PLoS Pathog. 2013 Dec;9(12):e1003809. doi: 10.1371/journal.ppat.1003809. Epub 2013 Dec 19.

Toxoplasma gondii-Induced Activation of EGFR Prevents Autophagy Protein-Mediated Killing of the Parasite

Muniz-Feliciano L1, Van Grol J1, Portillo JA2, Liew L3, Liu B3, Carlin CR4, Carruthers VB5, Matthews S3, Subauste CS6.

Author information

Abstract

Toxoplasma gondii resides in an intracellular compartment (parasitophorous vacuole) that excludes transmembrane molecules required for endosome - lysosome recruitment. Thus, the parasite survives by avoiding lysosomal degradation. However, autophagy can re-route the parasitophorous vacuole to the lysosomes and cause parasite killing. This raises the possibility that T. gondii may deploy a strategy to prevent autophagic targeting to maintain the non-fusogenic nature of the vacuole. We report that T. gondii activated EGFR in endothelial cells, retinal pigment epithelial cells and microglia. Blockade of EGFR or its downstream molecule, Akt, caused targeting of the parasite by LC3(+) structures, vacuole-lysosomal fusion, lysosomal degradation and killing of the parasite that were dependent on the autophagy proteins Atg7 and Beclin 1. Disassembly of GPCR or inhibition of metalloproteinases did not prevent EGFR-Akt activation. T. gondii micronemal proteins (MICs) containing EGF domains (EGF-MICs; MIC3 and MIC6) appeared to promote EGFR activation. Parasites defective in EGF-MICs (MIC1 ko, deficient in MIC1 and secretion of MIC6; MIC3 ko, deficient in MIC3; and MIC1-3 ko, deficient in MIC1, MIC3 and secretion of MIC6) caused impaired EGFR-Akt activation and recombinant EGF-MICs (MIC3 and MIC6) caused EGFR-Akt activation. In cells treated with autophagy stimulators (CD154, rapamycin) EGFR signaling inhibited LC3 accumulation around the parasite. Moreover, increased LC3 accumulation and parasite killing were noted in CD154-activated cells infected with MIC1-3 ko parasites. Finally, recombinant MIC3 and MIC6 inhibited parasite killing triggered by CD154 particularly against MIC1-3 ko parasites. Thus, our findings identified EGFR activation as a strategy used by T. gondii to maintain the non-fusogenic nature of the parasitophorous vacuole and suggest that EGF-MICs have a novel role in affecting signaling in host cells to promote parasite survival.

PMID:

 

24367261

 

[PubMed - in process] 

PMCID:

 

PMC3868508

 

PLoS Pathog. 2013 Dec;9(12):e1003779. doi: 10.1371/journal.ppat.1003779. Epub 2013 Dec 19.

Transcriptional analysis of murine macrophages infected with different toxoplasma strains identifies novel regulation of host signaling pathways

Melo MB1, Nguyen QP1, Cordeiro C2, Hassan MA1, Yang N1, McKell R1, Rosowski EE1, Julien L1, Butty V1, Dardé ML3, Ajzenberg D3,Fitzgerald K4, Young LH5, Saeij JP1.

Author information

Abstract

Most isolates of Toxoplasma from Europe and North America fall into one of three genetically distinct clonal lineages, the type I, II and III lineages. However, in South America these strains are rarely isolated and instead a great variety of other strains are found. T. gondii strains differ widely in a number of phenotypes in mice, such as virulence, persistence, oral infectivity, migratory capacity, induction of cytokine expression and modulation of host gene expression. The outcome of toxoplasmosis in patients is also variable and we hypothesize that, besides host and environmental factors, the genotype of the parasite strain plays a major role. The molecular basis for these differences in pathogenesis, especially in strains other than the clonal lineages, remains largely unexplored. Macrophages play an essential role in the early immune response against T. gondii and are also the cell type preferentially infected in vivo. To determine if non-canonical Toxoplasma strains have unique interactions with the host cell, we infected murine macrophages with 29 different Toxoplasma strains, representing global diversity, and used RNA-sequencing to determine host and parasite transcriptomes. We identified large differences between strains in the expression level of known parasite effectors and large chromosomal structural variation in some strains. We also identified novel strain-specifically regulated host pathways, including the regulation of the type I interferon response by some atypical strains. IFNβ production by infected cells was associated with parasite killing, independent of interferon gamma activation, and dependent on endosomal Toll-like receptors in macrophages and the cytoplasmic receptor retinoic acid-inducible gene 1 (RIG-I) in fibroblasts.

