Thursday, November 28, 2013

Acute Toxoplasma gondii Infection among Family Members in the United States

 2013 Dec;19(12):1981-4. doi: 10.3201/eid1912.121892.

Acute Toxoplasma gondii Infection among Family Members in the United States

Abstract

We investigated 32 families of persons with acute toxoplasmosis in which >1 other family member was tested for Toxoplasma gondii infection; 18 (56%) families had >1 additional family member with acute infection. Family members of persons with acute toxoplasmosis should be screened for infection, especially pregnant women and immunocompromised persons.

KEYWORDS:

Toxoplasma, Toxoplasma gondii, United States, acute Toxoplasma infection, acute toxoplasmosis, families, parasites, protozoa, toxoplasmosis
PMID:
 
24274896
 
[PubMed - in process]

A Toxoplasma patatin-like protein changes localization and alters the cytokine response during toxoplasmic encephalitis

 2013 Nov 25. [Epub ahead of print]

A Toxoplasma patatin-like protein changes localization and alters the cytokine response during toxoplasmic encephalitis

Source

Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, 1550 Linden Drive Madison, WI 53706.

Abstract

Toxoplasma gondii is an obligate intracellular parasite that forms a life-long infection within the central nervous system of its host. The T. gondii genome encodes six members of the patatin-like phospholipase family; related proteins are associated with host-microbe interactions in bacteria. T. gondii patatin-like protein 1 (TgPL1) was previously determined to be necessary for parasites to suppress nitric oxide and prevent degradation in activated macrophages. Here we show that in the rapidly replicating tachyzoite stage, TgPL1 is localized within vesicles inside the parasite that are distinct from the dense granules; however, in the encysted bradyzoite stage, TgPL1 localizes to the parasitophorous vacuole (PV) and cyst wall. While we had not previously seen a defect of the TgPL1 deletion mutant (ΔTgPL1) during acute and early chronic infection, the localization change of TgPL1 in bradyzoites caused us to reevaluate the ΔTgPL1 mutant during late chronic infection and in a toxoplasmic encephalitis (TE) mouse model. Mice infected with ΔTgPL1 are more resistant to TE and have fewer inflammatory lesions than wild type and ΔTgPL1 genetically complemented with TgPL1 infected mice. This increased resistance to TE could result from several contributing factors. First, we found that ΔTgPL1 bradyzoites did not convert back to tachyzoites readily in tissue culture. Second, a subset of cytokine levels were higher in ΔTgPL1 infected mice, including interferon gamma (IFN-γ), tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1). These studies suggest that the TgPL1 plays a role in the maintenance of T. gondii chronic infection.
PMID:
 
24277794
 
[PubMed - as supplied by publisher]

Toxoplasma gondii inhibits IFN-γ- and IFN-β-induced host cell STAT1 transcriptional activity by increasing the association of STAT1 with DNA

 2013 Nov 25. [Epub ahead of print]

Toxoplasma gondii inhibits IFN-γ- and IFN-β-induced host cell STAT1 transcriptional activity by increasing the association of STAT1 with DNA

Rosowski EE, Nguyen QP, Camejo A, Spooner E, Saeij JP.

Source

Massachusetts Institute of Technology, Department of Biology, Cambridge, MA, USA.

Abstract

The IFN-γ response, mediated by the STAT1 transcription factor, is crucial for host defense against the intracellular pathogen Toxoplasma gondii, but prior infection with Toxoplasma can inhibit this response. Recently it was reported that the Toxoplasma type II NTE strain prevents the recruitment of chromatin remodeling complexes containing Brahma related gene (BRG)-1to promoters of IFN-γ-induced secondary response genes such as Ciita and MHC class II genes in murine macrophages, thereby inhibiting their expression. Here we report that a type I strain of Toxoplasma inhibits the expression of primary IFN-γ response genes such as IRF1 through a distinct mechanism not dependent on the activity of histone deacetylases.Instead, infection with a type I, II, or III strain of Toxoplasma inhibits the dissociation of STAT1 from DNA, preventing its recycling and further rounds of STAT1-mediated transcriptional activation. This leads to increased IFN-γ-induced binding of STAT1 at the IRF1 promoter in host cells and increased global IFN-γ-induced association of STAT1 with chromatin. Toxoplasma type I infection also inhibits IFN-β-induced interferon-stimulated gene factor (ISGF) 3-mediated gene expression and this inhibition is also linked to increased association of STAT1 with chromatin. The secretion of proteins into the host cell by a type I strain of Toxoplasma without complete parasite invasion is not sufficient to block STAT1-mediated expression, suggesting that the effector protein responsible for this inhibition is not derived from the rhoptries.
PMID:
 
24277802
 
[PubMed - as supplied by publisher]

Severe South American Ocular Toxoplasmosis Is Associated with Decreased Ifn-γ/Il-17a and Increased Il-6/Il-13 Intraocular Levels

 2013 Nov 21;7(11):e2541. doi: 10.1371/journal.pntd.0002541.

Severe South American Ocular Toxoplasmosis Is Associated with Decreased Ifn-γ/Il-17a and Increased Il-6/Il-13 Intraocular Levels

Source

GEPAMOL, Centro de Investigaciones Biomédicas, Universidad del Quindío, Armenia, Colombia ; Institut de Parasitologie et Pathologie Tropicale, Fédération de Médecine Translationelle, Université de Strasbourg, Strasbourg, France ; Universidad del Rosario, Escuela de Medicina y Ciencias de la Salud, Departamento de Inmunología, Bogotá, Colombia.

