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PubMed1992

Passive immunization protects guinea pigs from lethal Toxoplasma infection.

The cellular and humoral interactions that contribute to protective immunity in toxoplasmosis were studied by adoptive transfer of selective cell populations or immune serum and its fractions into normal syngeneic strain 2 guinea pigs. The results of this study with the RH strain of Toxoplasma gondii confirm and extend the findings of previous studies by showing that the passive transfer of parasite-sensitized T cells or of immune serum from previously infected donors protected recipient guinea pigs against lethal toxoplasmosis. An additional key finding was that similar levels of complete protection against lethal infection occurred in guinea pigs receiving partially purified anti-Toxoplasma immunoglobulins or immune cells that had been enriched for B cells prior to transfer. Cells residing in the spleen, lymph nodes and peritoneal cavity, but not the thymus, were equally effective in conferring immunity to challenged recipients. In addition, cell titration experiments revealed that guinea pigs could survive T. gondii infection by infusing them with as little as 2 x 10(7) sensitized T cells or B cells. Unlike protection mediated by T cells, protection against lethal disease occurring in the B cell recipients was associated with the formation of Toxoplasma antibodies. These findings illustrate the major role of both humoral and cell-mediated immunity in affording protection against toxoplasmosis based on a guinea pig model of the human disease.

Animals↗
PubMed1998

Host cell surface sialic acid residues are involved on the process of penetration of Toxoplasma gondii into mammalian cells.

Tachyzoites of Toxoplasma gondii are able to infect several cell types tested (wild-type chinese hamster ovary (CHO) cells and glycosylation mutants, Vero and LLCMK2 cells). However, the extent of infection varied. Mutant cells which present few or no surface-exposed sialic acid residues were infected to a lower extent. Similar results were obtained if sialic acid residues were removed by previous neuraminidase treatment. Addition of sialic acid residues to surface-exposed glycoconjugates using fetuin as a sialic acid donor and the trans-sialidase of Trypanosoma cruzi rendered the cells more easily infected by Toxoplasma gondii. These observations indicate that surface-exposed carbohydrate residues of the host cell are involved on the process of Toxoplasma gondii-host cell recognition.

Animals↗
PubMed1975

The ultrastructural development of the macrogamete and formation of the oocyst wall of Toxoplasma gondii.

The macrogametes of Toxoplasma gondii develop within the epithelial cells of the cat ileum. As they develop the nucleus enlarges and dense patches of chromatin which were present in the nucleoplasm, disappear. Polysaccharide granules and lipid globules appear in the cytoplasm and increase in number during development. The wall-forming bodies of Type I (WFB I) appear before the wall-forming bodies of Type II (WFB II); WFB I are smaller, more osmiophilic and more numerous than the WFB II. The WFB I appear to form from vesicles produced by the smooth endoplasmic reticulum, and the WFB II form within the lacunae of the rough endoplasmic reticulum. Double membraned vacuoles appear to form from the nuclear membranes but the function of these is unknown. Throughout development the macrogamete retains a normal pellicle which possesses numerous micropores. The first evidence of oocyst wall formation is the appearance of participate matter in the parasitophorous vacuole which precipitates to form Layer 1 of the oocyst wall. Layers 2 and 3 are unit membranes which form between Layer 1 and the pellicle. During this development the organism has an organelle complement similar to that of the macrogamete. Layers 4 and 5 form between Layer 3 and the pellicle. Layer 4 is osmiophilic and its formation is accompanied by the disappearance of WFB I. Layer 5 is less osmiophilic than Layer 4 and its formation is accompanied by the disappearance of WFB II. The two innermost layers (Layers 4 & 5) in the oocyst wall of Toxoplasma are similar to those found in Isospora spp. and Eimeria spp. Toxoplasma seems to be unusual in that, firstly, it possesses an additional 3 layers and, secondly, all 5 layers are formed outside the pellicle of the original macrogamete.

Animals↗
PubMed1968

Toxoplasma gondii and cytomegalovirus: mixed infection by a parasite and a virus.

