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At least 1,063 records · Page 59Linked to original sources
PubMed1998

Drug evaluation of concurrent Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium complex infections in a rat model.

We present a new experimental model for the simultaneous evaluation of the activities of drugs against Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium complex infections. Rats latently infected with P. carinii were challenged with the MO-1 strain of M. avium and then immunosuppressed with corticosteroids for 7 weeks. At week 5 the RH strain of T. gondii was intraperitoneally injected. Organs were examined for the three pathogens after death or killing of the animals at week 7. Without treatment, rats challenged with T. gondii died with pulmonary P. carinii infection and disseminated T. gondii and M. avium infections. In order to assess the value of the model for evaluation of the activities of drugs, we administered by oral gavage for 7 weeks drugs or combinations of drugs selected for their individual efficacies against at least one pathogen. We found that clarithromycin with sulfamethoxazole, clarithromycin with atovaquone, roxithromycin with sulfamethoxazole or dapsone, and rifabutin with atovaquone were effective against the three infections, whereas PS-15 with dapsone and trimethoprim with sulfamethoxazole were active against Toxoplasma and Pneumocystis infections only. This triple-infection rat model offers a new tool for the simultaneous evaluation of the activities of drugs against three of the major opportunistic infections occurring in immunosuppressed individuals.

Animals↗
PubMed1999

Metabolism and selective toxicity of 6-nitrobenzylthioinosine in Toxoplasma gondii.

The purine nucleoside analogue NBMPR (nitrobenzylthioinosine or 6-[(4-nitrobenzyl)thio]-9-beta-D-ribofuranosylpurine) was selectively phosphorylated to its nucleoside 5'-monophosphate by Toxoplasma gondii but not mammalian adenosine kinase (EC 2.7.1.20). NBMPR was also cleaved in toxoplasma to its nucleobase, nitrobenzylmercaptopurine. However, nitrobenzylmercaptopurine was not a substrate for either adenosine kinase or hypoxanthine-guanine-xanthine phosphoribosyltransferase (EC 2.4.2.8). Because of this unique and previously unknown metabolism of NBMPR by the parasite, the effect of NBMPR as an antitoxoplasmic agent was tested. NBMPR killed T. gondii grown in human fibroblasts in a dose-dependent manner, with a 50% inhibitory concentration of approximately 10 microM and without apparent toxicity to host cells. Doses of up to 100 microM had no significant toxic effect on uninfected host cells. The promising antitoxoplasmic effect of NBMPR led to the testing of other 6-substituted 9-beta-D-ribofuranosylpurines, which were shown to be good ligands of the parasite adenosine kinase (M. H. Iltzsch, S. S. Uber, K. O. Tankersley, and M. H. el Kouni, Biochem. Pharmacol. 49:1501-1512, 1995), as antitoxoplasmic agents. Among the analogues tested, 6-benzylthioinosine, p-nitrobenzyl-6-selenopurine riboside, N(6)-(p-azidobenzyl)adenosine, and N(6)-(p-nitrobenzyl)adenosine, like NBMPR, were selectively toxic to parasite-infected cells. Thus, it appears that the unique characteristics of purine metabolism in T. gondii render certain 6-substituted 9-beta-D-ribofuranosylpurines promising antitoxoplasmic drugs.

Adenosine Kinase↗
PubMed2026

Toxoplasma gondii infection disrupts secondary bile acid transformation in feline gut microbiota.