Abstract

In a cross sectional study, 19 French and 23 Colombian cases of confirmed active ocular toxoplasmosis (OT) were evaluated. The objective was to compare clinical, parasitological and immunological responses and relate them to the infecting strains. A complete ocular examination was performed in each patient. The infecting strain was characterized by genotyping when intraocular Toxoplasma DNA was detectable, as well as by peptide-specific serotyping for each patient. To characterize the immune response, we assessed Toxoplasma protein recognition patterns by intraocular antibodies and the intraocular profile of cytokines, chemokines and growth factors. Significant differences were found for size of active lesions, unilateral macular involvement, unilateral visual impairment, vitreous inflammation, synechiae, and vasculitis, with higher values observed throughout for Colombian patients. Multilocus PCR-DNA sequence genotyping was only successful in three Colombian patients revealing one type I and two atypical strains. The Colombian OT patients possessed heterogeneous atypical serotypes whereas the French were uniformly reactive to type II strain peptides. The protein patterns recognized by intraocular antibodies and the cytokine patterns were strikingly different between the two populations. Intraocular IFN-γ and IL-17 expression was lower, while higher levels of IL-13 and IL-6 were detected in aqueous humor of Colombian patients. Our results are consistent with the hypothesis that South American strains may cause more severe OT due to an inhibition of the protective effect of IFN-γ.
PMID:
 
24278490
 
[PubMed - in process]

Tuesday, November 26, 2013

Patterns of Toxoplasma gondii cyst distribution in the forebrain associate with individual variation in predator odor avoidance and anxiety-related behavior in male Long-Evans rats

 2013 Nov 21. pii: S0889-1591(13)00543-6. doi: 10.1016/j.bbi.2013.11.012. [Epub ahead of print]

Patterns of Toxoplasma gondii cyst distribution in the forebrain associate with individual variation in predator odor avoidance and anxiety-related behavior in male Long-Evans rats

Source

Department of Biological Sciences, Stanford University, Stanford, CA 94305, USA. Electronic address: akelleyevans@gmail.com.

Abstract

Toxoplasma gondii (T. gondii) is one of the world's most successful brain parasites. T. gondii engages in parasite manipulation of host behavior and infection has been epidemiologically linked to numerous psychiatric disorders. Mechanisms by which T. gondii alters host behavior are not well understood, but neuroanatomical cyst presence and the localized host immune response to cysts are potential candidates. The aim of these studies was to test the hypothesis that T. gondii manipulation of specific host behaviors is dependent on neuroanatomical location of cysts in a time-dependent function post-infection. We examined neuroanatomical cyst distribution (53 forebrain regions) in infected rats after predator odor aversion behavior and anxiety-related behavior in the elevated plus maze and open field arena, across a 6-week time course. In addition, we examined evidence for microglial response to the parasite across the time course. Our findings demonstrate that while cysts are randomly distributed throughout the forebrain, individual variation in cyst localization, beginning 3 weeks post-infection, can explain individual variation in the effects of T. gondii on behavior. Additionally, not all infected rats develop cysts in the forebrain, and attenuation of predator odor aversion and changes in anxiety-related behavior are linked with cyst presence in specific forebrain areas. Finally, the immune response to cysts is striking. These data provide the foundation for testing hypotheses about proximate mechanisms by which T. gondii alters behavior in specific brain regions, including consequences of establishment of a homeostasis between T. gondii and the host immune response.
Copyright © 2013. Published by Elsevier Inc.

KEYWORDS:

Anxiety, Behavior, Cyst distribution, Immune, Individual variation, Kynurenine, Microglia, Neuroanatomy, Predator aversion, Seroconversion,Toxoplasma gondii
PMID:
 
24269877
 
[PubMed - as supplied by publisher]

Dark side illuminated: imaging of Toxoplasma gondii through the decades

 2013 Nov 22;6(1):334. [Epub ahead of print]

Dark side illuminated: imaging of Toxoplasma gondii through the decades

Abstract

In the more than 100 years since its discovery, our knowledge of Toxoplasma biology has improved enormously. The evolution of molecular biology, immunology and genomics has had profound influences on our understanding of this ubiquitous bug. However, it could be argued that in science today the adage "seeing is believing" has never been truer. Images are highly influential and in the time since the first description of T. gondii, advances in microscopy and imaging technology have been and continue to be dramatic. In this review we recount the discovery of T. gondii and the contribution of imaging techniques to elucidating its life cycle, biology and the immune response of its host.
PMID:
 
24267350
 
[PubMed - as supplied by publisher]

Thursday, November 21, 2013

Metabolic reconstruction identifies strain-specific regulation of virulence in Toxoplasma gondii

 2013 Nov 19;9:708. doi: 10.1038/msb.2013.62.

Metabolic reconstruction identifies strain-specific regulation of virulence in Toxoplasma gondii

Source

1] Program in Molecular Structure and Function, The Hospital for Sick Children, Toronto, Ontario, Canada [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.