PMID:

 

24367253

 

[PubMed - in process] 

PMCID:

 

PMC3868521

 

Antimicrob Agents Chemother. 2013 Dec 23. [Epub ahead of print]

Spiroindolone that inhibits PfATPase4 is a potent, cidal Inhibitor of Toxoplasma gondii tachyzoites in vitro and in vivo

Zhou Y, Fomovska A, Muench S, Lai BS, Mui E, McLeod R.

Author information

Abstract

Herein, we show that spiroindolone, an effective treatment of Plasmodia, is also active against T. gondii tachyzoites. In vitro, spiroindolone NITD 609 is cidal for tachyzoites (IC50= 1μM) and not toxic to human cells at ≥10μM. Two daily oral doses of 100mg/Kg reduced parasite burden by 90% (p=0.002), measured 3 days after last dose. This inhibition of T. gondii tachyzoites in vitro and in vivo indicates spiroindolone is a promising lead candidate for further medicine development.

PMID:

 

24366743

 

[PubMed - as supplied by publisher]

Characterization and binding analysis of a microneme adhesive repeat domain-containing protein from Toxoplasma

Parasitol Int. 2013 Dec 18. pii: S1383-5769(13)00207-9. doi: 10.1016/j.parint.2013.12.006. [Epub ahead of print]

Characterization and binding analysis of a microneme adhesive repeat domain-containing protein from Toxoplasma gondii

Gong H1, Kobayashi K2, Sugi T3, Takemae H4, Ishiwa A3, Recuenco FC3, Murakoshi F2, Xuan X4, Horimoto T2, Akashi H2, Kato K5.

Author information

Abstract

The intracellular parasite Toxoplasma gondii invades almost all nucleated cells, and has infected approximately 34% of the world's population to date. In order to develop effective vaccines against T. gondii infection, understanding of the role of the molecules that are involved in the invasion process is important. For this purpose, we characterized T. gondii proteins that contain microneme adhesive repeats (MAR), which are common in moving junction proteins. T. gondii MAR domain-containing protein 4a (TgMCP4a), which contains repeats of 17-22 amino acid segments at the N-terminus and three putative MAR domains at the C-terminus, is localized near the rhoptry of extracellular parasites. Following infection, TgMCP4a was detected in the parasitophorous vacuole. The recombinant Fc-TgMCP4a N-terminus protein (rTgMCP4a-1/Fc) showed binding activity to the surface proteins of Vero, 293T, and CHO cells. The recombinant GST-TgMCP4a N-terminus protein (rTgMCP4a-1/GST), which exhibited binding activity, was used to pull down the interacting factors from 293T cell lysate, and subsequent mass spectrometry analysis revealed that three types of heat shock proteins (HSPs) interacted with TgMCP4a. Transfection of a FLAG fusion protein of TgMCP4a-1 (rTgMCP4a-1/FLAG) into 293T cell and the following immunoprecipitation with anti-FLAG antibody confirmed the interactions of HSC70 with TgMCP4a. The addition of rTgMCP4a-1/GST into the culture medium significantly affected the growth of the parasite. This study hints that T. gondii may employ HSP proteins of host cell to facilitate their growth.

Copyright © 2013. Published by Elsevier Ireland Ltd.

KEYWORDS:

Heat shock protein, TgMCP4a, Toxoplasma

PMID:

 

24361285

 

[PubMed - as supplied by publisher]

Toxoplasma gondii infection of fibroblasts causes the production of exosome-like vesicles

J Extracell Vesicles. 2013 Dec 11;2. doi: 10.3402/jev.v2i0.22484.

Toxoplasma gondii infection of fibroblasts causes the production of exosome-like vesicles containing a unique array of mRNA and miRNA transcripts compared to serum starvation

Pope SM1, Lässer C2.

