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PubMed1991

Proliferation of Toxoplasma gondii in human neutrophils in vitro.

Human neutrophils were infected with tachyzoites of Toxoplasma gondii in vitro. Infection rates after 1 h of incubation were 38.6-52.0% and 16.0-25.8% in the presence or absence of specific antibody respectively. Apparently, neutrophils killed tachyzoites 18 h after infection in the presence of antibody, whereas tachyzoites proliferated in 25.0-35.0% of infected neutrophils in the absence of antibody. Total tachyzoite counts 18 h after infection were approximately 4 times as high as those 1 h after infection in the absence of antibody and complement. Complement also enhanced phagocytosis and killing of tachyzoites by neutrophils, but the effects were less than that of antibody. Superoxide anion was produced intensively within 1 h after infection, depending on the presence of antibody or complement. Neutrophils seem to be responsible for dissemination of tachyzoites in the host during the initial phase of Toxoplasma infection until antibody is produced.

Animals↗
PubMed1991

Naturally occurring immunoglobulin M antibodies to Toxoplasma gondii in Japanese populations.

Varying degrees of naturally occurring immunoglobulin (Ig) M antibodies to Toxoplasma gondii were observed in almost all of adult Japanese populations negative for IgG antibodies as determined by an enzyme-linked immunosorbent assay (ELISA). The antibody activity was reduced by absorption of sera with Toxoplasma soluble antigen or by 2-mercaptoethanol treatment of the IgM fraction after sucrose density gradient centrifugation. Umbilical cord sera had almost no detectable IgM antibodies, and the ELISA value in infants increased with age until 1 year. Most paired sera collected from adults at a 1-year interval showed constant IgM antibody levels, suggesting retention of natural IgM antibodies throughout their lives without changing ELISA values of greater than or equal to 0.1/year. Polar staining was observed in immunofluorescent studies for 14 serum samples with natural IgM antibody levels of greater than or equal to 0.5, while samples obtained from a pregnant woman with natural IgM antibody levels of greater than or equal to 0.9 reacted to the whole organism as was observed in positive sera of acute patients. Western blotting analysis revealed that natural IgM antibodies were directed to multiple antigen molecules. The band pattern differed slightly from one serum to another, but almost consistent patterns were observed in sera sequentially obtained from an adult over 4 years.

Absorption↗
PubMed1995

Genetic characterization of Toxoplasma gondii strains by random amplified polymorphic DNA polymerase chain reaction.

The technique of Random Amplified Polymorphic DNA (RAPD) PCR has been used to detect DNA polymorphisms among Toxoplasma gondii strains. Seven arbitrary oligonucleotides (10-mer) were used as primers to amplify total genomic DNAs and significant genetic heterogeneity was detected among 11 T. gondii strains with different virulence for mice. The polymorphisms observed allowed relationship dendrograms of T. gondii strains to be constructed by PHYLIP and PAUP analyses. The genetic relationships of the T. gondii strains generated by 2 analyses using completely different assumptions were similar. Both analyses revealed 2 groups of T. gondii strains, one formed by the 6 virulent strains and the other formed by the 5 avirulent strains. This suggests that the genus Toxoplasma may actually contain 2 groups, correlated with their virulence, which have probably evolved independently following their initial separation. Significant polymorphisms were also detected between 2 different laboratory stocks of the T. gondii RH strain.

Animals↗
PubMed2001

Anti-SAG1 peptide antibodies inhibit the penetration of Toxoplasma gondii tachyzoites into enterocyte cell lines.

The initial attachment of Toxoplasma tachyzoites to the target host cell is an important event in the life-cycle of the parasite and a critical stage in infection. Previous studies have shown that polyclonal antibodies directed against the major surface antigen of Toxoplasma gondii (SAG1) inhibit the infection of enterocyte cell lines. Here, we demonstrate that antibodies raised against a central peptide (V41T) of SAG1 and the SAGI protein itself are able to inhibit the infection of various cell lines by the tachyzoites. Antibodies directed against SAG1 peptides were used to define a site on the SAGI antigen that interacts with the host cell. The epitope carried by V41T was identified on the tachyzoite surface by immunofluorescence. The peptide sequence seems to be conserved in all the members of the SAGI Related Sequence family (SRS). Using undifferentiated and differentiated Caco-2 cells, we found that tachyzoites enter preferentially via the basolateral side of the cell. These findings highlight the role of the SRS family members in the mediation of host cell invasion.

Amino Acid Sequence↗
PubMed2006

The prevalence of Neospora caninum and co-infection with Toxoplasma gondii by PCR analysis in naturally occurring mammal populations.