Abstract

Increasingly, metabolic potential is proving to be a critical determinant governing a pathogen's virulence as well as its capacity to expand its host range. To understand the potential contribution of metabolism to strain-specific infectivity differences, we present a constraint-based metabolic model of the opportunistic parasite, Toxoplasma gondii. Dominated by three clonal strains (Type I, II, and III demonstrating distinct virulence profiles), T. gondii exhibits a remarkably broad host range. Integrating functional genomic data, our model (which we term as iCS382) reveals that observed strain-specific differences in growth rates are driven by altered capacities for energy production. We further predict strain-specific differences in drug susceptibilities and validate one of these predictions in a drug-based assay, with a Type I strain demonstrating resistance to inhibitors that are effective against a Type II strain. We propose that these observed differences reflect an evolutionary strategy that allows the parasite to extend its host range, as well as result in a subsequent partitioning into discrete strains that display altered virulence profiles across different hosts, different organs, and even cell types.
PMID:
 
24247825
 
[PubMed - in process] 

Toxoplasma gondii infection in the peritoneal macrophages of rats treated with glucocorticoids

 2013 Nov 19. [Epub ahead of print]

Toxoplasma gondii infection in the peritoneal macrophages of rats treated with glucocorticoids

Source

Center for Parasitic Organisms, State Key Laboratory of Biocontrol, School of Life Sciences and Key Laboratory of Tropical Disease Control of the Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510275, China.

Abstract

It is well known that toxoplasmosis can be life threatening to immunocompromised individuals such as AIDS and organ transplantation patients. Glucocorticoids (GCs) are widely used in the clinic for the treatment of autoimmune diseases and organ transplantation resulting in acute toxoplasmosis in these patients. However, the interaction and mechanism between the development of acute toxoplasmosis and GC therapy are still unknown. The aims of this study were to investigate the infection of Toxoplasma gondii in the peritoneal macrophages of rats treated with glucocorticoids. Our results showed that the growth rate of T. gondii RH strain was significantly increased in the peritoneal macrophages of rats treated with glucocorticoids in vivo. For instance, 242 (±16) tachyzoites were found in 100 macrophages from the rats treated with methylprednisolone (MP), while only 16 (±4) tachyzoites were counted in the macrophages from the non-treated control rats 24 h after infection (P < 0.01). We also demonstrated that a significant inhibition of nitric oxide (NO) production was detected in the macrophages collected from the rats post-treated with GCs with 12.90 μM (±0.99 μM) of nitrite production from the rats treated with MP, while 30.85 μM (±1.62 μM) was found in the non-treated control rats 36 h after incubation (P < 0.01). Furthermore, glucocorticoids could significantly inhibit the expression of inducible nitric oxide synthase mRNA and its protein in the rat peritoneal macrophages. Our results strongly indicate that the decrease of NO in the rat peritoneal macrophages is closely linked to the cause of acute toxoplasmosis in the host. Additionally, there was a significant increase in the number of cysts produced by the naturally cyst forming, T. gondii Prugniaud strain with an average of 2,795 (±422) cysts of the parasite being detected in the brains of the rats treated with dexamethasone, while only 1,356 (±490) cysts were found in the non-treated control animals (P < 0.01). As rats and humans are both naturally resistant to T. gondii infection, these novel data could lead to a better understanding of the development of acute toxoplasmosis during glucocorticoid therapy in humans.
PMID:
 
24248630
 
[PubMed - as supplied by publisher]

Direct genotyping of Toxoplasma gondii from amniotic fluids based on B1 gene polymorphism using minisequencing analysis

 2013 Nov 19;13(1):552. [Epub ahead of print]

Direct genotyping of Toxoplasma gondii from amniotic fluids based on B1 gene polymorphism using minisequencing analysis

Abstract

BACKGROUND:

Because some Toxoplasma gondii genotypes may be more virulent in pregnant women, discriminating between them appears valuable. Currently, the main genotyping method is based on single copy microsatellite markers, which limit direct genotyping from amniotic fluids (AFs) to samples with a high parasitic load. We investigated whether the multicopy gene B1 could type the parasite with a higher sensitivity. To estimate the amplifiable DNA present in AFs, we first compared three different PCR assays used for Toxoplasma infection diagnosis: the P30-PCR, targeting the single copy gene P30; the B1-PCR, targeting the repeated B1 gene; and RE-PCR, targeting the repeated element.