UNLABELLED: Bile acid (BA) transformation relies on gut microbiota and is vulnerable to Toxoplasma gondii infection, yet feline microbial BA-transforming capacity upon toxoplasmosis remains unclear. Here, we constructed a catalog of 2,474 nonredundant feline gut microbial genomes and integrated serum metabolomic data to verify BA transformation alterations. The results revealed that the feline gut microbiome harbored widespread genetic potential for BA transformation but lacked a complete 7α-dehydroxylation pathway due to the absence of the key gene baiE. The BA transformation-related genomes (2,045 in total) were predominantly from the phyla Bacillota_A and Actinomycetota, among which only 37 encoded baiB, all belonging to Bacillota_A. The distribution of BA transformation-related genes varied across intestinal regions: genes encoding 7α-HSDH were primarily enriched in the small intestine, whereas genes encoding 3α-HSDH, baiCD, and baiH were more abundant in the large intestine. Additionally, the abundance of genes encoding BSH and 3α-HSDH increased significantly in the small intestine on day 3 post-infection, accompanied by increases in the phylum Bacillota_C and genera such as Blautia_A, Enterococcus_E, and Ligilactobacillus. Serum metabolomics revealed a significant increase in cholesterol levels post-infection, supporting the impact of T. gondii infection on intestinal BA transformation. These findings illustrated that the feline gut microbiota played an important role in BA transformation and that T. gondii infection disrupted the microbial potential for secondary BA transformation. This study provided new insights into gut microbiota-associated metabolic perturbations during feline toxoplasmosis. IMPORTANCE: Bile acid (BA) transformation plays a critical role in host metabolism and immune regulation. Although studies on BA transformation are increasing, the capacity for BA transformation within the feline gut microbiota and the impact of Toxoplasma gondii infection on this capacity remain unclear. To bridge this gap, we constructed a catalog of 2,474 nonredundant feline gut microbial genomes and integrated serum metabolomic data to verify BA transformation alterations. Our findings revealed that the feline gut microbiome lacked a complete 7α-dehydroxylation pathway, and the specific functions involved in BA transformation may differ between the small and large intestines. Furthermore, integrated metagenomic and serum metabolomic analyses suggested that T. gondii infection disrupted BA transformation capacity in the small intestine. This study provided new insights into gut microbiota-associated metabolic perturbations during feline toxoplasmosis.

Toxoplasma gondii↗
PubMed2000

Serodiagnosis of recently acquired Toxoplasma gondii infection using an enzyme-linked immunosorbent assay with a combination of recombinant antigens.

An enzyme-linked immunosorbent assay (ELISA) using four recombinant antigens of Toxoplasma gondii (rP22, rP25, rP29, and rP35) was used in an attempt to differentiate pregnant women with toxoplasma serologic profiles (TSPs) indicative of recently acquired infections (acute profile) from those with TSPs indicative of infections acquired in the distant past (chronic profile). In general, immunoglobulin G antibodies in sera from women with the acute profile reacted more strongly with the recombinant antigens than did those in sera from women with the chronic profile. However, reactivities differed significantly between antigens that reacted with a single serum and between sera that reacted with a single antigen. Because of these variations, we employed a combination of the four antigens in an ELISA (Comb-ELISA) and evaluated its ability to distinguish pregnant women with the acute profile from those with the chronic profile. Eighteen of 20 (90%) sera from acute-profile women were positive in the Comb-ELISA, whereas 69 of 70 (98.6%) sera from the chronic-profile women were negative. Thus, the Comb-ELISA may be useful for diagnosis of toxoplasmosis in pregnant women and for differentiation between recently acquired infections and infections acquired in the more distant past.

Animals↗
PubMed2002

Cervical cat scratch disease lymphadenitis in a patient with immunoglobulin M antibodies to Toxoplasma gondii.

We report on a young patient with chronic cervical lymphadenopathy and serological and histological evidence for infection with Bartonella henselae and Toxoplasma gondii. Serological follow-up studies, including testing for avidity of Toxoplasma-specific immunoglobulin G antibodies, assisted in the determination of the cause of the acute lymphadenitis. Our results suggest that the clinical symptoms were most likely due to cat scratch disease rather than to acute toxoplasmosis.

Adult↗
PubMed2006

Targeted deletion of MIC5 enhances trimming proteolysis of Toxoplasma invasion proteins.