Author information

Abstract

BACKGROUND:

Until recently thought to be of little significance unless occurring during pregnancy, Toxoplasma gondii infection of human hosts is now known to play a larger role in mental health and is a growing concern in the health care community. We sought to elucidate a possible mechanism by which Toxoplasma infection may cause some of the behavioural pathology now associated with infection. We hypothesized that exosomes may be playing a role.

METHODS:

We utilized electron microscopy to detect the presence and size of extracellular vesicles in the supernatants of Toxoplasma-infected human foreskin fibroblasts (HFF). We then utilized microarray analysis to discern mRNA and miRNA content of the vesicles isolated from supernatants of Toxoplasma-infected (Toxo) and serum-starved (SS) HFF.

RESULTS:

We recovered extracellular vesicles with a size consistent with exosomes that we called exosome-like vesicles (ELVs) from the supernatants of SS and Toxo cultures. The mRNA and miRNA content of these ELVs was highly regulated creating specific and unique expression profiles comparing Toxo ELVs, SS ELVs and RNA isolated from whole cell homogenates. Interestingly, among the most enriched mRNA isolated from ELVs of Toxo cells are 4 specific mRNA species that have been described in the literature as having neurologic activity: Rab-13, eukaryotic translation elongation factor 1 alpha 1, thymosin beta 4 and LLP homolog. In addition, miRNA species uniquely expressed in Toxo ELVs include miR-23b, a well-known regulator of IL-17.

CONCLUSION:

While the production of ELVs containing mRNAs that modify behaviour are consistent with reported Toxoplasma pathology, the mechanism of enrichment and ultimate in vivo effect of these mRNA and miRNA containing ELVs remains to be investigated.

KEYWORDS:

Toxoplasma, exosomes, extracellular vesicles, mRNA, miRNA, microarray

PMID:

 

24363837

 

[PubMed]

Oncoimmunology. 2013 Nov 1;2(11):e26296. Epub 2013 Oct 9.

Non-replicating Toxoplasma gondii reverses tumor-associated immunosuppression

Fox BA, Sanders KL, Bzik DJ.

Author information

Abstract

We examined the efficacy of using attenuated non-replicating Toxoplasma gondii uracil auxotrophs that can be safely delivered as anticancer immunotherapeutics. This strategy exerted remarkable therapeutic activity in murine models of melanoma and ovarian carcinoma, and holds broad potential for the development of novel, highly effective anticancer vaccines.

KEYWORDS:

CD8+ T cells, anticancer vaccines, cancer immunotherapy, non-replicating Toxoplasma gondii, reversing tumor-derived immunosuppression

PMID:

 

24353916

 

[PubMed]

Int J Environ Res Public Health. 2013 Dec 9;10(12):6873-86. doi: 10.3390/ijerph10126873.

The evolutionary puzzle of suicide

Aubin HJ, Berlin I, Kornreich C.

Author information

Abstract

Mechanisms of self-destruction are difficult to reconcile with evolution's first rule of thumb: survive and reproduce. However, evolutionary success ultimately depends on inclusive fitness. The altruistic suicide hypothesis posits that the presence of low reproductive potential and burdensomeness toward kin can increase the inclusive fitness payoff of self-removal. The bargaining hypothesis assumes that suicide attempts could function as an honest signal of need. The payoff may be positive if the suicidal person has a low reproductive potential. The parasite manipulation hypothesis is founded on the rodent-Toxoplasma gondii host-parasite model, in which the parasite induces a "suicidal" feline attraction that allows the parasite to complete its life cycle. Interestingly, latent infection by T. gondii has been shown to cause behavioral alterations in humans, including increased suicide attempts. Finally, we discuss how suicide risk factors can be understood as nonadaptive byproducts of evolved mechanisms that malfunction. Although most of the mechanisms proposed in this article are largely speculative, the hypotheses that we raise accept self-destructive behavior within the framework of evolutionary theory.

PMID:

 

24351787

 

[PubMed - in process] 

Arch Microbiol. 2013 Dec 14. [Epub ahead of print]

DNA repair mechanisms and Toxoplasma gondii infection

Smolarz B, Wilczyński J, Nowakowska D.

