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Thesis (Ph. D.)--University of Wisconsin--Madison, 1982. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 195-211).

The occurrence of human Onchocerciasis has not previously been reported from the Anglo-Egyptian Sudan. It is my intention to show that the nematode Onchocerca Volvulus (Leuckart 1893) has a wide distribution in the southern Sudan, and that it, with its microfilariae, give rise to a variety of pathological conditions including grave ocular troubles, and that it is a parasite of serious economic importance, and not merely of academic interest. For the past six years I have been engaged on sleeping Sickness and Leprosy campaigns in the southern Sudan, and have come into close touch with the native population and learned much of their habits and customs, and got a working knowledge of some of their dialects. This experience has been invaluable in the necessarily rather interrupted researches into onchocerciasis, and has allowed one to pass fairer and more critical judgment on the often highly imaginative statements of natives. Microfilariae were often found in gland juice and blood smears during routine Trypanosomiasis inspections, and elephantiasis and hydroceles formed the basis of ones surgical practice, but the former were always imagined to be Microfilariae Wuchereria Bancrofii and the latter their sequelae. Some three years ago it was noticed that in certain arears an appreciable proportion of the young adult population were blind or had serious eye symptoms or complained of »night blindness». In 1932 Dr. Bryant, a colleague of mine working in Rumbek district described the disease as a retino-choroiditis and sometimes associated with signs of keratitis, iritis, iridocyclitis and synechiae. He pointed out that although "Simulium Damnosum", the vector, had not been found, the possibility of Onchocerca Volvulus as the cause must be borne in mind. Later, in 1933, he identified microfilariae of Onchocerca Volvulus in a case of hydrocele in the Heridi district. Since then a careful study of cases of elephantiasis, hydroceles, skin diseases, tumour formations, and of eye conditions has been made, the incidence and distribution of Onchocerca Volvulus roughly mapped out, and also the incidence of the insect vector. Other possible causal factors have been investigated, and a certain amount of experimental work done. Pathological specimens have been collected and examined by experts in London. The results of these investigations will be given and my arguments for considering Onchocerca Volvulus capable of causing those serious pathological changes set forth. A digest and historical review of the more important literature and a description of the parasite precedes the main Thesis.

No description available.

Onchocerciasis, caused by Onchocerca volvulus remains a major public health and socio-economic problem across the tropics, despite years of mass drug administration (MDA) with Ivermectin to reduce disease burden. Through modelling, it has been shown that elimination cannot be achieved with MDA alone and additional tools are needed, such as vaccination, which remains the most cost-effective tool for long-term disease control. The feasibility behind vaccination against O. volvulus can be demonstrated in the Litomosoides sigmodontis mouse model, which shows that vaccine induced protection can be achieved with immunisation using irradiated L3, the infective stage of L. sigmodontis and with microfilariae (Mf), the transmission stage of the parasite. There is further evidence of protective immunity in humans, with individuals living in endemic areas that show no signs of infection despite being exposed to the parasite (endemic normal). The protective efficacy of promising vaccine candidates were evaluated using an immunisation time course in the L. sigmodontis model, using either DNA plasmid or peptide vaccines. In immunisation experiments in L. sigmodontis, Mf numbers are used as a measure of protection and marks the end of an immunisation time course. However, when changes in gene expression were measured at the end of an immunisation time course, in attempts to identify gene signatures that could be used as markers of protection (correlates of protection) in the blood, no gene signatures were found to be associated with protection. This suggest that at the end of an immunisation time course, when protection is measured (change in Mf numbers), it is too late in infection to measure changes in immune pathways being triggered. Changes in gene expression were therefore measured in blood samples collected throughout an immunisation time course in the L. sigmodontis model, in order to identify the time point in an immunisation experiment which are the most indicative of protection. Two independent immunisation time courses were used, either using irradiated L3 or Mf as vaccine against L. sigmodontis, as these elicit the greatest protection. This generated a large high dimensional dataset, that was too large and complex for a differential fold-change analysis. Therefore, an analysis pipeline was created using machine learning algorithms, to detect changes in gene expression throughout the time courses to detect markers of protection. The 6 hour time point following immunisation showed the greatest change in gene expression, with the analysis pipeline identifying known pathways associated with vaccine-induced immunity. The pipeline was applied to gene expression data from human samples obtained from individuals living in endemic areas who were either infected with O. volvulus or endemic normal (naturally protected), this was to identify pathways associated with protective immunity in humans. When comparing vaccine induced immunity seen in mice and natural protective immunity in humans there was some overlap in pathways being triggered, suggesting that similar pathways are needed for protection and that if a vaccine can trigger the right pathways in mice, it is likely to be effective in humans. Overall the machine learning analysis of the gene expression data, not only shows that it is feasible to measure change in gene expression in blood during filarial infections, but that during an immunisation time course it is the early time points following immunisation that are the most predictive of vaccine efficacy (protection outcome). One of the vaccine candidates, cysteine protease inhibitor-2 (CPI), is a known immuno-modulator that inhibits MHC-II antigen presentation on antigen presenting cells such as dendritic cells (DC). This candidate has consistently been shown to induce protection if its immuno-modulatory active site was modified. In in vitro studies, it was shown that modification of the active site of CPI rescues antigen presentation in DC. This shows the importance of DC activation before the onset of infection, demonstrating the importance of triggering protective responses early in infection, and provides insight on how one of the vaccine candidates achieves protection.

Onchocerciasis, or river blindness, has historically represented one of the significant neglected tropical diseases on the planet in terms of socio-economic impact. The discovery that ivermectin was a safe and effective treatment for onchocerciasis, together with the decision of the manufacturer to donate the drug for the treatment of this disease became the basis for several large international programs to control and eventually eliminate the infection. These programs have managed to virtually eliminate transmission of the parasite causing Onchocerca volvulus from many foci in Africa and the Americas. Verifying that transmission has been halted requires sensitive and specific assays to detect the presence of the parasite. The gold standard to accomplish this has been to employ a PCR assay targeting a specific repeated sequence family encoded in the genome of O. volvulus to screen for the presence of the parasite in pools of vector black flies. While this assay is highly sensitive, obtaining the high specificity required to document an absence of transmission requires an independent confirmatory assay. To meet this need, an independent PCR assay targeting the cytochrome B (cytB) gene of the O. volvulus mitochondrion was developed. This assay could detect O. volvulus mitochondrial DNA purified by magnetic bead capture using the primers for the cytB gene and from the nuclear encoded repeated sequence DNA targeted in the primary assay. These preliminary data suggest that the mitochondrial PCR assay may be employed as a confirmatory assay to detect O. volvulus in pools of vector flies.

Onchocerca volvulus, a filarial nematode, is the causative agent of onchocerciasis. / O. volvulus is a human parasite with no animal model host and is endemic in the tropics. O. volvulus material is scarce and must be conserved as part of the Onchocerciasis Control Program. A genomic library was constructed to provide a substantial source of renewable genetic material, in place of original parasite DNA. / Currently there is only one glutamate-gated chloride channel that has been sequenced from O. volvulus, but this has not yet been characterized. This GluClx partial cDNA sequence isolated by Cully et al., 1997, may be found in GenBank, accession number U59745. Specific primers were designed to amplify this gene from the genomic library. A fragment of this gene was isolated but the primers were non-specific, amplifying genes in addition to GluClx. / A motif is a short recognition sequence within a protein that may allow the modification of the protein. The cysteine loop in the N-terminal of all the ligand-gated ion channels is interesting because it contains the neurotransmitter-gated ion channel signature sequence. (Abstract shortened by UMI.)

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Univ., 2006. / Härtill 5 uppsatser.