Thursday, December 31, 2009

EuPathDB: a portal to eukaryotic pathogen databases

Nucleic Acids Res. 2010 Jan;38(Database issue):D415-9. Epub 2009 Nov 13.

EuPathDB: a portal to eukaryotic pathogen databases

Aurrecoechea C, Brestelli J, Brunk BP, Fischer S, Gajria B, Gao X, Gingle A, Grant G, Harb OS, Heiges M, Innamorato F, Iodice J, Kissinger JC, Kraemer ET, Li W, Miller JA, Nayak V, Pennington C, Pinney DF, Roos DS, Ross C, Srinivasamoorthy G, Stoeckert CJ Jr, Thibodeau R, Treatman C, Wang H.

Center for Tropical & Emerging Global Diseases, University of Georgia, Athens, GA 30602, USA.

EuPathDB (http://EuPathDB.org; formerly ApiDB) is an integrated database covering the eukaryotic pathogens of the genera Cryptosporidium, Giardia, Leishmania, Neospora, Plasmodium, Toxoplasma, Trichomonas and Trypanosoma. While each of these groups is supported by a taxon-specific database built upon the same infrastructure, the EuPathDB portal offers an entry point to all these resources, and the opportunity to leverage orthology for searches across genera. The most recent release of EuPathDB includes updates and changes affecting data content, infrastructure and the user interface, improving data access and enhancing the user experience. EuPathDB currently supports more than 80 searches and the recently-implemented 'search strategy' system enables users to construct complex multi-step searches via a graphical interface. Search results are dynamically displayed as the strategy is constructed or modified, and can be downloaded, saved, revised, or shared with other database users.

PMID: 19914931 [PubMed - in process]

Wednesday, December 30, 2009

The Toxoplasma Apicoplast Phosphate Translocator Links Cytosolic and Apicoplast Metabolism and Is Essential for Parasite Survival

Cell Host Microbe. 2009 Dec 24. [Epub ahead of print]

The Toxoplasma Apicoplast Phosphate Translocator Links Cytosolic and Apicoplast Metabolism and Is Essential for Parasite Survival

Brooks CF, Johnsen H, van Dooren GG, Muthalagi M, Lin SS, Bohne W, Fischer K, Striepen B.

Center for Tropical and Emerging Global Diseases, University of Georgia, Paul D. Coverdell Center, 500 D.W. Brooks Drive, Athens, GA 30602, USA.

Apicomplexa are unicellular eukaryotic pathogens that carry a vestigial algal endosymbiont, the apicoplast. The physiological function of the apicoplast and its integration into parasite metabolism remain poorly understood and at times controversial. We establish that the Toxoplasma apicoplast membrane-localized phosphate translocator (TgAPT) is an essential metabolic link between the endosymbiont and the parasite cytoplasm. TgAPT is required for fatty acid synthesis in the apicoplast, but this may not be its most critical function. Further analyses demonstrate that TgAPT also functions to supply the apicoplast with carbon skeletons for additional pathways and, indirectly, with energy and reduction power. Genetic ablation of the transporter results in rapid death of parasites. The dramatic consequences of loss of its activity suggest that targeting TgAPT could be a viable strategy to identify antiparasitic compounds. HIGHLIGHTS: Toxoplasma apicoplast phosphate translocator links cytosolic and apicoplast metabolism TgAPT is required for fatty acid synthesis in the apicoplast TgAPT functions to supply the apicoplast with carbon, energy, and reduction power Genetic ablation of the transporter results in rapid death of parasites. Copyright © 2010 Elsevier Inc. All rights reserved.

PMID: 20036630 [PubMed - as supplied by publisher]

Reduction of Foxp3+ cells by depletion with the PC61 mAb induces mortality in resistant BALB/c mice infected with Toxoplasma

J Biomed Biotechnol. 2010;2010:786078. Epub 2009 Dec 13.

Reduction of Foxp3+ cells by depletion with the PC61 mAb induces mortality in resistant BALB/c mice infected with Toxoplasma gondii

Tenorio EP, Olguín JE, Fernández J, Vieyra P, Saavedra R.

Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Apartado Postal 70228, C.U., CP 04510, Mexico City, Mexico.