Limited proteolysis of proteins transiently expressed on the surface of the opportunistic pathogen Toxoplasma gondii accompanies cell invasion and facilitates parasite migration across cell barriers during infection. However, little is known about what factors influence this specialized proteolysis or how these proteolytic events are regulated. Here we show that genetic ablation of the micronemal protein MIC5 enhances the normal proteolytic processing of several micronemal proteins secreted by Toxoplasma tachyzoites. Restoring MIC5 expression by genetic complementation reversed this phenotype, as did treatment with the protease inhibitor ALLN, which was previously shown to block the activity of a hypothetical parasite surface protease called MPP2. We show that, despite its lack of obvious membrane association signals, MIC5 occupies the parasite surface during invasion in the vicinity of the proteins affected by enhanced processing. Proteolysis of other secretory proteins, including GRA1, was also enhanced in MIC5 knockout parasites, indicating that the phenotype is not strictly limited to proteins derived from micronemes. Together, our findings suggest that MIC5 either directly regulates MPP2 activity or it influences MPP2's ability to access substrate cleavage sites on the parasite surface.

Animals↗
PubMed2002

Toxoplasma gondii asexual development: identification of developmentally regulated genes and distinct patterns of gene expression.

Asexual development in Toxoplasma gondii is a vital aspect of the parasite's life cycle, allowing transmission and avoidance of the host immune response. Differentiation of rapidly dividing tachyzoites into slowly growing, encysted bradyzoites involves significant changes in both physiology and morphology. We generated microarrays of approximately 4,400 Toxoplasma cDNAs, representing a minimum of approximately 600 genes (based on partial sequencing), and used these microarrays to study changes in transcript levels during tachyzoite-to-bradyzoite differentiation. This approach has allowed us to (i) determine expression profiles of previously described developmentally regulated genes, (ii) identify novel developmentally regulated genes, and (iii) identify distinct classes of genes based on the timing and magnitude of changes in transcript levels. Whereas microarray analysis typically involves comparisons of mRNA levels at different time points, we have developed a method to measure relative transcript abundance between genes at a given time point. This method was used to determine transcript levels in parasites prior to differentiation and to further classify bradyzoite-induced genes, thus allowing a more comprehensive view of changes in gene expression than is provided by standard expression profiles. Newly identified developmentally regulated genes include putative surface proteins (a SAG1-related protein, SRS9, and a mucin-domain containing protein), regulatory and metabolic enzymes (methionine aminopeptidase, oligopeptidase, aminotransferase, and glucose-6-phosphate dehydrogenase homologues), and a subset of genes encoding secretory organelle proteins (MIC1, ROP1, ROP2, ROP4, GRA1, GRA5, and GRA8). This analysis permits the first in-depth look at changes in gene expression during development of this complex protozoan parasite.

Animals↗
PubMed2005

MYST family histone acetyltransferases in the protozoan parasite Toxoplasma gondii.

The restructuring of chromatin precedes tightly regulated events such as DNA transcription, replication, and repair. One type of chromatin remodeling involves the covalent modification of nucleosomes by histone acetyltransferase (HAT) complexes. The observation that apicidin exerts antiprotozoal activity by targeting a histone deacetyltransferase has prompted our search for more components of the histone modifying machinery in parasitic protozoa. We have previously identified GNAT family HATs in the opportunistic pathogen Toxoplasma gondii and now describe the first MYST (named for members MOZ, Ybf2/Sas3, Sas2, and Tip60) family HATs in apicomplexa (TgMYST-A and -B). The TgMYST-A genomic locus is singular and generates a approximately 3.5-kb transcript that can encode two proteins of 411 or 471 amino acids. TgMYST-B mRNA is approximately 7.0 kb and encodes a second MYST homologue. In addition to the canonical MYST HAT catalytic domain, both TgMYST-A and -B possess an atypical C2HC zinc finger and a chromodomain. Recombinant TgMYST-A exhibits a predilection to acetylate histone H4 in vitro at lysines 5, 8, 12, and 16. Antibody generated to TgMYST-A reveals that both the long and short (predominant) versions are present in the nucleus and are also plentiful in the cytoplasm. Moreover, both TgMYST-A forms are far more abundant in rapidly replicating parasites (tachyzoites) than encysted parasites (bradyzoites). A bioinformatics survey of the Toxoplasma genome reveals numerous homologues known to operate in native MYST complexes. The characterization of TgMYST HATs represents another important step toward understanding the regulation of gene expression in pathogenic protozoa and provides evolutionary insight into how these processes operate in eukaryotic cells in general.