RESULTS:

Of the 1792 AFs analyzed between 2008 and 2011, 73 were RE-PCR positive. Of those, 49 (67.1%) were P30-PCR and B1-PCR positive, and 14 (19.2%) additional AFs were B1-PCR positive only.All 63 BI-positive AFs (France n = 49; overseas n = 14) could be genotyped based on an analysis of eight nucleotide polymorphisms (SNPs) located within the B1 gene. Following high-resolution melting (HRM) analysis, minisequencing was carried out for each of the eight SNPs. DNA from six reference strains was included in the study, and AFs were assigned to one of the three major lineages (Types I, II, and III). In total, 26 genotypes were observed, and the hierarchical clustering distinguished two clades in lineages II (IIa, n = 30 and IIb, n = 4) and III (IIIa n = 23 and IIIb n = 6). There was an overrepresentation of overseas isolates in Clade IIb (4/4, 100%) and Clade IIIa (8/22; 36.4%) (p <0 .0001="" 17.4="" 50="" and="" clade="" death="" fetal="" iib="" iiia="" in="" interruption="" medical="" overrepresented="" p="0.049).</p" were="" whereas="">

CONCLUSIONS:

Although the current genotyping system cannot pretend to replace multilocus typing, we clearly show that targeting the multicopy B1 gene yields a genotyping capacity of AFs around 20% better than when single copy targets are used. The present genotyping method also allows clear identification of genotypes of potential higher virulence.
PMID:
 
24252188
 
[PubMed - as supplied by publisher]

Wednesday, November 20, 2013

Unique apicomplexan IMC sub-compartment proteins are early markers for apical polarity in the malaria parasite

 2013 Sep 16;2(11):1160-70. doi: 10.1242/bio.20136163.

Unique apicomplexan IMC sub-compartment proteins are early markers for apical polarity in the malaria parasite

Source

Centre for Genetics and Genomics, School of Life Sciences, Queens Medical Centre, University of Nottingham , Nottingham NG2 7UH , UK.

Abstract

The phylum Apicomplexa comprises over 5000 intracellular protozoan parasites, including Plasmodium and Toxoplasma, that are clinically important pathogens affecting humans and livestock. Malaria parasites belonging to the genus Plasmodium possess a pellicle comprised of a plasmalemma and inner membrane complex (IMC), which is implicated in parasite motility and invasion. Using live cell imaging and reverse genetics in the rodent malaria model P. berghei, we localise two unique IMC sub-compartment proteins (ISPs) and examine their role in defining apical polarity during zygote (ookinete) development. We show that these proteins localise to the anterior apical end of the parasite where IMC organisation is initiated, and are expressed at all developmental stages, especially those that are invasive. Both ISP proteins are N-myristoylated, phosphorylated and membrane-bound. Gene disruption studies suggest that ISP1 is likely essential for parasite development, whereas ISP3 is not. However, an absence of ISP3 alters the apical localisation of ISP1 in all invasive stages including ookinetes and sporozoites, suggesting a coordinated function for these proteins in the organisation of apical polarity in the parasite.

KEYWORDS:

ISP, Plasmodium, Polarity
PMID:
 
24244852
 
[PubMed]

Evidence for Finely-Regulated Asynchronous Growth of Toxoplasma gondii Cysts Based on Data-Driven Model Selection

 2013 Nov;9(11):e1003283. doi: 10.1371/journal.pcbi.1003283. Epub 2013 Nov 14.

Evidence for Finely-Regulated Asynchronous Growth of Toxoplasma gondii Cysts Based on Data-Driven Model Selection

Source

Department of Mechanical, Aerospace, and Biomedical Engineering, University of Tennessee, Knoxville, Tennessee, United States of America ; National Institute of Mathematical and Biological Synthesis, University of Tennessee, Knoxville, Tennessee, United States of America.

Abstract

Toxoplasma gondii establishes a chronic infection by forming cysts preferentially in the brain. This chronic infection is one of the most common parasitic infections in humans and can be reactivated to develop life-threatening toxoplasmic encephalitis in immunocompromised patients. Host-pathogen interactions during the chronic infection include growth of the cysts and their removal by both natural rupture and elimination by the immune system. Analyzing these interactions is important for understanding the pathogenesis of this common infection. We developed a differential equation framework of cyst growth and employed Akaike Information Criteria (AIC) to determine the growth and removal functions that best describe the distribution of cyst sizes measured from the brains of chronically infected mice. The AIC strongly support models in which T. gondii cysts grow at a constant rate such that the per capita growth rate of the parasite is inversely proportional to the number of parasites within a cyst, suggesting finely-regulated asynchronous replication of the parasites. Our analyses were also able to reject the models where cyst removal rate increases linearly or quadratically in association with increase in cyst size. The modeling and analysis framework may provide a useful tool for understanding the pathogenesis of infections with other cyst producing parasites.
PMID:
 
24244117
 
[PubMed - in process]

Tuesday, November 19, 2013

Latent Toxoplasma gondii infection leads to improved action control

2013 Nov 12. pii: S0889-1591(13)00535-7. doi: 10.1016/j.bbi.2013.11.004. [Epub ahead of print]

Latent Toxoplasma gondii infection leads to improved action control

Source

Cognitive Neurophysiology, Department of Child and Adolescent Psychiatry, University of Dresden, Schubertstrasse 42, D-01307 Dresden, Germany. Electronic address: ann-kathrin.stock@uniklinikum-dresden.de.

