Toxoplasma gondii: Histopathological, Biochemical and Pharmacological Aspects

Roberts, Fiona (1998) Toxoplasma gondii: Histopathological, Biochemical and Pharmacological Aspects. MD thesis, University of Glasgow.

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Toxoplasma gondii, a protozoan parasite, can cause severe, life-threatening disease, especially in newborns and immunosuppressed patients. It is an important cause of ocular disease and is considered to be the most common recognisable cause of posterior uveitis in immunocompetent individuals. The clinical and pathological manifestations of congenital toxoplasmosis in infants, children and adults are well characterised. However, until now, this disease has not been extensively studied in fetuses and there remain certain gaps in our understanding of the earliest stages of congenital disease. The first section of this thesis describes the early pathological changes in the eyes of fetuses and infants. The second section provides evidence for two novel biochemical pathways in T. gondii. These pathways are more commonly associated with plants and algae and may provide new targets for antimicrobial agents. This study of fetal and infant eyes represents the biggest most comprehensive study of its kind to date. Eyes from 10 fetuses and 2 infants with congenital toxoplasmosis were studied by light microscopy. In addition, immunohistochemistry was performed for infiltrating inflammatory cells and T. gondii antigens. The characteristic findings were of retinitis, retinal necrosis, disruption of the retinal pigment epithelium and choroidal inflammation and congestion. Optic neuritis was present in 5 fetal eyes. The eye obtained from a 32 week old fetus showed a well established retinochoroidal scar. At the edge of the scar the retinal architecture was disrupted with formation of rosettes. This was interpreted as focal retinal dysplasia. Mechanisms leading to abnormal retinal development is discussed. T cells, in particular CD4+ T cells, predominated within the retinal lesions and choroid. This demonstrates that the fetus is capable of mounting an immune response to T. gondii. However, this immune response may be less effective than in the child or adult. T gondii organisms were identified in 5 fetuses and two infants by immunohistochemical staining. In one infant eye and one fetal eye parasites were identified in a perivascular location supporting a haematogenous route of dissemination to the eye. These findings demonstrate that ocular toxoplasmosis causes severe irreversible damage to the retina in utero. The significance of these findings to current strategies for prenatal diagnosis and management is discussed. Current treatments are only effective against the rapidly dividing tachyzoite form associated with active disease. There are no treatments capable of eliminating the quiescent cystic bradyzoite stage. This is the source of disease reactivation in the congenitally infected and immunocompromised host. A combination of pyrimethamine and sulphadiazine, both anti-folate agents, is the most effective therapy for active disease currently available. However, there are significant side effects associated with both these drugs. For these reasons, new antimicrobial agents are urgently needed for the treatment of this disease. In recent years there has been considerable interest in the vestigial plastid organelle of T. gondii and Apicomplexans (the subphylum of parasites which include Plasmodium, Theileria, Babesia, Eimeria, Hepatozoon, Sarcocystis and T.gondii) in general. In addition certain other plant-like characteristics have been reported in Apicomplexans. These observations may provide exploitable differences between these parasites and their mammalian hosts. In the second part of this thesis, the possibility that T.gondii may depend on biochemical processes more normally restricted to plants is investigated. The shikimate pathway occurs within the plastid of plants and algae. It is a seven step reaction which catalyses the conversion of phosphoenol pyruvate to chorismate. Chorismate is then used for the synthesis of virtually all aromatic compounds, notably, p-aminobenzoic acid which is required for de novo folic acid synthesis; ubiquinone an essential component of the mitochondrial electron transport chain; and the aromatic amino acids. The studies described in this section of the thesis provide chemotherapeutic and genetic evidence for the shikimate pathway in T. gondii. Firstly, the in vitro growth of T. gondii was inhibited by the herbicide glyphosate, also known as N-(phosphonomethyl)glycine (NPMG), a well characterised inhibitor of the shikimate pathway enzyme 5-enolpyruvyl shikimate 3-phosphate (EPSP) synthase. Furthermore, the effect of NPMG on T.gondii was reversed by treatment with p-aminobenzoic acid, which suggests that the shikimate pathway supplies folate precursors for their growth.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Additional Information: Adviser: Rima McLeod
Keywords: Medicine, Parasitology
Date of Award: 1998
Depositing User: Enlighten Team
Unique ID: glathesis:1998-75866
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 19 Dec 2019 09:15
Last Modified: 19 Dec 2019 09:15

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