Author information

Abstract

Lately, we can observe significant progress in understanding mechanism of DNA repair owing to fast methods of DNA sequence analysis from different organisms the revealing of structure and function of DNA repair proteins in prokaryota and eukaryota. The protozoan parasites survival depends on DNA repair systems. Better understanding of DNA repair systems can help in new antipathogen drug development. This review is aimed at updating our current knowledge of the various repair pathways by providing an overview of DNA repair genes regarding Toxoplasma gondii infections and the corresponding proteins, participating either directly in DNA repair, or in checkpoint control and signaling of DNA damage.

PMID:

 

24337694

 

[PubMed - as supplied by publisher]

Parasit Vectors. 2013 Dec 16;6(1):356. [Epub ahead of print]

STAT3-dependent transactivation of mirna genes following Toxoplasma gondii infection in macrophage

Cai Y, Chen H, Jin L, You Y, Shen J.

Abstract

BACKGROUND:

The apicomplexan parasite Toxoplasma gondii can infect and replicate in virtually any nucleated cell in many species of warm-blooded animals; T. gondii has elaborate mechanisms to counteract host-cell apoptosis in order to maintain survival and breed in the host cells.

METHODS:

Using microarray profiling and a combination of conventional molecular approaches, we investigated the levels of microRNAs (miRNAs ) in human macrophage during T. gondii infection. We used molecular tools to examine Toxoplasma-upregualted miRNAs to revealed potential signal transducers and activators of transcription 3( STAT3) binding sites in the promoter elements of a subset of miRNA genes. We analysed the apoptosis of human macrophage with the functional inhibition of the STAT3-binding miRNAs by flow cytometry.

RESULTS:

Our results demonstrated differential alterations in the mature miRNA expression profile in human macrophage following T. gondii infection. Database analysis of Toxoplasma-upregulated miRNAs revealed potential STAT3 binding sites in the promoter elements of a subset of miRNA genes. We demonstrated that miR-30c-1, miR-125b-2, miR-23b-27b-24-1 and miR-17 ~ 92 cluster genes were transactivated through promoter binding of the STAT3 following T. gondii infection. Importantly, functional inhibition of selected STAT3-binding miRNAs in human macropahges increased apoptosis of host cells.

CONCLUSIONS:

A panel of miRNAs is regulated through promoter binding of the STAT3 in human macrophage and these miRNAs are involved in anti-apoptosis in response to T. gondii infection.

PMID:

 

24341525

 

[PubMed - as supplied by publisher]

Schizophr Res. 2013 Dec 14. pii: S0920-9964(13)00607-5. doi: 10.1016/j.schres.2013.11.011. [Epub ahead of print]

Evaluation of kynurenine pathway metabolism in Toxoplasma gondii-infected mice: Implications for schizophrenia

Notarangelo FM1, Wilson EH2, Horning KJ3, Thomas MA3, Harris TH2, Fang Q2, Hunter CA2, Schwarcz R3.

Author information

Abstract

Toxoplasma gondii, an intracellular protozoan parasite, is a major cause of opportunistic infectious disease affecting the brain and has been linked to an increased incidence of schizophrenia. In murine hosts, infection with T. gondii stimulates tryptophan degradation along the kynurenine pathway (KP), which contains several neuroactive metabolites, including 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN) and kynurenic acid (KYNA). As these endogenous compounds may provide a mechanistic connection between T. gondii and the pathophysiology of schizophrenia, we measured KP metabolites in both the brain and periphery of T. gondii-treated C57BL/6 mice 8 and 28days post-infection. Infected mice showed early decreases in the levels of tryptophan in the brain and serum, but not in the liver. These reductions were associated with elevated levels of kynurenine, KYNA, 3-HK and QUIN in the brain. In quantitative terms, the most significant increases in these KP metabolites were observed in the brain at 28days post-infection. Notably, the anti-parasitic drugs pyrimethamine and sulfadiazine, a standard treatment of toxoplasmosis, significantly reduced 3-HK and KYNA levels in the brain of infected mice when applied between 28 and 56days post-infection. In summary, T. gondii infection, probably by activating microglia and astrocytes, enhances the production of KP metabolites in the brain. However, during the first two months after infection, the KP changes in these mice do not reliably duplicate abnormalities seen in the brain of individuals with schizophrenia.

