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]

ROBERT SAPOLSKY on Toxoplasma and behavior modification

Read the transcript or see the video here:

http://www.edge.org/documents/archive/edge307.html#tc

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]

Toxoplasmosis and Other Intestinal Coccidial Infections in Cats and Dogs

Vet Clin North Am Small Anim Pract. 2009 Nov;39(6):1009-1034.

Toxoplasmosis and Other Intestinal Coccidial Infections in Cats and Dogs

Dubey JP, Lindsay DS, Lappin MR.

United States Department of Agriculture, Agricultural Research Service, Animal and Natural Resources Institute, Beltsville Agricultural Research Center, Building 1001, Beltsville, MD, 20705-2350, USA.

Toxoplasma gondii and related coccidians are intracellular protozoan parasites. Coccidia are obligate intracellular parasites normally found in the intestinal tract. Virtually all warm blooded animals, including humans are commonly infected with coccidians. This article reviews the diagnosis, treatment, and prevention of infections in cats and dogs related to Isospora spp, Toxoplasma gondii, and Neospora caninum. Much remains to be learned concerning the pathogenesis of clinical coccidiosis.

PMID: 19932360 [PubMed - as supplied by publisher]

Characterizaion of a leucine aminopeptidase from Toxoplasma gondii

Mol Biochem Parasitol. 2009 Nov 17. [Epub ahead of print]

Characterizaion of a leucine aminopeptidase from Toxoplasma gondii

Jia H, Nishikawa Y, Luo Y, Yamagishi J, Sugimoto C, Xuan X.

National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido 080-8555, Japan; Department of Collaboration and Education, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido 001-0020, Japan.

The M17 family leucine aminopeptidase (LAP) hydrolyzes amino acids from the N-terminus of peptides. Many LAPs from parasitic protozoa, including Plasmodium, Trypanosoma, and Leishmania, have been intensely investigated because of their crucial roles in parasite biology. In this study, the functional recombinant Toxoplasma gondii LAP (rTgLAP) was expressed in Escherichia coli (E. coli), and its enzymatic activity against synthetic substrates for aminopeptidase, as well as cellular localization, were determined. The activity was strongly dependent on metal divalent cations, and was inhibited by bestatin, which is an inhibitor for metalloprotease. Our results indicated that TgLAP is a functional aminopeptidase in the cytoplasm of T. gondii.

PMID: 19931316 [PubMed - as supplied by publisher]

Mollaret Meningitis may be Caused by Reactivation of Latent Cerebral Toxoplasmosis

Int J Neurosci. 2009;119(10):1655-1692.

Mollaret Meningitis may be Caused by Reactivation of Latent Cerebral Toxoplasmosis

Prandota J.

Department of Social Pediatrics, Faculty of Public Health, University Medical School, 5 Bartla Street, 51-618, Wroclaw, Poland.

Mollaret meningitis (MM) occurs mainly in females and is characterized by recurrent episodes of headache, transient neurological abnormalities, and the cerebrospinal fluid containing mononuclear cells. HSV-2 was usually identified as the causative agent. Recently, we found that recurrent headaches in non-HIV-infected subjects were due to acquired cerebral toxoplasmosis (CT). The aim of the study was therefore to focus on molecular pathomechanisms that may lead to reactivation of latent CT and manifest as MM. Literature data cited in this work were selected to illustrate that various factors may affect latent CNS Toxoplasma gondii infection/inflammation intensity and/or host defense mechanisms, i.e., the production of NO, cytokines, tryptophan degradation by indoleamine 2,3-dioxygenase, mechanisms mediated by an IFN-gamma responsive gene family, limiting the availability of intracellular iron to T. gondii, and production of reactive oxygen/nitrogen species, finally inducing choroid plexitis and/or vasculitis. Examples of triggers revealing MM and accompanying disturbances of IFN-gamma-mediated immune responses that control HSV-2 and T. gondii include: female predominance (female mice are more susceptible to T. gondii infection than males); HSV-2 infection (increased IFN-gamma, IL-12); metaraminol (increased plasma catecholamine levels, changes in cytokine expression favoring T(H)2 cells responses); probably cholesterol contained in debris from ruptured epidermoid cysts (decreased NO; increased TNF-alpha, IL-6, IL-8). These irregularities induced by the triggers may be responsible for reactivation of latent CT and development of MM. Thus, subjects with MM should have test(s) for T. gondii infection performed obligatorily.