5' Untranslated Regions↗
PubMed2005

Receptor for retrograde transport in the apicomplexan parasite Toxoplasma gondii.

Toxoplasma gondii and its apicomplexan relatives (such as Plasmodium falciparum, which causes malaria) are obligate intracellular parasites that rely on sequential protein release from specialized secretory organelles for invasion and multiplication within host cells. Because of the importance of these unusual membrane trafficking pathways for drug development and comparative cell biology, characterizing them is essential. In particular, it is unclear what role retrieval mechanisms play in parasite membrane trafficking or where they operate. Previously, we showed that T. gondii's beta-COP (TgBetaCOP; a subunit of coatomer protein complex I, COPI) and retrieval reporters localize exclusively to the zone between the parasite endoplasmic reticulum (ER) and Golgi apparatus. This suggested the existence of an HDEL receptor in T. gondii. We have now identified, cloned, and sequenced this receptor, TgERD2. TgERD2 localizes in a Golgi or ER pattern suggestive of the HDEL retrieval reporter (K. M. Hager, B. Striepen, L. G. Tilney, and D. S. Roos, J. Cell Sci. 112:2631-2638, 1999). A functional assay reveals that TgERD2 is able to complement the Saccharomyces cerevisiae ERD2 null mutant. Retrieval studies reveal that stable expression of a fluorescent exogenous retrieval ligand results in a dispersal of betaCOP signal throughout the cytoplasm and, surprisingly, results in betaCOP staining of the vacuolar space of the parasite. In contrast, stable expression of TgERD2GFP does not appear to disturb betaCOP staining. In addition to TgERD2, Toxoplasma contains two more divergent ERD2 relatives. Phylogenetic analysis reveals that these proteins belong to a previously unrecognized ERD2 subfamily common to plants and alveolate organisms and as such could represent mediators of parasite-specific retrieval functions. No evidence of class 2 ERD2 proteins was found in metazoan organisms or fungi.

Amino Acid Sequence↗
PubMed2006

Toxoplasma gondii inhibits toll-like receptor 4 ligand-induced mobilization of intracellular tumor necrosis factor alpha to the surface of mouse peritoneal neutrophils.

Neutrophils are well-known to rapidly respond to infection through chemotactic infiltration at sites of inflammation, followed by rapid release of microbicidal molecules, chemokines, and proinflammatory cytokines. For tumor necrosis factor alpha (TNF-alpha), we recently found that neutrophils contain intracellular pools of the cytokine and display the capacity to upregulate transcriptional activity of the gene during lipopolysaccharide (LPS) stimulation. We now show that triggering of mouse peritoneal neutrophils with Toll-like receptor 2 (TLR2), TLR4, and TLR9 ligands, but not ligands of TLR3, induces upregulation of surface membrane TNF-alpha. However, neutrophils infected with the protozoan Toxoplasma gondii displayed an inability to respond fully in terms of TLR ligand-induced increases in membrane TNF-alpha expression. Infected neutrophils failed to display decreased levels of intracellular TNF-alpha upon LPS exposure. In contrast to intermediate inhibitory effects in nontreated neutrophils, T. gondii induced a complete blockade in LPS-induced surface TNF-alpha expression in the presence of the protein synthesis inhibitor cycloheximide. Despite these inhibitory effects, the parasite did not affect LPS-induced upregulation of TNF-alpha gene transcription. Collectively, the results show that Toxoplasma prevents TLR ligand-triggered mobilization of TNF-alpha to the neutrophil surface, revealing a novel immunosuppressive activity of the parasite.

Animals↗
PubMed1976

Rosette-forming cells during immune response to Toxoplasma gondii in mice.

