Date of Award

1998

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

Abstract

Toxoplasma gondii is a complex protozoan parasite that can cause encephalitis (TE) in animals and humans when the immune system is suppressed (e.g. AIDS). The focus of this study has been the immuno-modulatory role of cold stress (CS) in the pathogenesis of acute murine toxoplasmosis. Female BALB/c mice subjected to CS for eight days followed by oral infection on day 9 with 20 cysts of the low-virulent T. gondii ME 49 strain. Control infection (INF) and cold stress + infection (CS + INF) mice were sacrificed at 7 to 10 day intervals to study cell mediated immunity (CMI), which is critical in mediating resistance to T. gondii infection. Activation of macrophages and microbicidal properties, as determined by measuring nitrite (NO - 2 ) production, were decreased significantly in CS + INF mice (p < 0.01). This correlated with increased parasite survival within these phagocytic cells. Splenic blastogenesis in response to in vitro mitogen and Toxoplasma lysate antigen (TLA) stimulation, as determined by [ 3 H]Thymidine incorporation, was used as a measure of lymphocyte activation. Enhanced splenic blastogenesis (p < 0.001) was observed in CS + INF mice in the first two weeks post infection ( p.i .). In contrast, splenic blastogenesis was decreased initially in INF mice. Inflammatory and infective foci in brain tissue, as detected by histopathology, and gliosis, as detected by immunocytochemistry, were more prevalent in CS + INF mice. In addition, CS also affected the intra-cerebral mRNA expression for several regulatory cytokines. Interleukin (IL)-1β, IL-12, IL-2, tumor necrosis factor (TNF)-α, inducible nitric oxide synthase (i-NOS), and interferon gamma (IFN)-γ mRNA transcripts as detected by reverse transcription coupled with polymerase chain reaction (RT-PCR) were decreased in CS + INF mice ten days p.i . Maximal increase in infective foci in CS + INF mice was associated with an increase in IL-1β, IL-6, IL-12 and TNF-α expression between 20 and 30 days p.i . This increased pathology was associated with the continual expression of surface antigen (SAG)-1 mRNA ( T. gondii tachyzoite specific antigen), in CS + INF mice, suggesting that these animals were unable to regulate parasite dissemination and multiplication in the brain. The findings of this study suggest that CS by decreasing intra-cerebral IFN-γ and TNF-α in CS + INF mice, immediately following infection, may be a central mechanism that promotes parasite survival. Measuring these immunological parameters has provided strong evidence that CS coupled with the development of TE is an excellent model for studying the immune-induced alterations by a physical stressor on host-parasite interactions.

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