Neospora caninum and Toxoplasma gondii are closely related intracellular protozoan parasites associated with bovine and ovine abortion respectively. Little is known about the extent of Neospora/Toxoplasma co-infection in naturally infected populations of animals. Using nested PCR techniques, based on primers from the Nc5 region of N. caninum and SAG1 for T. gondii, the prevalence of N. caninum and its co-infection with T. gondii were investigated in populations of Mus domesticus, Rattus norvegicus and aborted lambs (Ovis aries). A low frequency of infection with N. caninum was detected in the Mus domesticus (3%) and Rattus norvegicus (4.4%) populations. A relatively high frequency of infection with N. caninum was detected in the brains of aborted lambs (18.9%). There was no significant relationship between N. caninum and T. gondii co-infection. Investigation of the tissue distribution of Neospora, in aborted lambs, showed that Neospora could not be detected in tissues other than brain and this was in contrast to Toxoplasma where the parasite could be frequently detected in a range of tissues.

Abortion, Veterinary↗
PubMed2005

Behaviour of Toxoplasma gondii RH Ankara strain tachyzoites during continuous production in various cell lines.

Toxoplasma gondii is an obligate intracellular protozoan parasite. The objective of the present study was to examine the behaviour of Toxoplasma gondii RH Ankara strain tachyzoites in a cell culture environment. The study represents the first step in determining whether T. gondii RH Ankara strain tachyzoites, grown in cell culture, are of sufficient quality to allow cessation of in vivo tachyzoite production for diagnostic assays. In the present study, T. gondii RH Ankara strain tachyzoites were continuously produced in myeloma X63.Ag8.653, HeLa, Hep-2, and Vero cell cultures for 2 months. The average size of the tachyzoites was 3 x 5.7 microm prior to the first inoculation but after continuous production, a marked decrease was noted in average tachyzoite size. The smallest tachyzoite size, was 1 x 2.1 microm after 2 months, in myeloma cell cultures even though the yield of tachyzoites increased. With other cell cultures, tachyzoite yields were not as high as myeloma cell culture although decrease in size was less. The smallest decrease in tachyzoite size, averaging 2 x 3.8 microm after 2 months, was observed in tachyzoites produced in HeLa cell cultures. A virulence assay in small groups of BALB/c mice, using tachyzoites derived from cell cultures, was also conducted. The preliminary results of the virulence assay suggest that as the size of the tachyzoites decreased, the virulence in mice decreased. Future research will focus on the effect of the size of cell culture-derived T. gondii RH Ankara strain tachyzoites on the virulence, protein expression, and the reliability of diagnostic assays. Ultimately, the behaviour of tachyzoites from various T. gondii strains will be observed in cell culture to determine if size is altered.

Animals↗
PubMed2006

The complete set of Toxoplasma gondii ribosomal protein genes contains two conserved promoter elements.

Recently we showed that de novo ribosome biosynthesis is transcriptionally regulated in Coccidia, depending on their life-cycle stage. Since the expression of ribosomal protein genes is likely coordinated, the transcriptional control of all Toxoplasma gondii ribosomal protein (RP) genes was analysed. Therefore, the complete set of all cytoplasmic RPs was defined, containing 79 different RPs in T. gondii. RP genes were randomly distributed over the genome, each with a unique upstream region with the exception of 8 RP genes which were paired in a head-to-head orientation. To study if the RP genes share conserved promoter elements, a database was made containing upstream sequences of all T. gondii RP genes. Promoter activity was confirmed for the upstream sequences of 8 RP genes, some of which are comparable in strength to the alpha-tubulin promoter. In the complete set of RP upstream sequences 2 novel and highly conserved elements were identified, named Toxoplasma Ribosomal Protein (TRP)-1 (consensus: TCGGCTTATATTCGG) and TRP-2 ([T/C]GCATGC[G/A]). TRP-1 and/or TRP-2 were present in 95% of all RP upstream sequences and moreover, were specifically localized in a small region near the presumptive transcriptional start site (10-330 bp upstream). Although TRP elements were mostly absent in known T. gondii promoters, they are present elsewhere in the T. gondii genome suggesting that they operate not only in RP genes but in a larger set of genes. The identification of TRP elements creates a basis to further study the underlying mechanism by which RP transcription is controlled in T. gondii.

Animals↗
PubMed1998

Re-examination of resistance of Toxoplasma gondii tachyzoites and bradyzoites to pepsin and trypsin digestion.

