences between T. gondii and their mammalian host are found in purine metabolism. T. gondii, like most parasites studied, lack the ability to synthesize purines do novo and depend on the salvage of purines from their host to satisfy their requirements of purines. In this respect, the salvage of adenosine is the major source of purines in T. gondii. Therefore, interference with adenosine uptake and metabolism in T. gondii can be selectively detrimental to the parasite. The host cells, on the other hand, can still obtain their purine requirements by their de novo pathways. This review will focus on the broad aspects of the adenosine transport and the enzyme adenosine kinase (EC which are the two primary routes for adenosine utilization in T. gondii, in an attempt to illustrate their potentials as targets for chemotherapy against this parasite.

PMID: 17346176 [PubMed - in process]

Invasion and Egress: Potential Targets for Antiparasitic Drugs

Curr Pharm Des. 2007;13(6):641-51.

Invasion and Egress by the Obligate Intracellular Parasite Toxoplasma gondii: Potential Targets for the Development of New Antiparasitic Drugs

Lavine MD, Arrizabalaga G

Department of Microbiology, Molecular Biology and Biochemistry and Center for Reproductive Biology, University of Idaho, Moscow, ID 83843, USA.

Intracellular protozoan parasites are a great threat to animal and human health. To successfully disseminate through an organism these parasites must be able to enter and exit host cells efficiently and rapidly. The inhibition of invasion or egress of obligate intracellular parasites is regarded as a goal for drug development since these processes are essential for their survival and likely to require proteins unique to the parasites. Thus, a more comprehensive knowledge of invasion and egress proteins will aid in the development of drugs and vaccines against these intracellular pathogens. In recent years, the study of a particular parasite, Toxoplasma gondii, has yielded valuable information on how invasion and egress are achieved by some protozoan parasites. Besides being a good model system for the study of parasite biology, Toxoplasma is an important human pathogen capable of causing devastating disease in both immunocompromised individuals and developing fetuses. The lack of effective, inexpensive and tolerable drugs against Toxoplasma makes the development of new therapies an imperative. The following review describes how the identification and in depth study, using proteomics, forward genetics and pharmacology of the Toxoplasma proteins involved in entering and exiting human cells provide an important starting point in identifying targets for drug discovery.

PMID: 17346179 [PubMed - in process]

Rhoptries are major players in invasion and host cell interaction

Cell Microbiol. 2007 Mar 8; [Epub ahead of print]

Rhoptries are major players in Toxoplasma gondii invasion and host cell interaction

Dubremetz JF

UMR5539 CNRS-UM2, CC107, Universite de Montpellier 2, 2 Place Eugene Bataillon, 34090 Montpellier Cedex 05, France.

Rhoptries are unique secretory organelles shared by all Apicomplexan invasive stages. They are exocytosed upon host cell invasion and their contents are involved in creating the moving junction that propels the parasite in the cell and in building the parasitophorous vacuole in which the parasite will develop. In addition, some rhoptry proteins are targeted to the host cell nucleus. The array of roles played by these organelles has considerably expanded in the recent years, making them a major clue to the understanding of the early interaction between these parasites and their host. Yet, our knowledge on these organelles is still very poor and much has to be done before we get a clear view of the part they play in Apicomplexan biology.

PMID: 17346309 [PubMed - as supplied by publisher]

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Thursday, March 08, 2007

Toxo pneumonia in immunocompetent subjects

Clin Infect Dis. 2007 Mar 15;44(6):e62-6. Epub 2007 Feb 8.

Toxoplasma gondii pneumonia in immunocompetent subjects: case report and review.

Leal FE, Cavazzana CL, de Andrade HF Jr, Galisteo AJ Jr, de Mendonca JS, Kallas EG.

Hospital do Servidor Publico Estadual de Sao Paulo, Sao Paulo, SP, Brazil.

Pulmonary toxoplasmosis is rare in immunocompetent subjects. Here, we describe a 41-year-old previously healthy male patient who presented to the emergency department of a hospital with a life-threatening case of pneumonia due to Toxoplasma gondii infection, which responded to specific therapy. Clinical and image-based findings overlap with those for atypical pneumonias, and toxoplasmosis should be considered in the differential diagnosis--especially if immunoglobulin M-specific antibodies are detected.