Human fibroblasts infected in vitro with cytomegalovirus are relatively resistant to infection by Toxoplasma gondii during the first 4 days of virus infection. After 5 days, however, the cytomegalovirus-infected cells become susceptible to the parasites. The toxoplasmas replicate in paracentral rosettes surrounded by host cell mitochondria. This growth configuration differs from that seen in human fibroblasts infected in vitro with toxoplasma only but resembles the pattern seen in doubly infected cells found in human necropsy tissue.

Culture Techniques↗
PubMed1970

Toxoplasma gondii in cats: fecal stages identified as coccidian oocysts.

Isospora-type oocysts were excreted by cats following the ingestion of Toxoplasma fromn infected mice. Oocysts appeared 3 to 5 days after cyst. were ingested and 8 to 10 days after trophozoites were ingested, and also 21 to 24 days after the administration of infective fecal suspensions from cats. A close quanititative and biologic correlation between oocysts and Toxoplasma infectivity of the feces was observed which could not be separated by density gradient centrifugation and filtration methods. Toxoplasma is an intestinal coccidian of cats which is fecally spread. It has evolved to multiply in brain and muscle and in other species, making it possible for carnivorism to become another means of transmission.

Animals↗
PubMed1973

Sarcocystis in mice inoculated with toxoplasma-like oocysts from cat feces.

Sarcocysts morphologically similar to Sarcocystis muris were observed in mice after inoculation with Toxoplasma-like oocysts found in feces of a stray cat. Cats that were fed mice infected with the oocysts shed similar oocysts in their feces. Sarcocysts were found histologically in about 50 percent of mice inoculated with 40,000 or more oocysts and examined 42 days or longer after exposure. Most inoculated mice developed low Toxoplasma dye-test antibody titers 3 to 4 weeks after exposure, but Toxoplasma antibody was usually not detectable in infected cats.

Animals↗
PubMed1988

In vitro effects of four macrolides (roxithromycin, spiramycin, azithromycin [CP-62,993], and A-56268) on Toxoplasma gondii.

The effect of four macrolides against intracellular Toxoplasma gondii was determined in three different in vitro systems. Unactivated murine peritoneal macrophages were infected with the virulent RH strain of T. gondii. The activity of the macrolides was first measured with [3H]uracil, which is incorporated by the parasite but not the host cell. The 50% inhibitory concentrations (IC50s) and 95% confidence limits were calculated at 54 (38 to 73), 140 (98 to 201), 147 (101 to 214), and 246 (187 to 325) micron for roxithromycin, azithromycin (CP-62,993), A-56268, and spiramycin, respectively. Inhibition of Toxoplasma growth was confirmed by microscopic examination of the infected macrophages after treatment with roxithromycin. Compared with untreated controls, roxithromycin concentrations near the IC50s decreased the number of infected cells, the number of tachyzoites per vacuole, and the number of cells containing rosettes (i.e., clusters of more than eight tachyzoites). After treatment with the four macrolides, tachyzoites were released from the macrophages and subcultured in HeLa cells, which are nonprofessional phagocytes, to assess the viability of the remaining parasites. This showed that the macrolides at concentrations corresponding to four times their 90% inhibitory concentrations (IC90s) had no significant killing effect. At 8 times the IC90, roxithromycin showed an incomplete killing effect, similar to that of the combination of pyrimethamine (0.41 microM)-sulfadiazine (99.42 microM). All macrolides tested showed inhibitory effects against intracellular T. gondii, but amounts of azithromycin and A-56268 corresponding to the IC90 appeared to be toxic against the host macrophages, which might have had nonspecific activity against Toxoplasma metabolism.

Animals↗
PubMed1989

In vitro effects of folate inhibitors on Toxoplasma gondii.