Regulatory T cells (Tregs) are CD4(+)Foxp3(+) cells that modulate autoimmune responses. Tregs have been shown to be also involved during the immune response against infectious agents. The aim of this work is to study the role of Tregs during the infection with the intracellular protozoan Toxoplasma gondii. Resistant BALB/c mice were injected with 200 microg of anti-CD25 mAb (clone PC61) and 2 days later they were infected with 20 cysts of the ME49 strain of T. gondii. We observed that depleted mice showed 50-60% mortality during the acute infection. When FACS analysis was carried out, we observed that although injection of PC61 mAb eliminated 50% of Tregs, infected-depleted mice showed a similar percentage of CD25(+)Foxp3(-) (activated T cells, Tact) to those observed in infected nondepleted animals, demonstrating that in our depletion/infection system, injection of PC61 mAb did not hamper T cell activation while percentage of Tregs was reduced by 75% 10 days post infection. We concluded that Tregs are essential during protection in the acute phase of T. gondii infection.

PMID: 20037737

Friday, December 18, 2009

Toxoplasma gondii Antibody Titers and History of Suicide Attempts in Patients With Recurrent Mood Disorders

J Nerv Ment Dis. 2009 Dec;197(12):905-908.

Toxoplasma gondii Antibody Titers and History of Suicide Attempts in Patients With Recurrent Mood Disorders

Arling TA, Yolken RH, Lapidus M, Langenberg P, Dickerson FB, Zimmerman SA, Balis T, Cabassa JA, Scrandis DA, Tonelli LH, Postolache TT.

*Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD; daggerStanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD; double daggerEpidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, MD; section signStanley Research Center, Sheppard Pratt Health System, Baltimore, MD; and paragraph signDepartment of Family and Community Health, University of Maryland School of Nursing, Baltimore, MD.

Toxoplasma gondii (T.gondii) is an obligate intracellular protozoan parasite infecting one-third of the world population, residing relatively silently in the brain of the immunocompetent host. We hypothesized that T.gondii seropositivity and serointensity are associated with having a history of attempting suicide and, in those attempting suicide, a greater number of attempts. T.gondii seropositivity and antibody titers were compared between (a) patients with recurrent mood disorders with history of suicide attempt (99 individuals) versus (b) patients with recurrent mood disorders without history of suicide attempt (119 individuals), and (c) healthy controls (39 individuals). Diagnosis was made using the Structured Clinical Interview for DSM-IV. Statistical methods included chi square, analysis of variance, and linear and logistic regression analyses. Suicide attempters had higher T.gondii antibody titers than nonsuicide attempters (p = 0.004). The logistic regression analysis revealed a predictive association between titers of anti- T.gondii antibodies and history of suicide attempt with OR = 1.55 (1.14-2.12), p = 0.006. No significant relationship was found between T.gondii seropositivity and suicide attempt status, number of prior suicide attempts, and recurrent mood disorder diagnosis. Although preliminary and bearing replication, this is the first report, to our knowledge, of an association between attempting suicide and T. gondii.

PMID: 20010026 [PubMed - as supplied by publisher]

Thursday, December 10, 2009

(IL)-23 mediates Toxoplasma gondii-induced immunopathology in the gut via matrixmetalloproteinase-2 and IL-22 but independent of IL-17

J Exp Med. 2009 Dec 7. [Epub ahead of print]

Interleukin (IL)-23 mediates Toxoplasma gondii-induced immunopathology in the gut via matrixmetalloproteinase-2 and IL-22 but independent of IL-17

Muñoz M, Heimesaat MM, Danker K, Struck D, Lohmann U, Plickert R, Bereswill S, Fischer A, Dunay IR, Wolk K, Loddenkemper C, Krell HW, Libert C, Lund LR, Frey O, Hölscher C, Iwakura Y, Ghilardi N, Ouyang W, Kamradt T, Sabat R, Liesenfeld O.

Institute of Microbiology and Hygiene and 2 Department of Pathology/Research Center ImmunoSciences, Campus Benjamin Franklin, Charité Medical School, 12203 Berlin, Germany.

Peroral infection with Toxoplasma gondii leads to the development of small intestinal inflammation dependent on Th1 cytokines. The role of Th17 cells in ileitis is unknown. We report interleukin (IL)-23-mediated gelatinase A (matrixmetalloproteinase [MMP]-2) up-regulation in the ileum of infected mice. MMP-2 deficiency as well as therapeutic or prophylactic selective gelatinase blockage protected mice from the development of T. gondii-induced immunopathology. Moreover, IL-23-dependent up-regulation of IL-22 was essential for the development of ileitis, whereas IL-17 was down-regulated and dispensable. CD4(+) T cells were the main source of IL-22 in the small intestinal lamina propria. Thus, IL-23 regulates small intestinal inflammation via IL-22 but independent of IL-17. Gelatinases may be useful targets for treatment of intestinal inflammation.