PMID: 19922380 [PubMed - as supplied by publisher]

Diagnosis of congenital toxoplasmosis using whole-blood interferon-{gamma} release assay

J Clin Microbiol. 2009 Nov 18. [Epub ahead of print]

Diagnosis of congenital toxoplasmosis using whole-blood interferon-{gamma} release assay

Chapey E, Wallon M, Debize G, Rabilloud M, Peyron F.

Hospices Civils de Lyon, Service de Parasitologie, Hôpital de la Croix Rousse, F-69317 Lyon, France; Université Claude Bernard Lyon 1, Service de Parasitologie, Faculté de Médecine Lyon Sud, F-69372 Lyon, France; Hospices Civils de Lyon, Laboratoire d'Hématologie, Hôpital de la Croix Rousse, F-69317 Lyon, France; Hospices Civils de Lyon, Service de Biostatistique, F-69424 Lyon, France; Université Claude Bernard Lyon 1, F-69622 Villeurbanne, France; CNRS, UMR 5558, Laboratoire Biostatistique Santé, F-69495 Pierre-Bénite, France.

Congenital toxoplasmosis at birth is generally subclinical but infected infants are at risk of developing ocular lesions. Diagnosis at birth relies mainly on serological tests. Cell- mediated immunity plays the major role in resistance to infection but is not routinely investigated for diagnostic purposes. Here we describe a simple test based on the response to interferon-gamma (IFN-gamma) after stimulation of whole blood by crude parasitic antigens. One millilitre of heparinized blood was centrifuged; plasma was kept for routine serological tests and pellets were resuspended in culture medium. After 24 h of culture in the presence of crude Toxoplasma gondii antigen, the cells were centrifuged and IFN-gamma was assayed in the supernatant. In 62 infants under 1 year of age born to mothers who were infected during pregnancy, the sensitivity and specificity were 94% (16/17) and 98% (44/45), respectively. The false negative was in a treated baby who turned positive after withdrawal of treatment. The false positive was observed in 3-month-old baby. In a cohort of 124 congenitally infected patients aged between 1 and 30 years, the sensitivity of the test was 100%. We present a simple test based on IFN-gamma secretion to assess cell-mediated immunity in toxoplasmosis. As only 1 mL of blood is required to investigate humoral and cellular immunity, our assay is well adapted for the study of congenital toxoplasmosis in infants. Using purified antigens or recombinant peptides might improve the test performances.

PMID: 19923492 [PubMed - as supplied by publisher]

Asymptomatic diffuse "encephalitic" cerebral toxoplasmosis in a patient with chronic lymphocytic leukemia: case report and review of the literature

Int J Clin Exp Pathol. 2009 Mar 15;3(1):106-9.

Asymptomatic diffuse "encephalitic" cerebral toxoplasmosis in a patient with chronic lymphocytic leukemia: case report and review of the literature

Abedalthagafi M, Rushing EJ, Garvin D, Cheson B, Ozdemirli M.

Opportunistic infections account for the majority of central nervous system lesions in adult immunosuppressed patients. In this setting, toxoplasmosis typically manifests as multiple abscesses readily seen on routine neuroimaging studies. Asymptomatic, widely disseminated Toxoplasma cysts without parenchymal reaction are also recognized. In contrast, widespread parasites in the brain parenchyma with an inflammatory "encephalitic" reaction and little or no necrosis have been reported in only four patients with acquired immune deficiency syndrome (AIDS). We describe a 70 year old male with stage IV chronic lymphocytic leukemia complicated by aplastic anemia. Neurological examination and imaging revealed no significant abnormalities. At autopsy, the brain revealed multifocal cysts and free tachyzoites of Toxoplasma gondii with diffuse microglial nodules and no necrosis. To the best of our knowledge, this case represents the first report of the "encephalitic" form of toxoplasmosis in a non-AIDS patient.

PMID: 19918334 [PubMed - in process]

Patient with toxoplasmosis and glucose-6-phosphate dehydrogenase deficiency: a case report

Cases J. 2009 Aug 6;2:8826.

Patient with toxoplasmosis and glucose-6-phosphate dehydrogenase deficiency: a case report

Nunes AA.