Copyright © 2013 Elsevier B.V. All rights reserved.

KEYWORDS:

3-HK, 3-Hydroxykynurenine, 3-hydroxykynurenine, Astrocytes, IDO, KYNA, Kynurenic acid, Microglia, QUIN, Quinolinic acid, T. gondii, Toxoplasma gondii, indoleamine 2,3-dioxygenase, quinolinic acid

PMID:

 

24345671

 

[PubMed - as supplied by publisher]

MBio. 2013 Dec 10;4(6). pii: e00922-13. doi: 10.1128/mBio.00922-13.

The Histone Code of Toxoplasma gondii Comprises Conserved and Unique Posttranslational Modifications

Nardelli SC, Che FY, Silmon de Monerri NC, Xiao H, Nieves E, Madrid-Aliste C, Angel SO, Sullivan WJ Jr, Angeletti RH, Kim K, Weiss LM.

Source

Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.

Abstract

ABSTRACT Epigenetic gene regulation has emerged as a major mechanism for gene regulation in all eukaryotes. Histones are small, basic proteins that constitute the major protein component of chromatin, and posttranslational modifications (PTM) of histones are essential for epigenetic gene regulation. The different combinations of histone PTM form the histone code for an organism, marking functional units of chromatin that recruit macromolecular complexes that govern chromatin structure and regulate gene expression. To characterize the repertoire of Toxoplasma gondii histone PTM, we enriched histones using standard acid extraction protocols and analyzed them with several complementary middle-down and bottom-up proteomic approaches with the high-resolution Orbitrap mass spectrometer using collision-induced dissociation (CID), higher-energy collisional dissociation (HCD), and/or electron transfer dissociation (ETD) fragmentation. We identified 249 peptides with unique combinations of PTM that comprise the T. gondii histone code. T. gondii histones share a high degree of sequence conservation with human histones, and many modifications are conserved between these species. In addition, T. gondii histones have unique modifications not previously identified in other species. Finally, T. gondii histones are modified by succinylation, propionylation, and formylation, recently described histone PTM that have not previously been identified in parasitic protozoa. The characterization of the T. gondii histone code will facilitate in-depth analysis of how epigenetic regulation affects gene expression in pathogenic apicomplexan parasites and identify a new model system for elucidating the biological functions of novel histone PTM. IMPORTANCE Toxoplasma gondii is among the most common parasitic infections in humans. The transition between the different stages of the T. gondii life cycle are essential for parasite virulence and survival. These differentiation events are accompanied by significant changes in gene expression, and the control mechanisms for these transitions have not been elucidated. Important mechanisms that are involved in the control of gene expression are the epigenetic modifications that have been identified in several eukaryotes. T. gondii has a full complement of histone-modifying enzymes, histones, and variants. In this paper, we identify over a hundred PTM and a full repertoire of PTM combinations for T. gondii histones, providing the first large-scale characterization of the T. gondii histone code and an essential initial step for understanding how epigenetic modifications affect gene expression and other processes in this organism.

PMID:

24327343

[PubMed - in process]

Brain Behav Immun. 2013 Dec 6. pii: S0889-1591(13)00578-3. doi: 10.1016/j.bbi.2013.11.019. [Epub ahead of print]

Toxoplasma gondii impairs memory in infected seniors

Gajewski PD, Falkenstein M, Hengstler JG, Golka K.

Source

Leibniz Research Centre for Working Environment and Human Factors (IfADo) WHO Collaborating Centre for Occupational Health, Dortmund, Germany. Electronic address: gajewski@ifado.de.