PMID: 19995958 [PubMed - as supplied by publisher]

Protection against lethal Neospora caninum infection in mice induced by heterologous vaccination with a mic1-3 knockout Toxoplasma

Infect Immun. 2009 Dec 7. [Epub ahead of print]

Protection against lethal Neospora caninum infection in mice induced by heterologous vaccination with a mic1-3 knockout Toxoplasma gondii strain

Penarete Vargas DM, Mévélec MN, Dion S, Sèche E, Dimier-Poisson I, Fandeur T.

Université François-Rabelais de Tours, INRA, UMR 0483 Université-INRA d'Immunologie Parasitaire, Vaccinologie et Biothérapie Anti-Infectieuse, IFR des Agents Transmissibles et Infectiologie, UFR de Pharmacie, 31, Avenue Monge, 37200 Tours, France; VitamFero, UFR de Pharmacie, 31, Avenue Monge, 37200 Tours, France; Institut Pasteur, Unité d'Immunologie Moléculaire des Parasites - CNRS URA 2581 25, rue du Docteur-Roux, 75724 Paris cedex 15, France.

Neospora caninum and Toxoplasma gondii are closely related, obligate intracellular parasites infecting a wide range of vertebrate hosts and causing abortion and neonatal morbidity and mortality. Several lines of evidence suggest that cross immunity between these two pathogens could be exploited in the design of strategies for heterologous vaccination. We assessed the ability of an attenuated strain of T. gondii (mic1-3KO) conferring strong protection against chronic and congenital toxoplasmosis to protect mice against lethal N. caninum infection. Mice immunized with mic1-3KO tachyzoites, by the oral and intraperitoneal routes, developed a strong cellular Th1 response and displayed significant protection against lethal heterologous N. caninum infection, with survival rates of 70% and 80%, respectively; whereas only 30% of the non immunized mice survived. We report here the acquisition of heterologous protective immunity against N. caninum following immunization with a live attenuated mic1-3KO strain of T. gondii.

PMID: 19995895 [PubMed - as supplied by publisher]

Ovine toxoplasmosis

Parasitology. 2009 Dec;136(14):1887-94.

Ovine toxoplasmosis

Innes EA, Bartley PM, Buxton D, Katzer F.

Moredun Research Institute, Pentlands Science Park, Edinburgh EH26 OPZ.

SUMMARYCongenital infection with Toxoplasma gondii is an important cause of abortion in sheep worldwide. The cat is the definitive host of the parasite, and infected cats may shed millions of oocysts in their faeces resulting in extensive environmental contamination and an important source of infection for grazing herbivorous animals. Studies looking at development of specific antibodies in sheep, as an indicator of exposure to T. gondii, have shown that there is an increase in seroprevalence associated with age indicating that most infections in sheep occur following birth. The stage of gestation when transplacental transmission of T. gondii to the developing foetus occurs is critical in determining the clinical outcome. The importance of endogenous transplacental transmission in persistently infected ewes and its clinical importance is a subject of current debate. Ewes infected prior to mating develop immune responses that help protect against disease in a subsequent pregnancy and also against experimental challenge administered during pregnancy. Both innate and adaptive immune responses are activated following T. gondii infection and experiments involving the chronic cannulation of peripheral lymph nodes in sheep have allowed the dynamics of the immune responses to be analysed in real time. A live vaccine, Toxovax(R) is the only commercially available vaccine worldwide to protect against congenital toxoplasmosis.

PMID: 19995468 [PubMed - in process]

Modelling parasite dissemination: Host cell subversion and immune evasion by Toxoplasma

Cell Microbiol. 2009 Dec 8. [Epub ahead of print]

Modelling parasite dissemination: Host cell subversion and immune evasion by Toxoplasma gondii

Lambert H, Barragan A.

Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, SE-141 86 Stockholm, Sweden.

Protozoan parasites belong to the most widespread and devastating human pathogens. Their ability to manipulate host responses and establish infection in their hosts continues to puzzle researchers. Recent developments of experimental model systems are contributing to the discovery of new aspects of the biology of parasite dissemination. Here, we review current knowledge on strategies utilized by the apicomplexan parasite Toxoplasma gondii to disseminate and establish infection in its host. Recent findings have revealed intricate mechanisms by which this obligate intracellular protozoan sequesters cellular functions of the immune system to assure propagation. These mechanisms include the hijacking of migratory leukocytes, modulation of migratory properties of infected cells, and rapid transfer of parasites between different leukocyte populations by cytotoxicity-induced parasite egress. Collectively, Toxoplasma strikes a delicate balance, assuring efficient dissemination and establishment of asymptomatic life-long infection in its host while protecting its intracellular entity and limiting host pathology.