Department of Social Medicine, University of Sao Paulo, Avenida Bandeirantes 3900 - Monte Alegre, 14.048-900 - Ribeirao Preto SP Brazil.

INTRODUCTION: Toxoplasmosis, a zoonotic protozoal disease caused by toxoplasma gondii, is prevalent throughout the world, affecting a large proportion of persons who usually have no symptoms. Glucose 6 phosphate dehydrogenase deficiency, an X-linked inherited disorder, is present in over 400 million people world wide. It is more common in tropical and subtropical countries and is one of the important causes of hemolytic anemia. CASE PRESENTATION: This case report relates the occurrence of the two diseases simultaneously in a child of five years old. CONCLUSION: Patients with glucose-6-phosphate dehydrogenase deficiency are more susceptible to toxoplasmosis and this case report, reinforce the findings of this propensity and alert us for such possibility, what it is important, therefore, the treatment of toxoplasmosis can cause serious hemolysis in these patients.

PMID: 19918404 [PubMed - in process]

Congenital toxoplasmosis from a chronically infected woman with reactivation of retinochoroiditis during pregnancy - an underestimated event?

J Pediatr (Rio J). 2009 Nov 16;86(1). [Epub ahead of print]

Congenital toxoplasmosis from a chronically infected woman with reactivation of retinochoroiditis during pregnancy - an underestimated event?

Andrade GM, Vasconcelos-Santos DV, Carellos EV, Romanelli RM, Vitor RW, Carneiro AC, Januario JN.

Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil.

OBJECTIVE: To report a rare case of congenital toxoplasmosis from an immunocompetent mother with chronic infection who had reactivation of ocular disease during pregnancy. DESCRIPTION: The newborn was asymptomatic at birth and identified by neonatal screening (IgM anti-Toxoplasma gondii in dried blood) among other 190 infants with congenital toxoplasmosis during a 7-month period. His mother had had a non-treated episode of reactivation of toxoplasmic retinochoroiditis during pregnancy, with stable IgG titers and negative IgM results. Results of IgM and IgG in the newborn's serum, as well as IgG immunoblotting were positive and active retinochoroidal lesions were detected in his peripheral retina. The neonate was treated with sulfadiazine, pyrimethamine and folinic acid. At 14 months of life, the child remained asymptomatic, with regression of retinochoroidal lesions and persistence of IgG. COMMENTS: It is possible that systematic neonatal screening in areas with high prevalence of infection may identify these cases.

PMID: 19918624 [PubMed - as supplied by publisher]

Early Response of Mucosal Epithelial Cells during Toxoplasma gondii Infection

J Immunol. 2009 Nov 16. [Epub ahead of print]

Early Response of Mucosal Epithelial Cells during Toxoplasma gondii Infection

Ju CH, Chockalingam A, Leifer CA.

Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.

The innate immune response of mucosal epithelial cells during pathogen invasion plays a central role in immune regulation in the gut. Toxoplasma gondii is a protozoan intracellular parasite that is usually transmitted through oral infection. Although much of the information on immunity to T. gondii has come from i.p. infection models, more recent studies have revealed the importance of studying immunity following infection through the natural peroral route. Oral infection studies have identified many of the key players in the intestinal response; however, they have relied on responses detected days to weeks following infection. Much less is known about how the gut epithelial layer senses and reacts during initial contact with the pathogen. Given the importance of epithelial cells during pathogen invasion, this study uses an in vitro approach to isolate the key players and examine the early response of intestinal epithelial cells during infection by T. gondii. We show that human intestinal epithelial cells infected with T. gondii elicit rapid MAPK phosphorylation, NF-kappaB nuclear translocation, and secretion of IL-8. Both ERK1/2 activation and IL-8 secretion responses were shown to be MyD88 dependent and TLR2 was identified to be involved in the recognition of the parasite regardless of the parasite genotype. Furthermore, we were able to identify additional T. gondii-regulated genes in the infected cells using a pathway-focused array. Together, our findings suggest that intestinal epithelial cells were able to recognize T. gondii during infection, and the outcome is important for modulating intestinal immune responses.

PMID: 19917706 [PubMed - as supplied by publisher]

The importance of toxoplasma gondii infection in diseases presenting with headaches

Int J Neurosci. 2009;119(12):2144-82.

