Addition of paclitaxel (Taxol) at a concentration of 1 μM toToxoplasma gondii-infected human foreskin fibroblasts arrested parasite multiplication. Division of theT. gondii tachyzoite nucleus was inhibited, leading to syncytium-like parasite structures within the fibroblasts by 24 h after infection and treatment of the cultures. By 4 days after infection and treatment of the cultures with paclitaxel, this inhibition was irreversible, since the arrested intracellular form was incapable of leaving the host cell, infecting new cells, and initiating the growth of tachyzoites with normal morphology. Specifically, when paclitaxel was added to infected cells for 4 days and then removed by washing and the infected, paclitaxel-treated cells were cultured for 4 more days, there were no remaining T. gondii organisms with normal morphology. Syncytium-like structures in the cultures that were infected and treated with paclitaxel for 8 days were similar in appearance to those in preparations of infected paclitaxel-treated fibroblasts that had been cultured for 24 to 48 h. Pretreatment of the tachyzoites for 1 h with paclitaxel followed by the removal of the paclitaxel by repeatedly centrifuging and resuspending the parasites in fresh medium without paclitaxel and then adding fresh medium prior to culture of the parasites with fibroblasts did not prevent their invasion of fibroblasts but did affect their subsequent ability to replicate within fibroblasts. Pretreatment of the fibroblasts with paclitaxel also diminished subsequent replication ofT. gondii in such host cells after 8 days. Thus, paclitaxel alters the ability of T. gondii to replicate in host cells. Inhibition of parasite microtubules by such compounds at concentrations which do not interfere with the function of host cell microtubules may be useful for development of novel medicines to treat T. gondii infections in the future.
Monoclonal and polyclonal, monospecific antibodies to the major surface antigen of Toxoplasma gondii (SAG-1, P30) inhibit infection of human fibroblasts and murine enterocytes. Fab prepared from polyclonal, monospecific antibody to P30 also have this inhibitory effect on invasion, which indicates that this antibody directly blocks parasite infection of host cells rather agglutinating the parasite. Antibodies to another surface protein (P22) did not alter in vitro infection. If the inhibitory effect of antibody to P30 was due to steric hindrance or complexing of surface epitopes contiguous to P30, antibodies to other surface epitopes would also be inhibitory and they are not. Urea treatment of antibody (which permits discrimination of high and low avidity antibody) did not alter the effect of anti-P30 antibody. This observation indicates that the effect of the antibody to P30 was not an artifact of differences in the avidity of the antibody to P22 and P30. Heat inactivated antisera from mice infected with either RH or PTg strain T. gondii (P30+) inhibit infection of fibroblasts when challenged with autologous wild-type parasites by 87 and 40%, respectively. In contrast, these antisera have little inhibitory effect (13 and 19%, respectively) against infection of human fibroblasts by a P30-deficient mutant (PTgB). Antisera raised to the P30-deficient mutant had no significant effect on infection of cells by wild-type strains that have surface P30. The neoglycoprotein, BSA-glucosamide, competitively blocks infection of human fibroblasts by P30+ tachyzoites with surface P30 in higher level than those without surface P30. This observation indicates that there is likely to be a glycosylated host cell receptor to which T. gondii's major surface Ag SAG-1 (P30) binds. Mice infected perorally develop intestinal IgA antibody to the major 30-kDa epitope of T. gondii. Thus, the major surface epitope of T. gondii, SAG-1 (P30), has an important, functional role in infection of host cells by T. gondii and elicits an intestinal antibody response after peroral infection.
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