Three sulfonamides and four dihydrofolate reductase inhibitors were tested alone and in combination to determine their in vitro effects on two strains of Toxoplasma gondii grown in MRC5 fibroblast tissue culture. Toxoplasma growth was quantitated by an enzyme immunoassay performed directly on the fixed cultures, and linear regression models were used to quantify the relationship between the optical density values generated by the enzyme-linked immunosorbent assay and the concentrations of the antimicrobial agents in the culture medium. The cytopathic effects of antimicrobial agents on T. gondii were examined in Giemsa-stained cultures. Sulfonamides and dihydrofolate reductase inhibitors exhibited similar patterns of inhibition, consisting of an important increase of the inhibitory effect within a narrow range of concentrations. Sulfadiazine, sulfamethoxazole, and sulfisoxazole were all found to have important inhibitory effects on T. gondii; the 50% inhibitory concentrations estimated from the regression models were 2.5 micrograms/ml for sulfadiazine, 1.1 micrograms/ml for sulfamethoxazole, and 6.4 micrograms/ml for sulfisoxazole. This inhibition of growth was associated with a reduction of the number of parasitized cells and intracellular parasites that were morphologically normal. With dihydrofolate reductase inhibitors, including pyrimethamine, trimethoprim, trimetrexate-glycuronate, and piritrexim, a strong inhibition of Toxoplasma growth was observed, which was associated with striking morphological changes of the parasites. The 50% inhibitory concentrations were 0.04 microgram/ml for pyrimethamine, 2.3 micrograms/ml for trimethoprim, 0.16 ng/ml for trimetrexate-glycuronate, and 6.9 ng/ml for piritrexim. When sulfonamides and dihydrofolate reductase inhibitors were used in combination, a synergistic effect was observed with sulfadiazine combined with pyrimethamine, trimetrexate-glycuronate, and piritrexim; sulfisoxazole combined with pyrimethamine; and trimethoprim combined with sulfamethoxazole. These results were analyzed in comparison with human pharmacokinetics data.

Animals↗
PubMed1993

In vitro and in vivo activities of the hydroxynaphthoquinone atovaquone alone or combined with pyrimethamine, sulfadiazine, clarithromycin, or minocycline against Toxoplasma gondii.

The efficacy of atovaquone alone or combined with pyrimethamine, sulfadiazine, clarithromycin, and minocycline was examined in vitro and in a murine model of acute toxoplasmosis. In vitro studies were performed with MRC5 fibroblast tissue cultures, with quantification of Toxoplasma growth by an enzyme-linked immunosorbent assay. For in vivo studies, mice were acutely infected intraperitoneally with 10(4) tachyzoites of the virulent RH strain and then treated perorally for 10 days from day 1 postinfection. The following drug regimens were investigated: atovaquone at 100 and 50 mg/kg of body weight per day and the combinations of atovaquone at 50 mg/kg with sulfadiazine at 200 mg/kg, pyrimethamine at 12.5 mg/kg, clarithromycin at 200 mg/kg, or minocycline at 50 mg/kg. Efficacy was assessed by determination of survival rates and sequential determination of parasite burdens in blood, brain, and lungs. In vitro, atovaquone inhibited Toxoplasma growth at a concentration of > or = 0.02 mg/liter; the 50% inhibitory concentration was estimated to be 0.023 mg/liter. No synergistic effect was observed when it was combined with sulfadiazine, clarithromycin, or minocycline, whereas a significant antagonistic effect was noted for the combination of atovaquone with pyrimethamine. In vivo, administration of atovaquone at 100 or 50 mg/kg/day for 10 days resulted in prolonged survival compared with that in untreated mice; this survival was associated with a reduction of parasite burdens in blood and tissues during the course of treatment. The combinations of atovaquone with pyrimethamine, clarithromycin, or sulfadiazine were more efficient than each drug administered alone, in terms of survival, but parasite burdens in blood and organs were not reduced compared with those in mice treated with any of the agents alone. These experimental results confirmed the activity of atovaquone against Toxoplasma gondii, but no marked improvement in efficacy was observed in vitro and in vivo when this drug was combined with pyrimethamine, sulfadiazine, minocycline, or clarithromycin.