The rosette-forming cell (RFC) response of mice immunized with varying doses of Toxoplasma gondii was studied by immunocytoadherence (ICA). The specificity of ICA in the present system was tested by passive sensitization with hyperimmune serum in vivo and in vitro. A slight increase in RFC was observed with the latter. Prior treatment of spleen cells from immunized animals with rabbit anti-mouse immunoglobulin resulted in total inhibition of ICA. During the primary and the secondary response after 10 days, the number of RFC rose rapidly to reach the peak on the 3rd day. With secondary immunization 30 days later, the peak shifted to the 2nd day. Mice infected with a lower dose of Toxoplasma had a greater number of RFC during the secondary response after 10 days than with a larger dose.

Animals↗
PubMed1980

Lack of immunoglobulin M suppression by immunoglobulin G antibody in thymectomized, irradiated, and bone marrow-reconstituted mice infected with Toxoplasma gondii.

Thymectomized, irradiated, bone marrow-reconstituted (T-deprived) mie infected with an avirulent strain of Toxoplasma gondii produced antibody titers comparable to those produced in intact syngeneic mice. Both immunoglobulin M (IgM) and IgG antibodies were produced in T-deprived animals; however, the IgM antibody remained constant in the presence of increasing amounts of IgG. In the intact animals, IgM became undetectable by day 50 postinfection as expected. Feedback inhibition of IgM by IgG seems to be dependent upon T-cells in Toxoplasma-infected mice.

Animals↗
PubMed1980

Antibody responses to toxoplasma antigens in mice infected with strains of different virulence.

Swiss Webster mice were infected with either the relatively virulent C56 strain or the relatively avirulent C37 strain of Toxoplasma gondii, and the sequence of their antibody response to surface antigens of the parasite was studied. An immunoglobulin M (IgM) agglutinating antibody was the first serologically detectable antibody and was first detected on day 2 in mice infected with the C37 strain and on day 5 in mice infected with the C56 strain. IgG antibodies were first detected on day 8 for both strains. The major component of the IgG antibodies was IgG2:IgG3 antibodies had lower titers, and no IgG1 antibodies were detected. The IgG antibodies were active in direct parasite agglutination and in the complement-dependent cytotoxicity assay of Sabin and Feldman (Science 108:660-663, 1948). On sodium dodecyl sulfate-polyacrylamide gel electrophoresis, sera from mice infected with T. gondii detected all major radioiodinated surface proteins of toxoplasma tachyzoites. The earliest time point at which these antigens were detected differed for the two strains. Serum from mice infected with C56 strain immunoprecipitated all cell surface antigens by day 10 of infection, whereas serum from mice infected with the C37 strain did not do so until day 15 of infection.

Animals↗
PubMed1982

Augmented followed by suppressed levels of natural cell-mediated cytotoxicity in mice infected with Toxoplasma gondii.

The cytotoxic activity of effector cells from mice infected with Toxoplasma gondii was tested in a 4- to 5-hr (51)Cr release assay, using RL [vertical male] 1 and YAC-1 target cells. They showed enhanced cytotoxicity with a peak on the 3rd day postinfection followed by suppression with a peak on the 12th day. The cytotoxicity seemed to be exhibited by natural killer (NK) cells because: (i) pretreatment of the effector cells with antiasialo GM(1) or antiasialo GM(2) plus complement abolished the cytotoxic activity; (ii) the altered cytotoxicity levels were also induced in nude mice; and (iii) the activity was elicited by nonadherent-nonphagocytic cells. The alteration occurred simultaneously in various lymphoid organs with a similar profile. Neither spleen nor bone marrow cells of 12-day-postinfected mice inhibited NK activity of uninfected mice. Culture fluids of the infected mouse spleen and bone marrow cells did not affect the normal mouse NK activity. The proportion of effector cells capable of binding to target cells was constant during the infection. There was no positive correlation between NK activity and serum interferon level; i.e., interferon was detected in the serum of 12-day-postinfected mice but not in that of 3-day-postinfected or uninfected mice. Passively administered interferon or polyinosinic-polycytidylic acid could not restore the suppressed NK activity of 12-day-postinfected mice. Moreover, in vitro treatment of spleen cells from 12-day-postinfected mice with interferon failed to restore the suppressed NK activity. These results suggested that after toxoplasma infection, defective sensitivity to interferon was induced in NK precursor cells, and differentiation to functionally active NK cells might be blocked.