Publication Types:
Case Reports
Research Support, Non-U.S. Gov't

PMID: 17304443 [PubMed - indexed for MEDLINE]

Toxo strains lacking oral transmission are defective in stage differentiation

Infect Immun. 2007 Mar 5; [Epub ahead of print]

Toxoplasma gondii strains lacking oral transmission are defective in stage differentiation

Fux B, Nawas J, Khan A, Gill D, Su C, Sibley LD

Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO 63110, USA.; Department of Microbiology, University of Tennessee, Knoxville, TN, 37996.

Toxoplasma gondii undergoes differentiation from rapidly growing tachyzoites to slowly growing bradyzoites during its life cycle in the intermediate host, and conversion can be induced in vitro by stress. Representative strains of the three clonal lineages showed equal capacity to differentiate into bradyzoites in vitro as evidenced by induction of BAG1, staining with the lectin Dolichos biflorus (DBL), pepsin resistance, and oral infectivity to mice. We also examined several recently described exotic strains of T. gondii, which are genetically diverse and have a different ancestry from the clonal lineages. The exotic strain COUG was essentially like the clonal lineages and showed a high capacity to induce bradyzoites in vitro and in vivo, consistent with its ability to be efficiently transmitted by the oral route. In contrast, exotic strains MAS and FOU, which are defective in oral transmission, showed a decreased potential to develop into bradyzoites in vitro. This defect was evident by reduced staining with the lectin DBL and the cyst antigen CST1, failure down-regulate tachyzoite antigens such as SAG1 and SAG2A, and decreased resistance to pepsin treatment. Despite normal in vitro differentiation, the exotic strains CAST and GPHT also showed decreased oral transmission due to formation of smaller cysts and a lower tissue burden during chronic infection, traits also shared by MAS and FOU. Collectively, these findings reveal that limited oral transmission in some strains of T. gondii is due to inefficient differentiation to the bradyzoite form, leading to defects in formation of tissue cysts.

PMID: 17339346 [PubMed - as supplied by publisher]

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Wednesday, March 07, 2007

ATP-binding cassette protein

Toxoplasma gondii strain NED ATP-binding cassette protein subfamily B member 2 mRNA, complete cds

Toxoplasma gondii strain PRU ATP-binding cassette protein subfamily B member 2 mRNA, complete cds

Toxoplasma gondii strain RH ATP-binding cassette protein subfamily B member 2 mRNA, complete cds

Tuesday, March 06, 2007

Toxo book "Toxoplasma gondii: The Model Apicomplexan" PRE-ORDER

Now available for pre-ordering...

Toxoplasma gondii: The Model Apicomplexan. Perspectives and Methods (Hardcover)

by Louis M Weiss (Editor), Kami Kim (Editor)

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Inconsistent dissemination patterns following oral infection in mice

Exp Parasitol. 2007 Jan 25; [Epub ahead of print]

Toxoplasma gondii: Inconsistent dissemination patterns following oral infection in mice

Boyle JP, Saeij JP, Boothroyd JC

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Since Toxoplasma gondii is transmitted in the wild through the ingestion of infective cysts, oral infection is a preferred model for studying the natural mode of parasite dissemination and pathogenesis. Using luciferase-expressing strains of T. gondii and in vivo imaging, we observed different patterns of disease progression in mice depending of the method of oral infection. Oral gavage of infective cysts (e.g., bradyzoites) resulted in an inconsistent pattern of parasite dissemination; in the majority (20/29) of infected mice, luciferase-derived signal (indicating high numbers of Toxoplasma tachyzoites) was first observed in the right chest area. At later time points this signal spread to other parts of the mouse, including the abdominal area. In the remaining mice (9/29), parasites were first observed replicating in the abdominal area, as might be expected. In contrast, when mice were infected naturally (either via ingestion of whole brains from previously infected mice or brain cyst homogenate-soaked bread), parasites were first observed replicating in the abdominal area in all mice examined (10/10). Based on the inconsistency of infections initiated with oral gavage, it is recommended that natural feeding be used to infect mice when a consistent oral infection is desired.

PMID: 17335814 [PubMed - as supplied by publisher]

Early Infections of Toxo and Later Development of Schizophrenia

Schizophr Bull. 2007 Feb 28; [Epub ahead of print]

Early Infections of Toxoplasma gondii and the Later Development of Schizophrenia

Mortensen PB, Norgaard-Pedersen B, Waltoft BL, Sorensen TL, Hougaard D, Yolken RH

2The National Centre for Register-based Research, University of Aarhus, Taasingegade 1, 8000 Aarhus C, Denmark.