Abstract

The parasite Toxoplasma gondii has been found to manipulate the behavior of its secondary hosts to increase its own dissemination which is commonly believed to be to the detriment of the host (manipulation hypothesis). The manipulation correlates with an up-regulation of dopaminergic neurotransmission. In humans, different pathologies have been associated with T. gondii infections but most latently infected humans do not seem to display overt impairments. Since a dopamine plus does not necessarily bear exclusively negative consequences in humans, we investigated potential positive consequences of latent toxoplasmosis (and the presumed boosting of dopaminergic neurotransmission) on human cognition and behavior. For this purpose, we focused on action cascading which has been shown to be modulated by dopamine. Based on behavioral and neurophysiological (EEG) data obtained by means of a stop-change paradigm, we were able to demonstrate that healthy young humans can actually benefit from latent T. gondii infection as regards their performance in this task (as indicated by faster response times and a smaller P3 component). The data shows that a latent infection which is assumed to affect the dopaminergic system can lead to paradoxical improvements of cognitive control processes in humans.
Copyright © 2013. Published by Elsevier Inc.

KEYWORDS:

Action cascading, Dopamine, EEG, Executive functions, Human, Latent toxoplasmosis, Manipulation hypothesis, Parasite, Stop–change paradigm, Toxoplama gondii
PMID:
24231154
[PubMed - as supplied by publisher]

Saturday, November 16, 2013

Direct Effect of Two Naphthalene-Sulfonyl-Indole Compounds on Toxoplasma gondii Tachyzoite

 2013;2013:716976. doi: 10.1155/2013/716976. Epub 2013 Oct 21.

Direct Effect of Two Naphthalene-Sulfonyl-Indole Compounds on Toxoplasma gondii Tachyzoite

Source

Department of Parasitology and Mycology, Faculty of Health, Tehran University of Medical Sciences, Tehran 14177613191, Iran ; Department of Parasitology and Mycology, Shiraz University of Medical Sciences, Shiraz, Iran.

Abstract

Past studies have stated that the parasitostatic effect of IFN-γ is most likely due to the starvation of Toxoplasma gondii for tryptophan in the host cell. The aim of this study was to evaluate the direct effect of two new Naphthalene-Sulfonyl-Indole compounds as competitive molecules for tryptophan on viability and infectivity of Toxoplasma tachyzoites. Tachyzoites of RH strain were incubated in various concentrations (25-800 μM) of 1-(naphthalene-2-sulfonyl)-2,3-dihydro-1H-indole and 1-[5-(2,3-dihydro-1H-indole-1-sulfonyl)naphthalene-1-sulfonyl]-2,3-dihydro-1H-indole for 1.5 hours. Then, they were stained by PI and analyzed by FACS. To evaluate the infectivity, 2 × 10(6) tachyzoites exposed to the concentrations mentioned above were intraperitoneally inoculated into five mice from each group. Also, naïve parasites and parasites exposed to DMSO (control) were inoculated in both groups of mice. The LD50 of 1-(naphthalene-2-sulfonyl)-2,3-dihydro-1H-indole was 62 μmol whilst the quantity of 1-[5-(2,3-dihydro-1H-indole-1-sulfonyl)naphthalene-1-sulfonyl]-2,3-dihydro-1H-indole was more than 800 μmol. The infectivity of tachyzoites exposed to both of the compounds preserved and killed mice. No statistical correlation was seen between longevity of mice groups and different doses of the compounds. If we consider a well-organized transporter mechanism for indole compounds in the parasite, thus the designation of an antagonist that has indole groups can assist with the production of new drugs.
PMID:
 
24228173
 
[PubMed]

Mechanisms of cellular invasion by intracellular parasites

 2013 Nov 13. [Epub ahead of print]

Mechanisms of cellular invasion by intracellular parasites

Source

Department of Microbial Infection and Immunity, Wexner Medical Center, The Ohio State University, Columbus, OH, 43210, USA.