The effect of digestion in trypsin and acid pepsin on Toxoplasma gondii tachyzoites and bradyzoites was re-evaluated because of recent use of this method to distinguish tachyzoites from bradyzoites. Toxoplasma gondii tachyzoites survived better in 0.5% trypsin solution for 1 h than in 1.0% solution, and occasionally survived for 2 h in acid pepsin solution. Extracellular tachyzoites (> or = 1000) were also infectious orally to mice and cats. Bradyzoites survived equally in trypsin and acid pepsin solutions but the digestion of brain tissue in 0.5% trypsin solution was better than in acid pepsin solution. The resistance to digestion in acid pepsin solution is not a reliable method to distinguish tachyzoites from bradyzoites.

Animals↗
PubMed1992

Longitudinal study of Toxoplasma seroprevalence in South Yorkshire.

Serum samples collected from individuals of a wide range of ages in South Yorkshire between 1969 and 1990 provided the basis for a longitudinal seroprevalence survey of Toxoplasma gondii antibodies. Sera numbering 3868 were screened for T. gondii specific antibodies using a commercial latex agglutination test. The resultant temporal series of serological profiles revealed a rise, with age, in seroprevalence, the rate of which showed a decrease through time. A plateau of around 40-50% prevalence was attained by the 41- to 45-year age-class in 1969 which was not approached until the 66- to 70-year class in the 1988-90 data set. This trend for decline in seroprevalence was confirmed by statistical analysis for the age range 21-60 years. These results may be indicative of a decrease in the rate of toxoplasma exposure in this study community over the 20-year period. The survey of 1988-90 provides a base-line profile of present-day seroprevalence in which 11% of individuals in the age range 16-45 years (roughly corresponding to the childbearing age-range) show evidence of past infection. The representative nature of the serum collection and public-health implications of these results are discussed.

Adolescent↗
PubMed2004

Population-based Toxoplasma seroprevalence study in The Netherlands.

During 1995--1996 a population-based seroprevalence study was conducted in The Netherlands. Risk factors were established for postnatally acquired toxoplasmosis. The results were compared with a study conducted during 1987-1988 in pregnant women in the Southwest of The Netherlands in order to estimate the change in seroprevalence. In total, 7521 sera were tested and the national seroprevalence was 40.5 % (95 % CI 37.5-43.4). Living in the Northwest, having professional contact with animals, living in a moderately urbanized area, being divorced or widowed, being born outside The Netherlands, frequent gardening and owning a cat were independently associated with Toxoplasma seropositivity. Risk factors like eating undercooked meat could not be studied. The seroprevalence among women aged 15-49 years was 10 % lower (35.2 %, 95 % CI 32.9-38.6) in the study of 1995-1996, compared to the Toxoplasma study of 1987--1988 (45.8 %, 95 % CI 45.2-46.3). The steepest rise in seroprevalence still occurred among the subjects aged 25-44 years.

Adolescent↗
PubMed1999

The relationship between ocular toxoplasmosis and levels of specific toxoplasma antibodies.

The relationship between ocular toxoplasmosis and levels of toxoplasma specific antibodies was examined in 195 patients. Using clinical information collected by questionnaires, patients were divided into: 97 with ocular toxoplasmosis (group 1) and 98 with ocular lesions not due to toxoplasma (group 2). The geometric mean of dye test titres (+/-S.D. natural log titre) in group 1 was 53.2 (+/-0.95) compared with 24.6 (+/-1.11) in group 2 (P < 0.001). Young females tended to have more active lesions compared with young males (P < 0.05). There was an age-dependent difference in dye test titres between the groups (P < 0.001). Group 1 showed a decline in titre with age compared with an increase in group 2. Ocular toxoplasmosis was diagnosed most frequently among 21-30 year olds. More group 1 patients had dye test titres > or = 65 iu/ml than group 2 (P < 0.05). Dye test titres > or = 65 iu/ml support a diagnosis of ocular toxoplasmosis whereas lower titres suggest other causes for eye lesions.

Adolescent↗
PubMed1992

Toxoplasma gondii stimulates the release of 13- and 9-hydroxyoctadecadienoic acids by human platelets.

We have recently demonstrated a novel cytotoxic effect of human platelets against Toxoplasma gondii and a role for thromboxane (TX) in this process (Yong et al., 1991). We now report on the spectrum of lipid mediators released by human platelets after interaction with T. gondii. In addition to TXB2, human platelets after incubation with T. gondii for 90 min released 12-hydroxyheptadecatrienoic acid (12-HHT), 12-hydroxyeicosatetraenoic acid (12-HETE), and an unidentified peak (UVmax 234 nm) as determined by reverse-phase high-performance liquid chromatography. Thermospray-liquid chromatography/mass spectrometry analysis and straight-phase HPLC identified the unknown peak as a mixture of 13-hydroxyoctadecadienoic acid (HODE) and 9-HODE. Radiolabeling studies with [14C]linoleic acid indicated that the platelets were the cellular source of the octadecanoids with 13-HODE (87.7%) greater than 9-HODE (12.3%). Inhibitor studies with indomethacin indicated that 13-HODE was a lipoxygenase product and 9-HODE was a cyclooxygenase product of linoleic acid. Thus, Toxoplasma-stimulated platelets release oxygenated products of both arachidonic acid and linoleic acid which may be important in the host response to T. gondii infection.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed2005

Bisphosphonate inhibitors of Toxoplasma gondi growth: in vitro, QSAR, and in vivo investigations.