Abstract

Almost 30% of humans present a Toxoplasma gondii positive antibody status and its prevalence increases with age. The central nervous system is the main target. However, little is known about the influence of asymptomatic i.e. latent Toxoplasmosis on cognitive functions in humans. To investigate neurocognitive dysfunctions in asymptomatic older adults with Toxoplasma gondii positive antibody status a double-blinded neuropsychological study was conducted. The participants were classified from a population-based sample (N=131) of healthy participants with an age of 65 years and older into two groups with 42 individuals each: Toxoplasmosis positive (T-pos; IgG50 IU/ml) and Toxoplasmosis negative (T-neg; IgG=0 IU/ml). The outcome measures were a computer-based working-memory test (2-back) and several standardized psychometric tests of memory and executive cognitive functions. T-pos seniors showed an impairment of different aspects of memory. The rate of correctly detected target symbols in a 2-back task was decreased by nearly 9% (P=0.020), corresponding to a performance reduction of about 35% in working memory relative to the T-neg group. Moreover, T-pos seniors had a lower performance in a verbal memory test, both regarding immediate recall (10% reduction; P=0.022), delayed recognition (6%; P=0.037) and recall from long-term memory assessed by the word fluency tests (12%; P=0.029). In contrast, executive functions were not affected. The effects remained mostly unchanged after controlling for medication. The impairment of memory functions in T-pos seniors was accompanied by a decreased self-reported quality of life. Because of the high prevalence of asymptomatic Toxoplasmosis and an increasing population of older adults this finding is of high relevance for public health.
Copyright © 2013. Published by Elsevier Inc.

KEYWORDS:

Aging, Cognition, Dopamine, Memory, Toxoplasma gondii

PMID:

24321215

[PubMed - as supplied by publisher]

ScientificWorldJournal. 2013 Nov 12;2013:480231. doi: 10.1155/2013/480231.

In Astrocytes the Accumulation of the Immunity-Related GTPases Irga6 and Irgb6 at the Vacuole of Toxoplasma gondii Is Dependent on the Parasite Virulence

Lubitz FP, Degrandi D, Pfeffer K, Mausberg AK.

Source

Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University, Universitaetsstrasse 1, 40225 Duesseldorf, Germany.

Abstract

Toxoplasma gondii is an obligate intracellular protozoan parasite responsible for a common infection of the central nervous system. Interferon (IFN) γ is the key cytokine of host defence against T. gondii. However, T. gondii strains differ in virulence and T. gondii factors determining virulence are still poorly understood. In astrocytes IFN γ primarily induces immunity-related GTPases (IRGs), providing a cell-autonomous resistance system. Here, we demonstrate that astrocytes prestimulated with IFN γ inhibit the proliferation of various avirulent, but not virulent, T. gondii strains. The two analyzed immunity-related GTPases Irga6 and Irgb6 accumulate at the PV only of avirulent T. gondii strains, whereas in virulent strains this accumulation is only detectable at very low levels. Both IRG proteins could temporarily be found at the same PV, but did only partially colocalize. Coinfection of avirulent and virulent parasites confirmed that the accumulation of the two analyzed IRGs was a characteristic of the individual PV and not determined by the presence of other strains of T. gondii in the same host cell. Thus, in astrocytes the accumulation of Irga6 and Irgb6 significantly differs between avirulent and virulent T. gondii strains correlating with the toxoplasmacidal properties suggesting a role for this process in parasite virulence.

PMID:

24324375

[PubMed - in process]

Biochemistry. 2013 Dec 2. [Epub ahead of print]

Discrimination of Potent Inhibitors of Toxoplasma gondii Enoyl-Acyl Carrier Protein Reductase by Thermal Shift Assay

Afanador GA, Muench SP, McPhillie M, Fomovska A, Schön A, Zhou Y, Cheng G, Stec J, Freundlich JS, Shieh HM, Anderson JW, Jacobus DP, Fidock DA, Kozikowski AP, Fishwick CW, Rice DW, Freire E, McLeod R, Prigge ST.