PMID: 19995386 [PubMed - as supplied by publisher]

Toxoplasma gondii infection and cerebral toxoplasmosis in HIV-infected patients

Future Microbiol. 2009 Dec;4:1363-79.

Toxoplasma gondii infection and cerebral toxoplasmosis in HIV-infected patients

Pereira-Chioccola VL, Vidal JE, Su C.

Laboratório de Parasitologia, Instituto Adolfo Lutz, Av. Dr Arnaldo, 351, 8 andar, CEP 01246-902, São Paulo, SP, Brazil. pchioccola@ial.sp.gov.br.

Cerebral toxoplasmosis is a major cause of morbidity and mortality among HIV-infected patients, particularly from developing countries. This article summarizes current literature on cerebral toxoplasmosis. It focuses on: Toxoplasma gondii genetic diversity and its possible relationship with disease presentation; host responses to the parasite antigens; host immunosupression in HIV and cerebral toxoplasmosis as well as different diagnostic methods; clinical and radiological features; treatment; and the direction that studies on cerebral toxoplasmosis will likely take in the future.

PMID: 19995194 [PubMed - in process]

Saturday, December 05, 2009

4-Bromophenacyl Bromide Specifically Inhibits Rhoptry Secretion during Toxoplasma Invasion

PLoS One. 2009 Dec 2;4(12):e8143.

4-Bromophenacyl Bromide Specifically Inhibits Rhoptry Secretion during Toxoplasma Invasion

Ravindran S, Lodoen MB, Verhelst SH, Bogyo M, Boothroyd JC.

Department of Microbiology and Immunology, Stanford University, Stanford, California, United States of America.

Toxoplasma gondii is a eukaryotic parasite of the phylum Apicomplexa that is able to infect a wide variety of host cells. During its active invasion process it secretes proteins from discrete secretory organelles: the micronemes, rhoptries and dense granules. Although a number of rhoptry proteins have been shown to be involved in important interactions with the host cell, very little is known about the mechanism of secretion of any Toxoplasma protein into the host cell. We used a chemical inhibitor of phospholipase A2s, 4-bromophenacyl bromide (4-BPB), to look at the role of such lipases in the secretion of Toxoplasma proteins. We found that 4-BPB was a potent inhibitor of rhoptry secretion in Toxoplasma invasion. This drug specifically blocked rhoptry secretion but not microneme secretion, thus effectively showing that the two processes can be de-coupled. It affected parasite motility and invasion, but not attachment or egress. Using propargyl- or azido-derivatives of the drug (so-called click chemistry derivatives) and a series of 4-BPB-resistant mutants, we found that the drug has a very large number of target proteins in the parasite that are involved in at least two key steps: invasion and intracellular growth. This potent compound, the modified "click-chemistry" forms of it, and the resistant mutants should serve as useful tools to further study the processes of Toxoplasma early invasion, in general, and rhoptry secretion, in particular.

PMID: 19956582 [PubMed - in process]

Thursday, December 03, 2009

IL-33 receptor (T1/ST2) signalling is necessary to prevent the development of encephalitis in mice infected with Toxoplasma gondii

Eur J Immunol. 2009 Nov 30. [Epub ahead of print]

IL-33 receptor (T1/ST2) signalling is necessary to prevent the development of encephalitis in mice infected with Toxoplasma gondii

Jones LA, Roberts F, Nickdel MB, Brombacher F, McKenzie AN, Henriquez FL, Alexander J, Roberts CW.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.

T1/ST2 is an immunoregulatory protein of the IL-1 receptor (IL-1R) family that has recently been reported as being a component of the IL-33 receptor (IL-33R). IL-33 is a newly described cytokine known to amplify the Th2 response and reduce production of Th1 cytokines. The function of T1/ST2 during Toxoplasma gondii infection is as yet undescribed. Given the requirement of a balanced type 1/type2 response for effective control of parasite number and immunopathology, it is likely that T1/ST2 may play a part in aiding this process. Accordingly, we have shown that T1/ST2 mRNA transcripts are upregulated in the brains of mice infected with T. gondii and that mice deficient in T1/ST2 demonstrated increased susceptibility to infection with T. gondiithat correlated with increased pathology and greater parasite burden in the brains. Real time PCR analysis of cerebral cytokine levels revealed increased mRNA levels of iNOS, IFN-gamma and TNF-alpha in infected T1/ST2-/- mice. These effects were independent of changes in IL-10 production. This study provides the first evidence of a specific role for IL-33 receptor signaling in the brain as well as highlighting the requirement of this mechanism in limiting infection with an intracellular parasite.

PMID: 19950183 [PubMed - as supplied by publisher]