Animals↗
PubMed1996

In vitro and in vivo effects of rifabutin alone or combined with atovaquone against Toxoplasma gondii.

The efficacy of rifabutin (RIFA) alone or in combination with atovaquone (ATO) was examined in vitro and in a murine model of acute toxoplasmosis. In vitro studies were performed with MRC5 fibroblast tissue cultures, with quantification of Toxoplasma growth by enzyme-linked immunosorbent assay. For in vivo studies, mice were acutely infected with 10(4) tachyzoites of the virulent RH strain and were then treated perorally for 10 days from day 1 or day 4 postinfection. The efficacy of each drug regimen was assessed by determination of survival rates and sequential titration of parasites in blood, brain, and lungs by a tissue culture method. In vitro, RIFA was inhibitory for Toxoplasma growth at concentrations between 0.5 and 20 micrograms/ml; the 50% inhibitory concentration was estimated to be 1.68 micrograms/ml. When RIFA and ATO were combined, synergistic effects were noted for RIFA at 20 micrograms/ml combined with ATO at 0.01 or 0.02 microgram/ml and RIFA at 1, 2, or 5 micrograms/ml combined with ATO at 0.02 microgram/ml. In vivo, administration of RIFA at 200 mg/kg of body weight per day from day 1 to day 10 resulted in a 100% protection during treatment, with clearance of parasites from the blood, brain, and lungs. After the cessation of therapy, relapses occurred in the brain and lungs; the mortality was 46% at the end of the experiment (day 30). Among the mice treated with RIFA at 200 mg/kg/day from day 4 to day 14, no death was recorded during the treatment period and a marked reduction in parasite burdens was observed in blood and tissues; however, relapses occurred and 10% of mice survived until day 30. Administration of RIFA at 200 mg/kg/day in combination with ATO at 100 mg/kg/day resulted in a marked prolongation of survival compared with that for mice that received ATO or RIFA alone. However, in mice receiving the combination, parasite burdens in blood and organs were similar to those in mice treated with RIFA alone. These results confirmed the activity of RIFA in the treatment of acute toxoplasmosis and the potential of the combination of RIFA-ATO since the two drugs act synergistically against Toxoplasma gondii.

Animals↗
PubMed2000

Anti-toxoplasma activities of antiretroviral drugs and interactions with pyrimethamine and sulfadiazine in vitro.

The anti-Toxoplasma activities of nine antiretroviral drugs were examined in vitro. Nucleoside analogs had no effect on parasite growth, whereas ritonavir and nelfinavir were inhibitory for Toxoplasma, with 50% inhibitory concentrations of 5.4 and 4.0 microg/ml, respectively. None of the antiviral drugs affected the anti-Toxoplasma activity of pyrimethamine or sulfadiazine.

Animals↗
PubMed1998

Detection of Toxoplasma gondii oocysts in drinking water.

The world's largest outbreak of waterborne toxoplasmosis occurred in a municipality in the western Canadian province of British Columbia. When drinking water emerged as a possible source of infection during the outbreak investigation, a laboratory method was needed to attempt detection of the parasite, Toxoplasma gondii. The method developed was based on the current U.S. Environmental Protection Agency method for detection of Cryptosporidium oocysts. Collection of large-volume drinking water samples and cartridge filter processing were unchanged, although identification of Toxoplasma oocysts in the filter retentate was carried out by using a previously described rodent model. Validation of the method developed was tested by using oocysts from a well-characterized Toxoplasma strain.

Animals↗
PubMed2003

Development and application of different methods for the detection of Toxoplasma gondii in water.