Abstract

Numerous disease-causing parasites must invade host cells in order to prosper. Collectively, such pathogens are responsible for a staggering amount of human sickness and death throughout the world. Leishmaniasis, Chagas disease, toxoplasmosis, and malaria are neglected diseases and therefore are linked to socio-economical and geographical factors, affecting well-over half the world's population. Such obligate intracellular parasites have co-evolved with humans to establish a complexity of specific molecular parasite-host cell interactions, forming the basis of the parasite's cellular tropism. They make use of such interactions to invade host cells as a means to migrate through various tissues, to evade the host immune system, and to undergo intracellular replication. These cellular migration and invasion events are absolutely essential for the completion of the lifecycles of these parasites and lead to their for disease pathogenesis. This review is an overview of the molecular mechanisms of protozoan parasite invasion of host cells and discussion of therapeutic strategies, which could be developed by targeting these invasion pathways. Specifically, we focus on four species of protozoan parasites Leishmania, Trypanosoma cruzi, Plasmodium, and Toxoplasma, which are responsible for significant morbidity and mortality.
PMID:
 
24221133
 
[PubMed - as supplied by publisher]

NLRP1 is an inflammasome sensor for Toxoplasma gondii

 2013 Nov 11. [Epub ahead of print]

NLRP1 is an inflammasome sensor for Toxoplasma gondii

Source

Department of Microbiology and Immunology, Stanford School of Medicine, Stanford, California, USA.

Abstract

The obligate intracellular parasite Toxoplasma gondii is able to infect nearly all nucleated cell types of warm-blooded animals. This is achieved through the injection of hundreds of parasite effectors into the host cell cytosol allowing the parasite to establish a vacuolar niche for growth, replication and persistence. Here we show that Toxoplasma infection actives an inflammasome response in mice and rats, an innate immune sensing system designed to survey the host cytosol for foreign components leading to inflammation and cell death. Oral infection with Toxoplasma triggers an inflammasome response that is protective to the host, limiting parasite load and dissemination. Toxoplasma infection is sufficient to generate an inflammasome response in germ-free animals. IL-1β secretion by macrophage requires the effector caspases-1 and -11, the adapter ASC and NLRP1, the sensor previously described to initiate the inflammasome response to Bacillus anthracis lethal factor. The allele of NLRP1b derived from 129 mice is sufficient to enhance the B6 BMDM inflammasome response to Toxoplasma independent of the lethal factor proteolysis site. Moreover, N-terminal processing of NLRP1b, the only mechanism of activation known to date, is not observed in response to Toxoplasma infection. Cumulatively, these data indicate that NLRP1 is an innate immune sensor for Toxoplasma infection, activated via a novel mechanism that corresponds with a host-protective innate immune response to the parasite.
PMID:
 
24218483
 
[PubMed - as supplied by publisher]

Interaction between Toxoplasma gondii rhoptry neck protein 4 and host cellular β-tubulin

 2013 Nov 12;3:3199. doi: 10.1038/srep03199.

Characterization of the interaction between Toxoplasma gondii rhoptry neck protein 4 and host cellular β-tubulin

Source

1] National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido 080-8555, Japan [2] Department of Veterinary Microbiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.

Abstract

Toxoplasma rhoptry neck protein 4 (TgRON4) is a component of the moving junction macromolecular complex that plays a central role during invasion. TgRON4 is exposed on the cytosolic side of the host cell during invasion, but its molecular interactions remain unclear. Here, we identified host cellular β-tubulin as a binding partner of TgRON4, but not Plasmodium RON4. Coimmunoprecipitation studies in mammalian cells demonstrated that the C-terminal 15-kDa region of β-tubulin was sufficient for binding to TgRON4, and that a 17-kDa region in the proximal C-terminus of TgRON4 was required for binding to the C-terminal region of β-tubulin. Analysis of T. gondii-infected lysates from CHO cells expressing the TgRON4-binding region showed that the C-terminal region of β-tubulin interacted with TgRON4 at early invasion step. Our results provide evidence for a parasite-specific interaction between TgRON4 and the host cell cytoskeleton in parasite-infected cells.
PMID:
 
24217438
 
[PubMed - in process] 
PMCID:
 
PMC3824165

Wednesday, November 13, 2013

Morphometric changes in C57BL/6 mice retina infected by Toxoplasma gondii ME 49 strain

2013 Nov 6. pii: S0014-4894(13)00278-6. doi: 10.1016/j.exppara.2013.10.013. [Epub ahead of print]

Morphometric changes in C57BL/6 mice retina infected by Toxoplasma gondii ME 49 strain

Source

Faculdade de Medicina da Universidade Federal de Minas Gerais;Hospital São Geraldo - Hospital das Clínicas da UFMG, Pampulha, Belo Horizonte, Minas Gerais, Brasil.

Abstract

This study evaluated the morphometric implications in C57BL/6 mouse retina infected by Toxoplasma gondii, ME 49 strain. Twenty C57BL/6 female mice were divided into group 1 (n=8, intraperitoneally infected with 30 cysts of T. gondii ME 49 strain) and group 2 (n=12 non-infected controls). The eyes were enucleated on the 60th day after infection, fixed and processed for light microscopy. Changes in retinal thickness and in the perimeter/area ratio (P/A) of the retinal layers were analyzed by digital morphometry. We considered that P/A was the measurement of retinal architecture distortion induced by toxoplasmosis. This study considered the ganglion cells and nerve fiber layers as a monolayer, thus six layers of retina were evaluated: photoreceptors (PRL), outer nuclear (ONL), outer plexiform (OPL), inner nuclear (INL), inner plexiform (IPL) and ganglion cells/nerve fiber monolayer (GNL). Histological analysis of infected mouse retina showed inflammatory infiltrate, necrosis, glial reaction and distortion of the retina architecture. It also presented increased thickness (167.8 ± 24.9 μm versus 121.1 ± 15.4 μm, in controls) and increased retinal thickness within the retinitis foci (187.7 ± 16.6 μm versus 147.9 ± 12.2 μm out of the retinitis foci). A statistically significant difference in P/A was observed between infected and uninfected mouse retinas. The same was observed in PRL, OPL, INL and GNL. Retinal morphometry may be used to demonstrate differences between infected and uninfected mouse retinas.
Copyright © 2013. Published by Elsevier Inc.