Abstract

Many microbial pathogens rely on a type II fatty acid synthesis (FASII) pathway which is distinct from the type I pathway found in humans. Enoyl-Acyl Carrier Protein Reductase (ENR) is an essential FASII pathway enzyme and the target of a number of antimicrobial drug discovery efforts. The biocide triclosan is established as a potent inhibitor of ENR and has been the starting point for medicinal chemistry studies. We evaluated a series of triclosan analogs for their ability to inhibit the growth of Toxoplasma gondii, a pervasive human pathogen, and its ENR enzyme (TgENR). Several compounds were identified that inhibited TgENR at low nanomolar concentrations, but could not be further differentiated due to the limited dynamic range of the TgENR activity assay. Thus, we adapted a thermal shift assay (TSA) to directly measure the dissociation constant (Kd) of the most potent inhibitors identified in this study as well as inhibitors from previous studies. Furthermore, the TSA allowed us to determine the mode of action of these compounds in the presence of NADH or NAD+ cofactors. We found that all of the inhibitors bind to a TgENR/NAD+ complex, but that they differed in their dependence on NAD+ concentration. Ultimately, we were able to identify compounds which bind to the TgENR/NAD+ complex in the low femtomolar range. This shows how TSA data combined with enzyme inhibition, parasite growth inhibition data and ADMET predictions allow for better discrimination between potent ENR inhibitors for future medicine development.

PMID:

24295325

[PubMed - as supplied by publisher]

Job opening: University Lectureship in Parasitology

The Department of Pathology is seeking to appoint a suitably qualified individual to a University Lectureship in Parasitology available from 1 October 2014 or as soon thereafter as practicable.
Applicants are expected to demonstrate excellence in research and a commitment to teaching at both undergraduate and postgraduate levels. The successful candidate will have a strong publication record in research and the potential to attract independent research funding is essential. The person appointed will be required to give lectures, to supervise graduate students, to examine at both undergraduate and graduate levels, to contribute to the Department's work in research and to actively participate in the general life of the Department including membership of committees.

The post has tenure, subject to satisfactory performance in the first 5 years, and is remunerated on the above scale according to experience.

Informal enquiries can be made to the Head of Department at hod.sec@path.cam.ac.uk
Interviews will be held the week commencing 27th January 2014

You may also be interested to note other opportunities on a related subject: 1) Research Group Leader, Department of Pathology, University of Cambridge

Once an offer of employment has been accepted, the successful candidate will be required to undergo a health assessment and a security check.

Applications can be made online, any queries should be emailed to jobs@path.cam.ac.uk or you can contact us on 01223 333940

Please quote reference PK02220 on your application and in any correspondence about this vacancy.
The University values diversity and is committed to equality of opportunity.
The University has a responsibility to ensure that all employees are eligible to live and work in the UK.

Further information

• Further Information
  Further Information - University Lecturer in Parasitology

Eur J Pharmacol. 2013 Nov 28. pii: S0014-2999(13)00886-8. doi: 10.1016/j.ejphar.2013.11.015. [Epub ahead of print]

Intracellular Calcium Channels in Protozoa

Docampo R, Moreno SN, Plattner H.

Source

Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, GA 30606, USA. Electronic address: rdocampo@uga.edu.

Abstract

Ca²⁺-signaling pathways and intracellular Ca²⁺ channels are present in protozoa. Ancient origin of inositol 1,4,5-trisphosphate receptors (IP₃Rs) and other intracellular channels predates the divergence of animals and fungi as evidenced by their presence in the choanoflagellate Monosiga brevicollis, the closest known relative to metazoans. The first protozoan IP₃R cloned, from the ciliate Paramecium, displays strong sequence similarity to the rat type 3 IP₃R. This ciliate has a large number of IP₃- and ryanodine(Ry)-like receptors in 6 subfamilies suggesting the evolutionary adaptation to local requirements for an expanding diversification of vesicle trafficking. IP₃Rs have also been functionally characterized in trypanosomatids, where they are essential for growth, differentiation, and establishment of infection. The presence of the mitochondrial calcium uniporter (MCU) in a number of protozoa indicates that mitochondrial regulation of Ca²⁺ signaling is also an early appearance in evolution, and contributed to the discovery of the molecular nature of this channel in mammalian cells. There is only sequence evidence for the occurrence of two-pore channels (TPCs), transient receptor potential Ca²⁺ channels (TRPCs) and intracellular mechanosensitive Ca²⁺-channels in Paramecium and in parasitic protozoa.
© 2013 Published by Elsevier B.V.

KEYWORDS:

Calcium channels, Mitochondrial calcium uniporter, Paramecium, Protozoa, Toxoplasma, Trypanosoma

PMID:

24291099

[PubMed - as supplied by publisher]