The importance of toxoplasma gondii infection in diseases presenting with headaches. Headaches and aseptic meningitis may be manifestations of the Jarisch-Herxheimer reaction

Prandota J.

Department of Social Pediatrics, Faculty of Public Health, University Medical School, Wroclaw, Poland. Prandota@ak.am.wroc.pl

Worldwide, approximately 2 billion people are chronically infected with T. gondii with largely unknown consequences. This review presents clinical symptoms, differential diagnosis, triggering factors, treatment, and pathomechanisms responsible for idiopathic intracranial hypertension, pseudotumor cerebri, and aseptic meningitis. Literature cited in this work illustrates that immune state and other biologic mediator imbalances due to various endogenous and exogenous triggering factors may markedly affect latent central nervous system T. gondii infection/inflammation intensity, and cause reactivation of cerebral toxoplasmosis (CT). Irregularities in pro- and anti-inflammatory processes may markedly disturb the host and/or T. gondii defense mechanisms important for immune control of the parasite thereby manifesting as a wide range of neurologic symptoms and signs observed in some patients with migraine, epilepsy, celiac disease, Henoch-Schönlein purpura, and other brain disorders. This is consistent with reactivation of CT in mice after treatment with dexamethasone associated with depression of type T(H)1 immune response, and development of CT after administration of etanercept or other bioproducts. It seems that various types of headaches, epilepsy, aseptic meningitis, systemic adverse reactions to drugs or other substances represent the Jarisch-Herxheimer reaction due to apoptosis of T. gondii tachyzoites. Also development of some brain tumors, such as ependymoma and glioma may be associated with a chronic course of CT. Thus, all these patients should be tested for T. gondii infection.

PMID: 19916846 [PubMed - in process]

EuPathDB: a portal to eukaryotic pathogen databases

Nucleic Acids Res. 2009 Nov 13. [Epub ahead of print]

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, Penn Center for Bioinformatics, University of Pennsylvania, Philadelphia, PA 19104, Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, Center for Applied Genetic Technologies, University of Georgia, Athens, GA 30602, Department of Genetics, University of Georgia, Athens, GA 30602 and Department of Computer Science, 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 - as supplied by publisher]

Up-regulation of hyaluronan receptors in Toxoplasma gondii-infected monocytic cells

Biochem Biophys Res Commun. 2009 Nov 12. [Epub ahead of print]

Up-regulation of hyaluronan receptors in Toxoplasma gondii-infected monocytic cells

Unno A, Kitoh K, Takashima Y.

Department of Veterinary Parasitological Diseases, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan; United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.

The apicomplexan, obligate intracellular parasite Toxoplasma gondii orally infects humans and animals. The parasites cross the intestinal epithelium, invade leukocytes in the general circulation and then disseminate into the peripheral organs. The mechanism of extravasation of the infected leukocytes, however, remains poorly understood. It is known that adhesion of leukocytes to extracellular matrix (ECM) is an important factor in extravasation, and CD44 and ICAM-1 on the leukocyte surface are known receptors for hyaluronan (HA), an ECM component. In this study, we demonstrated up-regulation of CD44 and ICAM-1 expression on the surface of T. gondii-infected human monocytic THP-1 cells and fresh isolated human monocyte. T. gondii-infected THP-1 cells adhered more efficiently to immobilized HA than did non-infected cells. T. gondii-infected monocytes in the general circulation might preferentially adhere to the ECM and migrate out from blood vessels, so transporting parasites into the peripheral organs.

PMID: 19914206 [PubMed - as supplied by publisher]

Toll-like receptor initiated host defense against Toxoplasma gondii

J Biomed Biotechnol. 2010;2010:737125. Epub 2009 Nov 11.

Toll-like receptor initiated host defense against Toxoplasma gondii

Denkers EY.

Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA. eyd1@cornell.edu

Toxoplasma gondii is an intracellular pathogen notable for its ability to establish a stable host-parasite relationship amongst a wide range of host species and in a large percentage of the human population. Toll-like receptor signaling through MyD88 is a critical pathway in initiating defense against this opportunistic protozoan and may also be a mediator of pathology during immune dysfunction. Other MyD88 independent signaling pathways are also involved in the host-parasite interaction. These responses can be triggered by the parasite itself, but interactions with the intestinal microbiota add additional complexity during enteric infection.