We have investigated the activity of 60 bisphosphonates against the replication of Toxoplasma gondii in vitro and of three of the most active compounds, in vivo. The two most active compounds found were n-alkyl bisphosphonates containing long (n = 9 or 10) hydrocarbon chains, not the nitrogen-containing species used in bone resorption therapy. The target of all of the most active bisphosphonates appears to be the isoprene biosynthesis pathway enzyme farnesyl pyrophosphate synthase (FPPS), as indicated by the correlations between T. gondii growth inhibition and FPPS (human and Leishmania major) enzyme inhibition and by the fact that a T. gondii strain engineered to overexpress FPPS required considerably higher levels of bisphosphonates to achieve 50% growth inhibition, while the IC(50) for atovaquone (which does not inhibit FPPS) remained the same in the overexpressing strain. The phosphonate inhibitor of the non-mevalonate pathway, fosmidomycin, which inhibits the enzyme 1-deoxyxylulose-5-phosphate reductoisomerase, had no effect on T. gondii growth. To investigate structure-activity relationships (SARs) in more detail, we used two three-dimensional quantitative SAR methods: comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), to investigate all 60 bisphosphonates. Both the CoMFA and CoMSIA models indicated a 60-70% contribution from steric interactions and a 30-40% contribution from electrostatic interactions and using four N = 55 training sets for each method, we found on average between a factor of 2 and 3 error in IC(50) prediction. The three most active compounds found in vitro were tested in vivo in a Smith-Webster mouse model and the two most active bisphosphonates were found to provide up to an 80% protection from death, a considerable improvement over that found previously with nitrogen-containing bisphosphonates. This effect may originate in the much higher therapeutic indices of these alkyl bisphosphonates, as deduced from in vitro assays using LD(50) values for growth inhibition of a human cell line. Overall, these results indicate that alkyl bisphosphonates are promising compounds for further development as agents against Toxoplasma gondii growth, in vivo.

Aldose-Ketose Isomerases↗
PubMed1998

2,4-Diamino-6,7-dihydro-5H-cyclopenta[d]pyrimidine analogues of trimethoprim as inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase.

Three previously unreported (R,S)-2,4-diamino-5-[(3,4,5-trimethoxyphenyl) alkyl]-6,7-dihydro-5H-cyclopenta[d]pyrimidines 15a-c were synthesized as analogues of trimethoprim (TMP) and were tested as inhibitors of Pneumocystis carinii, Toxoplasma gondii, and rat liver dihydrofolate reductase (DHFR). The length of the alkyl bridge between the cyclopenta[d]pyrimidine and trimethoxyphenyl moiety ranged from one in 15a to three carbons in 15c. The products were tested as competitive inhibitors of the reduction of dihydrofolate by Pneumocystis carinii, Toxoplasma gondii, and rat liver DHFR. Compounds 15a-c had IC50 values of > 32, 1.8 and 1.3 microM, respectively, against P. carinii DHFR, as compared to 12 microM for TMP. Against the T. gondii enzyme, 15a-c had IC50 values of 21, 0.14 and 0.14 microM, respectively, as compared to 2.7 microM for TMP. Inhibitors 15b and 15c with two- and three-carbon bridges were significantly more potent than 15a against all three enzymes. Unlike TMP, 15b and 15c were better inhibitors of the rat liver enzyme than of the microbial enzymes. The potency of 15b and 15c against rat liver DHFR was less than has been reported for the corresponding 6,7-dihydro-5H-cyclopenta[d]pyrimidines with a classical p-aminobenzoyl-L-glutamate side chain as inhibitors of bovine, murine, and human DHFR.

Animals↗
PubMed2002

Toxoplasma gondii pneumonia in liver transplantation: survival after a severe case of reactivation.