KEYWORDS:

Eye, Mice, Morphometry, Ocular toxoplasmosis
PMID:
24211418
[PubMed - as supplied by publisher]

Evolutionary repurposing of endosomal systems for apical organelle biogenesis in Toxoplasma gondii

2013 Nov 6. pii: S0020-7519(13)00256-7. doi: 10.1016/j.ijpara.2013.10.003. [Epub ahead of print]

Evolutionary repurposing of endosomal systems for apical organelle biogenesis in Toxoplasma gondii

Source

Center for Infection and Immunity of Lille, CNRS UMR 8204, INSERM U 1019, Institut Pasteur de Lille, Université Lille Nord de France, France. Electronic address: Stan.Tomavo@pasteur-lille.fr.

Abstract

It is very difficult to define an endocytic system in Toxoplasma gondii. The parasite does not appear to take up exogenous materials via classical endocytosis. The presence of Rab5 and Rab7, classical markers of endocytic compartments, and their decoration of endomembranous structures suggest, however, that an endosomal-like system may operate. Additionally, new findings reveal that dynamin and the transmembrane type-I receptor sortilin are involved in the biogenesis of T. gondii micronemes and rhoptries, unique apical secretory organelles required for parasite migration and host-cell invasion, manipulation and egress. Evidence suggests that the parasite uses an endosomal-like system to traffic and sort proteins to rhoptries and micronemes via the endoplasmic reticulum and Golgi. In this review, I discuss recent findings suggesting that T. gondii and other apicomplexans have reduced their endosomal system and repurposed the evolutionarily conserved regulators of the system to build the apical secretory organelles. This review is also intended to serve as a resource for future investigations of apicomplexan biology and evolution.
Copyright © 2013. Published by Elsevier Ltd.

KEYWORDS:

Apical organelle biogenesis, Endosomal-like system, Intracellular pathogen, Protein trafficking, Toxoplasma gondii
PMID:
24211609
[PubMed - as supplied by publisher]

Monday, November 11, 2013

Protein Trafficking through the Endosomal System Prepares Intracellular Parasites for a Home Invasion

2013 Oct;9(10):e1003629. doi: 10.1371/journal.ppat.1003629. Epub 2013 Oct 24.

Protein Trafficking through the Endosomal System Prepares Intracellular Parasites for a Home Invasion

Source

Center for Infection and Immunity of Lille, CNRS UMR 8204, INSERM U 1019, Institut Pasteur de Lille, Université Lille Nord de France, Lille, France.

Abstract

Toxoplasma (toxoplasmosis) and Plasmodium (malaria) use unique secretory organelles for migration, cell invasion, manipulation of host cell functions, and cell egress. In particular, the apical secretory micronemes and rhoptries of apicomplexan parasites are essential for successful host infection. New findings reveal that the contents of these organelles, which are transported through the endoplasmic reticulum (ER) and Golgi, also require the parasite endosome-like system to access their respective organelles. In this review, we discuss recent findings that demonstrate that these parasites reduced their endosomal system and modified classical regulators of this pathway for the biogenesis of apical organelles.
PMID:
24204248
[PubMed - in process]

Tuesday, November 05, 2013

Toxoplasma gondii within skeletal muscle cells: A critical interplay for food-borne parasite transmission

2013 Oct 30. pii: S0020-7519(13)00250-6. doi: 10.1016/j.ijpara.2013.10.001. [Epub ahead of print]

Toxoplasma gondii within skeletal muscle cells: A critical interplay for food-borne parasite transmission

Source

Institute for Medical Microbiology, University Medical Center Göttingen, Georg-August-University, Kreuzbergring 57, 37075 Göttingen, Germany.

