Date of Award

1985

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Abstract

Toxoplasma gondii is a protozoan parasite which resides in modified endocytic compartments of host cells. Extensive intracellular replication and host cell lysis leads to acute toxoplasmosis which is eventually limited by the host immune response to a chronic state of infection. The features of this unique intracellular compartment, which enables Toxoplasma to survive in macrophages, are reported here. Although Toxoplasma survives in normal macrophages, activated macrophages from immune animals rapidly killed Toxoplasma by production of oxygen radicals and intermediates generated during parasite invasion. In addition, activated macrophages inhibited Toxoplasma growth by an oxygen-independent mechanism. Qualitative and quantitative features of oxygen intermediate detoxifying enzymes, catalase and superoxide dismutase, were described from two strains of Toxoplasma. These enzymes did not appear to be the basis for differences in strain virulence, but may contribute to intracellular survival in normal macrophages. A newly recognized microbicidal mechanism involves the rapid acidification during the formation of endocytic compartments. Live Toxoplasma entered into modified phagocytic vacuoles in normal macrophages that do not show characteristic acidification, but remain at near neutral pH. In contrast, the enhanced acidification capacity of activated macrophages and of normal macrophages in the presence of specific antibody may contribute to the toxoplasmacidal response of these cells. The unique modified endocytic vacuole occupied by Toxoplasma is characterized by an accumulation of membrane-like tubules which may contribute to growth of the vacuole membrane. Purification of this significant host parasite interface confirmed that the tubules are parasite derived, are comprised of membrane vesicles which are responsive to calcium levels, and contain proteins recognized by mouse anti-Toxoplasma sera.

Pages

74

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