Toxoplasmosis is an infrequent infection in solid organ transplantation, except in heart transplantation, where the grafting of a positive organ in a negative recipient transmits the infection in a high percentage of cases, in the absence of prophylaxis. We report a case of pneumonia by Toxoplasma gondii in a woman who received a liver transplant and had pre-transplant positive serology. Diagnosis was made by cytologic examination of bronchoalveolar lavage fluid, where the parasite was observed with hematoxylin-eosin and Giemsa staining. That finding was confirmed by direct immunofluorescence and positive polymerase chain reaction. The patient had a favorable outcome, although she had not initially received first-choice drugs. This was a case of severe illness secondary to reactivation of Toxoplasma infection, diagnosed pre-mortem and with a favorable outcome. Duration of treatment and need for secondary prophylaxis in these patients are discussed in the literature. Although infrequent, toxoplasmosis must be considered among the differential diagnoses of pulmonary infiltrates in solid organ transplantation.

Animals↗
PubMed1997

Inhibition of Toxoplasma gondii replication in IFN-gamma-activated human intestinal epithelial cells.

Toxoplasma gondii is an obligate intracellular parasite which is responsible for severe disease after congenital infection and in immunocompromised patients, for which there is no effective therapy. In acquired toxoplasmosis, T. gondii first invade enterocytes and are disseminated throughout the body. Treatment of the adherent human intestinal cell line CaCO2 with recombinant human IFN-gamma inhibited the replication of T. gondii. Growth of the parasite was measured in vitro by [3H]-uracil incorporation assays 18 h after infection. This assay showed that when cells were pretreated with IFN-gamma concentrations ranging from 2.5 to 5000 U/ml, a high degree of inhibition of T. gondii replication could be observed, with the effect being dose dependent. This could be of relevance as a first line of defence against human Toxoplasma infection. Inhibition is due to a different mechanism from that existing in mouse macrophages and human fibroblasts: L-arginine-dependent production of reactive nitrogen intermediates, reactive oxygen intermediates synthesis or production of indoleamine 2.3 dioxygenase were not responsible for inhibition of T. gondii proliferation.

Animals↗
PubMed1996

Common cis-acting elements critical for the expression of several genes of Toxoplasma gondii.

Transient transformation of Toxoplasma using the CAT (chloramphenicol acetyl transferase) reporter gene has been used to map promoter elements of four genes encoding dense granule proteins (GRA1, GRA2, GRA5 and GRA6). Intense CAT activities (GRA1 > GRA5 > GRA2 > GRA6) are detected for constructs containing 379bp, 276bp, 209bp and 265bp upstream of the transcription start site of the GRA1, GRA2, GRA5 and GRA6 genes, respectively. Deletion analysis shows that optimal promoter activity of each gene is contained in the proximal region of the transcription start site: -129 to -47 for GRA1, -87 to -37 for GRA2, -156 to -30 for GRA5 and -146 to -27 for GRA6. Quantitative CAT assay and mutation analysis show that repeated motifs (A/TGAGACG) found in either orientation with respect to transcription are critical elements of these defined promoter regions. We have found such sequence elements in the upstream region of other Toxoplasma genes such as Tub1 and within the stretch of 27bp repeats of the SAG1 promoter.

Animals↗
PubMed2002

An rRNA mutation identifies the apicoplast as the target for clindamycin in Toxoplasma gondii.

Toxoplasma gondii is a protozoan sensitive to several inhibitors of prokaryotic translation (e.g. clindamycin, macrolides and tetracyclines). A priori, two prokaryotic-like organelles, the 'apicoplast' (a non-photosynthetic plastid) and the mitochondrion, are likely targets for these drugs. Without using overt mutagenesis, we selected two independent clones (ClnR-4 and ClnR-21) with strong and stable clindamycin resistance. Several lines with substantial but lower levels of resistance were also isolated with (XR-46) or without (ClnR-23) overt mutagenesis. The ClnR-4 and ClnR-21 mutants uniquely possess a G-->U point mutation at position 1857 of the apicoplast large-subunit rRNA, whereas no mutation was identified in this region for ClnR-23 or XR-46. Position 1857 corresponds to position 2061 in Escherichia coli where it is predicted to bind clindamycin. The mutation is present in all the apicoplast rDNA copies (an estimated 12 per organelle), indicative of a strong selective advantage in the presence of clindamycin. In the absence of drug, however, such a mutation is unlikely to be neutral, as the G is a critical contributor to the transpeptidation reaction and absolutely conserved in all kingdoms. This may explain why ClnR-4 shows a slight growth defect in vitro. These mutants provide direct genetic evidence that apicoplast translation is the target for clindamycin in Toxoplasma. Further, their sensitivity profiles to other antibiotics specific for the large ribosomal subunit (macrolides and chloramphenicol) and, intriguingly, the small subunit (doxycycline) argue that these drugs also target the apicoplast ribosome.

Animals↗