Animals↗
PubMed1971

Effects of an interferon inducer, poly I:C, on acute ocular infection produced by intracameral inoculation of Toxoplasma gondii.

A potent interferon inducer, synthetic polyinosinic acid-polycytidylic acid complex (poly I:C), was used prophylactically and therapeutically in experimental ocular Toxoplasma infections in rabbits. Daily intravenous injections of poly I:C alone or when combined with daily subconjunctival injections of the inducer delayed the appearance of conjunctivitis, corneal opacity, and iritis in Toxoplasma-infected eyes provided that the treatment was started 1 day before the infection. When the treatment was begun at the same time or 1 day after the infection, no delay in the production of the ocular lesions was noted. In no case was the treatment curative or completely suppressive.

Animals↗
PubMed1984

Partially purified antigen preparations of Toxoplasma gondii protect against lethal infection in mice.

Antigens of Toxoplasma gondii eluted from polyacrylamide gels after electrophoresis under reducing conditions were examined for their capacity to react with antibodies from infected humans, to induce antibody formation, and to protect mice against T. gondii. Antigens with approximate molecular weights of 35,000 and 14,000 strongly reacted in an enzyme-linked immunosorbent assay of human immunoglobulin M (IgM) and IgG antibodies to T. gondii. Mice injected with the eluted antigen preparations formed antibodies that reacted differently in four serological tests for Toxoplasma antibodies. All mice formed antibodies that reacted in the IgG and IgM enzyme-linked immunosorbent assay. Antibodies reacting in the conventional indirect immunofluorescent antibody test were detected in all mice except those injected with low-molecular-weight (14,000 or less) antigens. Sabin-Feldman dye test antibodies were not detected in any of the mice. Antibodies reacting in the latex agglutination test were detected mainly in mice injected with antigens with an approximate molecular weight of 66,000. Challenge of the injected mice with a lethal inoculum of T. gondii revealed that the highest survival rate was in animals that received antigens with approximate molecular weights of 35,000 and 14,000.

Agglutination↗
PubMed1985

Detection of circulating antigens in sera of rabbits infected with Toxoplasma gondii.

Experiments were performed to investigate the usefulness of an enzyme-linked immunosorbent assay utilizing avidin-biotin interaction as a diagnostic tool for detection of Toxoplasma antigen in blood. The lower limit of sensitivity of the assay by this method was ca. 4 ng/ml, and standard assays provided a linear plot of antigen concentration over a range up to 250 ng/ml. In rabbits inoculated subcutaneously with trophozoites of the RH strain, Toxoplasma antigen became demonstrable in the circulation 3 days after injection, before emergence of antibody in serum and development of parasitemia. Analysis of the antigen in serum from infected rabbits by high-permeation liquid gel chromatography suggested the occurrence of antigens of four different molecular weights, greater than or equal to 400,000, 220,000, 130,000, and 45,000. Of these antigens, those of molecular weights 220,000 and 130,000 showed a conspicuous elevation with time after infection.

Animals↗
PubMed1985

Effect of genetic modification of antibody responsiveness on resistance to Toxoplasma gondii infection.

Resistance to Toxoplasma gondii infection was studied in the high (H/f) and low (L/f) antibody responder lines of mice that were selected on the basis of quantitative antibody responsiveness to the flagellar antigen of Salmonella (selection III). No interline difference was observed in resistance to a highly virulent strain of T. gondii. In contrast, H/f mice were much more resistant than L/f mice to a moderately virulent strain of T. gondii: a 5000-fold difference in terms of the 50% lethal dose was found. The degree of resistance in (H/f X L/f)F1 hybrids was intermediate compared with that in parental lines for both mortality and survival time. The antibody titers to Toxoplasma antigens measured during the course of the infection were significantly higher in H/f than in L/f mice. This interline difference was underestimated because parasite multiplication occurs faster in L/f mice, which increases antigenic stimulation. The stronger resistance of H/f mice is probably due to their higher capacity of antibody production in the course of infection.

Animals↗