Abstract

Toxoplasma gondii infects virtually any nucleated cell type of warm-blooded animals and humans including skeletal muscle cells (SkMCs). Infection of SkMCs by T. gondii, differentiation from the highly replicative tachyzoites to dormant bradyzoites and tissue cyst formation are crucial for parasite persistence in muscle tissue. These processes are also prerequisites for one of the major routes of transmission to humans via undercooked or cured meat products. Evidence obtained in vitro and in vivo indicates that SkMCs are indeed a preferred cell type for tissue cyst formation and long-term persistence of T. gondii. This raises intriguing questions about what makes SkMCs a suitable environment for parasite persistence and how the SkMC-T. gondii interaction is regulated. Recent data from our laboratory show that differentiation of SkMCs from myoblasts to syncytial myotubes, rather than the cell type itself, is critical for parasite growth, bradyzoite formation and tissue cyst maturation. Myotube formation is accompanied by a permanent withdrawal from the cell cycle, and the negative cell cycle regulator cell division autoantigen (CDA)-1 directly or indirectly promotes T. gondii stage conversion in SkMCs. Moreover, host cell cycle regulators are specifically modulated in mature myotubes, but not myoblasts, following infection. Myotubes also up-regulate the expression of various pro-inflammatory cytokines and chemokines after T. gondii infection and they respond to IFN-γ by exerting potent anti-parasitic activity. This highlights that mature myotubes are active participants rather than passive targets of the local immune response to T. gondii which may also govern the interaction between SkMCs and the parasite.
Copyright © 2013. Published by Elsevier Ltd.

KEYWORDS:

Cell cycle, Immune response, Myogenesis, Persistence, Skeletal muscle cell, Toxoplasma gondii
PMID:
24184158
[PubMed - as supplied by publisher]

Regulation of immunopathogenesis during Plasmodium and Toxoplasma infections: more parallels than distinctions?

2013 Oct 31. pii: S1471-4922(13)00163-3. doi: 10.1016/j.pt.2013.10.002. [Epub ahead of print]

Regulation of immunopathogenesis during Plasmodium and Toxoplasma infections: more parallels than distinctions?

Source

Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. Electronic address: noah-butler@ouhsc.edu.

Abstract

Toxoplasma and Plasmodium parasites exact a significant toll on public health. Host immunity required for efficient control of infection by these Apicomplexans involves the induction of potent T cell responses, which sometimes results in immunopathological damage. Thus, protective immune responses must be balanced by regulatory networks that limit immunopathology. We review several key cellular and molecular immunoregulatory networks operational during Toxoplasma and Plasmodium infections. Accumulating data show that despite differences in how the immune response controls these parasites, many host immunoregulatory pathways and cellular networks are common to both. Thus, understanding the cellular and molecular circuits that prevent or regulate immunopathological responses against one parasite is likely to inform our understanding of the host response to the other parasite.
Copyright © 2013 Elsevier Ltd. All rights reserved.

KEYWORDS:

IL-10, IL-27, Plasmodium, TGF-β, Toxoplasma, immunopathology
PMID:
24184186
[PubMed - as supplied by publisher]

Emerging roles for protein S-palmitoylation in Toxoplasma biology

2013 Oct 31. pii: S0020-7519(13)00252-X. doi: 10.1016/j.ijpara.2013.09.004. [Epub ahead of print]

Emerging roles for protein S-palmitoylation in Toxoplasma biology

Source

Department of Microbiology and Molecular Medicine, University of Geneva, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland. Electronic address: karine.frenal@unige.ch.

Abstract

Post-translational modifications (PTMs) are refined, rapidly responsive and powerful ways to modulate protein function. Among PTMs, acylation is now emerging as a widespread modification exploited by eukaryotes, bacteria and viruses to control biological processes. Protein palmitoylation involves the attachment of palmitic acid, also known as hexadecanoic acid, to cysteine residues of integral and peripheral membrane proteins and increases their affinity for membranes. Importantly, similar to phosphorylation, palmitoylation is reversible and is becoming recognised as instrumental for the regulation of protein function by modulating protein interactions, stability, folding, trafficking and signalling. Palmitoylation appears to play a central role in the biology of the Apicomplexa, regulating critical processes such as host cell invasion which is vital for parasite survival and dissemination. The recent identification of over 400 palmitoylated proteins in Plasmodium falciparum erythrocytic stages illustrates the broad spread and impact of this modification on parasite biology. The main enzymes responsible for protein palmitoylation are multi-membrane protein S-acyl transferases (PATs) harbouring a catalytic Asp-His-His-Cys (DHHC) motif. A global functional analysis of the repertoire of PATs in Toxoplasma gondii and Plasmodium berghei has recently been performed. The essential nature of some of these enzymes illustrates the key roles played by this PTM in the corresponding substrates implicated in fundamental processes such as parasite motility and organelle biogenesis. Toward a better understanding of the depalmitoylation event, a protein with palmitoyl protein thioesterase (PPT) activity has been identified in T. gondii. TgPPT1/TgASH1 is the main target of specific acyl protein thioesterase inhibitors but is dispensable for parasite survival, suggesting the implication of other genes in depalmitoylation. Palmitoylation/depalmitoylation cycles are now emerging as potential novel regulatory networks and T. gondii represents a superb model organism in which to explore their significance.
Copyright © 2013. Published by Elsevier Ltd.

KEYWORDS:

Acyl protein thioesterases, Apicomplexa, Palmitoylation, Post-translational modification, Protein S-acyl transferases, Toxoplasma gondii
PMID:
24184909
[PubMed - as supplied by publisher]