Two methods, centrifugation and flocculation, were evaluated to determine their efficiencies of recovery of Toxoplasma gondii oocysts from contaminated water samples. Demineralized and tap water replicates were inoculated with high numbers of sporulated or unsporulated T. gondii oocysts (1 x 10(5) and 1 x 10(4) oocysts). The strain, age, and concentration of the seeded oocysts were recorded. Oocysts were recovered either by centrifugation of the contaminated samples at various g values or by flocculation with two coagulants, Fe(2)(SO(4))(3) and Al(2)(SO(4))(3). The recovery rates were determined with the final pellets by phase-contrast microscopy. Sporulated oocysts were recovered more effectively by flocculation with Al(2)(SO(4))(3) (96.5% +/- 21.7%) than by flocculation with Fe(2)(SO(4))(3) (93.1% +/- 8.1%) or by centrifugation at 2,073 x g (82.5% +/- 6.8%). For the unsporulated oocysts, flocculation with Fe(2)(SO(4))(3) was more successful (100.3% +/- 26.9%) than flocculation with Al(2)(SO(4))(3) (90.4% +/- 19.1%) or centrifugation at 2,565 x g (97.2% +/- 12.5%). The infectivity of the sporulated oocysts recovered by centrifugation was confirmed by seroconversion of all inoculated mice 77 days postinfection. These data suggest that sporulated Toxoplasma oocysts purified by methods commonly used for waterborne pathogens retain their infectivity after mechanical treatment and are able to induce infections in mammals. This is the first step in developing a systematic approach for the detection of Toxoplasma oocysts in water.

Alum Compounds↗
PubMed2006

Toxoplasma gondii targets a protein phosphatase 2C to the nuclei of infected host cells.

Intracellular pathogens have evolved a wide array of mechanisms to invade and co-opt their host cells for intracellular survival. Apicomplexan parasites such as Toxoplasma gondii employ the action of unique secretory organelles named rhoptries for internalization of the parasite and formation of a specialized niche within the host cell. We demonstrate that Toxoplasma gondii also uses secretion from the rhoptries during invasion to deliver a parasite-derived protein phosphatase 2C (PP2C-hn) into the host cell and direct it to the host nucleus. Delivery to the host nucleus does not require completion of invasion, as evidenced by the fact that parasites blocked in the initial stages of invasion with cytochalasin D are able to target PP2C-hn to the host nucleus. We have disrupted the gene encoding PP2C-hn and shown that PP2C-hn-knockout parasites exhibit a mild growth defect that can be rescued by complementation with the wild-type gene. The delivery of parasite effector proteins via the rhoptries provides a novel mechanism for Toxoplasma to directly access the command center of its host cell during infection by the parasite.

Amino Acid Sequence↗
PubMed1980

Use of monoclonal antibodies to detect antigens of Toxoplasma gondii in serum and other body fluids.

Monoclonal antibodies to Toxoplasma gondii were used in an enzyme-linked immunosorbent assay to detect antigens of the parasite in toxoplasma lysate, in peritoneal fluid of mice, and in sera from humans acutely infected with T. gondii. Four of the six monoclonal antibodies were able to detect antigens of toxoplasma in these specimens. Control sera from individuals not infected with T. gondii and from individuals chronically infected with the parasite were negative in the enzyme-linked immunosorbent assay. Sera from individuals not infected with T. gondii but with positive titers from rheumatoid factor were also negative; 2 or 10 sera from individuals not infected with T. gondii but with positive titers for antinuclear antibodies reacted with the monoclonal antibodies. When the results of the enzyme-linked immunosorbent assay with monoclonal antibodies and with the F(ab)2 fraction of an immunoglobulin G from a rabbit infected with T. gondii were compared, it was noted that the F(ab)2 was more active in detecting parasite antigens than were the monoclonal antibodies. Thus, although monoclonal antibodies can be used to detect antigens of T. gondii in sera and other body fluids, polyvalent antibody (such as the F(ab)2 fraction) appears to be more satisfactory for this purpose.

Animals↗
PubMed1981

Nonspecific suppression of initiation of memory cells in Toxoplasma gondii-infected mice.