Early exposure to several infectious agents has been associated with the later development of schizophrenia. Two recent studies assessed in utero or early postnatal exposure to Toxoplasma gondii. In one study of 63 individuals, who developed schizophrenia spectrum disorders, maternal sera obtained during pregnancy showed an increased risk (OR 2.61) of having IgG antibodies to T. gondii. In the other study of 71 individuals who developed schizophrenia, sera obtained shortly after birth also showed an increased risk (OR 1.79) of having IgG antibodies to T. gondii. Causal linking mechanisms are at present speculative but include possible direct effects of maternal IgG on the developing central nervous system (CNS) of the offspring. Additional studies are underway.

PMID: 17329231 [PubMed - as supplied by publisher]

The Evolution of Spliceosomal Introns in Alveolates

Mol Biol Evol. 2007 Mar 1; [Epub ahead of print]

The Evolution of Spliceosomal Introns in Alveolates

Nguyen HD, Yoshihama M, Kenmochi N.

Frontier Science Research Center, University of Miyazaki 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.

Many issues concerning the evolution of spliceosomal introns remain poorly understood. In this respect, the reconstruction of the evolution of introns in deep branching species such as alveolates is of special significance. In this study, we inferred the intron evolution in alveolates using 3,368 intron positions in 162 orthologs from 10 species (nine alveolates and one outgroup, Homo sapiens). We found that although very few intron gains and losses have occurred in Theileria and Plasmodium recently, many intron gains and losses have occurred in the evolution of alveolates. Thus, the rates of intron gain and loss in alveolates have varied greatly across time and lineage. Our results seem to support the notion that massive intron gains and losses have occurred during short episodes, perhaps coinciding with major evolutionary events.

PMID: 17331959 [PubMed - as supplied by publisher]

Thursday, March 01, 2007

Toxo enoyl acyl carrier protein reductase

Acta Crystallogr D Biol Crystallogr. 2007 Mar;63(Pt 3):328-38. Epub 2007 Feb 21.

Studies of Toxoplasma gondii and Plasmodium falciparum enoyl acyl carrier protein reductase and implications for the development of antiparasitic agents

Muench SP, Prigge ST, McLeod R, Rafferty JB, Kirisits MJ, Roberts CW, Mui EJ, Rice DW

The Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, England

Recent studies have demonstrated that submicromolar concentrations of the biocide triclosan arrest the growth of the apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii and inhibit the activity of the apicomplexan enoyl acyl carrier protein reductase (ENR). The crystal structures of T. gondii and P. falciparum ENR in complex with NAD(+) and triclosan and of T. gondii ENR in an apo form have been solved to 2.6, 2.2 and 2.8 A, respectively. The structures of T. gondii ENR have revealed that, as in its bacterial and plant homologues, a loop region which flanks the active site becomes ordered upon inhibitor binding, resulting in the slow tight binding of triclosan. In addition, the T. gondii ENR-triclosan complex reveals the folding of a hydrophilic insert common to the apicomplexan family that flanks the substrate-binding domain and is disordered in all other reported apicomplexan ENR structures. Structural comparison of the apicomplexan ENR structures with their bacterial and plant counterparts has revealed that although the active sites of the parasite enzymes are broadly similar to those of their bacterial counterparts, there are a number of important differences within the drug-binding pocket that reduce the packing interactions formed with several inhibitors in the apicomplexan ENR enzymes. Together with other significant structural differences, this provides a possible explanation of the lower affinity of the parasite ENR enzyme family for aminopyridine-based inhibitors, suggesting that an effective antiparasitic agent may well be distinct from equivalent antimicrobials.

PMID: 17327670 [PubMed - in process]

Toxoplasma encephalitis after autologous stem cell transplantation

Leuk Lymphoma. 2007 Jan;48(1):201-3.

Toxoplasma encephalitis after autologous stem cell transplantation

Grosu I, Ghekiere O, Layios N, Hantson P, Cosnard G

Department of Intensive Care

(No abstract)

Toxoplasmosis Conference - Registration OPEN!

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