PMID: 19911079 [PubMed - in process]

A single polymorphic amino acid on Toxoplasma gondii kinase ROP16 determines the direct and strain-specific activation of Stat3

J Exp Med. 2009 Nov 9. [Epub ahead of print]

A single polymorphic amino acid on Toxoplasma gondii kinase ROP16 determines the direct and strain-specific activation of Stat3

Yamamoto M, Standley DM, Takashima S, Saiga H, Okuyama M, Kayama H, Kubo E, Ito H, Takaura M, Matsuda T, Soldati-Favre D, Takeda K.

Department of Microbiology and Immunology and 2 Department of Cardiovascular Medicine, Graduate School of Medicine, and 3 Laboratory of Mucosal Immunology and 4 Laboratory of Systems Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.

Infection by Toxoplasma gondii down-regulates the host innate immune responses, such as proinflammatory cytokine production, in a Stat3-dependent manner. A forward genetic approach recently demonstrated that the type II strain fails to suppress immune responses because of a potential defect in a highly polymorphic parasite-derived kinase, ROP16. We generated ROP16-deficient type I parasites by reverse genetics and found a severe defect in parasite-induced Stat3 activation, culminating in enhanced production of interleukin (IL) 6 and IL-12 p40 in the infected macrophages. Furthermore, overexpression of ROP16 but not ROP18 in mammalian cells resulted in Stat3 phosphorylation and strong activation of Stat3-dependent promoters. In addition, kinase-inactive ROP16 failed to activate Stat3. Comparison of type I and type II ROP16 revealed that a single amino acid substitution in the kinase domain determined the strain difference in terms of Stat3 activation. Moreover, ROP16 bound Stat3 and directly induced phosphorylation of this transcription factor. These results formally establish an essential and direct requirement of ROP16 in parasite-induced Stat3 activation and the significance of a single amino acid replacement in the function of type II ROP16.

PMID: 19901082 [PubMed - as supplied by publisher]

Members of a novel protein family containing MAR domains act as sialic acid-binding lectins during host cell invasion by apicomplexan parasites

J Biol Chem. 2009 Nov 9. [Epub ahead of print]

Members of a novel protein family containing MAR domains act as sialic acid-binding lectins during host cell invasion by apicomplexan parasites

Friedrich N, Santos JM, Liu Y, Palma AS, Leon E, Saouros S, Kiso M, Blackman MJ, Matthews S, Feizi T, Soldati-Favre D.

University of Geneva, Faculty of Medicine, Switzerland;

Numerous intracellular pathogens exploit cell surface glycoconjugates for host cell recognition and entry. Unlike bacteria and viruses, Toxoplasma gondii and other parasites of the phylum Apicomplexa actively invade host cells and this process critically depends on adhesins (MICs) released onto the parasite surface from intracellular organelles called micronemes. The microneme adhesive repeat (MAR) domain of T. gondii MIC1 (TgMIC1) recognizes sialic acid (Sia), a key determinant on the host-cell surface for invasion by this pathogen. By complementation and invasion assays, we demonstrate that TgMIC1 is one important player in Sia-dependent invasion, and that another novel Sia-binding lectin, designated TgMIC13, is also involved. Using BLAST searches, we identify a family of MAR-containing proteins in enteroparasitic coccidians, a subclass of apicomplexans including T. gondii, suggesting that all these parasites exploit sialylated glycoconjugates on host-cells as determinants for enteric invasion. Furthermore this protein family might provide a basis for the broad host-cell range observed for coccidians that form tissue cysts during chronic infection. Carbohydrate microarray analyses, corroborated by structural considerations, show that TgMIC13, TgMIC1 and its homologue Neospora caninum MIC1 (NcMIC1) share a preference for alpha2-3- over alpha2-6-linked sialyl-N-acetyllactosamine sequences. However, the three lectins also display differences in binding preferences. Intense binding of TgMIC13 to alpha2-9-linked disialyl-sequence reported on embryonal cells and relatively strong binding to 4-O-acetylated-Sia found on gut epithelium, and binding of NcMIC1 to 6'sulpho-sialyl Lewis(x) might have implications for tissue tropism.

PMID: 19901027 [PubMed - as supplied by publisher]