The effect of Toxoplasma infection on initiation and expression of memory cells to dinitrophenol (DNP)-conjugated protein antigens in humoral immune responses was studied in mice. Marked suppression in the initiation of memory cells to DNP-conjugated keyhole limpet hemocyanin occurred in the acute phase of infection. However, once the memory cells were induced before infection, expression of the memory cells was not affected. Moreover, the suppression of priming occurred on both T and B cells. The suppressive effect was observed in all immunoglobulin classes tested, i.e., immunoglobulin M (IgM), IgG1, IgG2, and IgE, regardless of the four kinds of DNP-conjugated protein antigens. This nonspecific suppression could be induced only by living toxoplasmas, by either the peroral or parenteral route, but not by lysed organisms. A transfer of normal spleen cells could not restore the ability of infected mice to initiate memory cells. Furthermore, the suppressive effect of the infected mice was not removed by 400 R of gamma-irradiation. These results suggested that irradiation-resistant suppressor cells cause nonspecific suppression of the initiation of memory cells in Toxoplasma-infected mice.

Animals↗
PubMed1987

Specific and nonspecific mediation of protective immunity to Toxoplasma gondii.

We studied the specificity of protection conferred by Toxoplasma gondii immune lymphocytes and their supernatants on infected hamster kidney cells, using Besnoitia jellisoni immune lymphocytes as a nonspecific control. The intracellular growth of the organisms was measured by [3H]uracil incorporation, and inhibition of multiplication was used as a measurement of immunity. Although the immune lymphocytes restricted principally the multiplication of homologous organisms, partial protection, expressed against the heterologous organism, was found. This was true for either parasite with intact lymphocytes or their supernatants. Exposure of immune lymphocytes to antigen for 18 to 24 h and treatment of kidney cells with supernatant fluids for 18 to 24 h were required for maximal protection. The specific protective mediator in supernatants of immune lymphocytes was characterized by dialysis as having a molecular weight between 3,000 and 12,000 and was found in the 3,000 to 5,000 peak after Sephadex G-50 chromatography. Nonspecific protective activity was greater than 12,000 by dialysis; it chromatographed in the excluded peak, measuring over 43,000, and was destroyed by exposure to pH 2. In vitro production of lymphokines from toxoplasma immune lymphocytes was first detected 7 to 10 days after vaccination of hamsters. At about the same time, hamsters began to resist challenge infection with the pathogenic RH strain of T. gondii and were able to prevent its multiplication in lungs, liver, spleen, and the subcutaneous infection site. The expression of tissue immunity and the production of toxoplasma-immune lymphokines appear to be time-related events.

Animals↗
PubMed1994

Toxoplasma encephalitis in congenic B10 and BALB mice: impact of genetic factors on the immune response.

Factors which determine the pathogenesis and course of Toxoplasma encephalitis are poorly understood. In the present study, the influence of genetic factors in congenic B10 and BALB mice of H-2q, H-2k, and H-2b haplotypes was examined following oral infection with a low-virulence strain of Toxoplasma gondii (DX). There were striking differences among these strains. Whereas B10 mice were highly susceptible, BALB mice had a less severe and more protracted disease. In all animals with a fatal outcome, Toxoplasma encephalitis was the cause of death. Within the two congenic groups, the major histocompatibility complex haplotype had a strong impact on the disease. The H-2k haplotype was associated with early death in B10 mice but with a favorable outcome in BALB mice, whereas the reverse was observed for the H-2q haplotype. These findings indicate that genetically determined factors are critically involved in determining the intracerebral immune response and the course of murine toxoplasmosis. Some of these factors appear to be associated with the major histocompatibility complex haplotype, but significant differences between B10 and BALB mice point to a modulating role of additional genetic loci. Immunohistochemical studies and cytokine analyses of cerebrospinal fluid and serum revealed significant differences in the intracerebral immune response between susceptible and resistant strains. A poor outcome was associated with a large number of intracerebral parasites, significant tissue necrosis, a reduced number of intracerebral CD4+ T cells, low intrathecal tumor necrosis factor levels, and, to a lesser extent, a reduced number of intracerebral CD8+ T cells.

Animals↗