Thesis (Ph. D.)--University of Hawaii at Manoa, 1990. / Includes bibliographical references (leaves 134-152) / Microfiche. / xvi, 152 leaves, bound ill. 29 cm

Some parasites may modify the behavior of their hosts. Altered behaviors may: 1) benefit the host in that they defend against the pathogen, 2) benefit the pathogen and represent manipulations of the host response, and 3) benefit neither the host or the pathogen and simply be a product of the host response to infection. In this thesis I examine four host/parasite systems. For each system, I explore host/parasite behavioral interactions, and examine them with regard to selective pressures that may be acting on both the host and the parasite. I test the Hamilton and Zuk hypothese in 26 species of lizards. I find an inverse relationship between a lizard species' brightness and parasite prevalence. My result lend credence to criticisms of the Hamilton and Zuk Hypothesis. If infection does occur, animals may alter their behavior to impair the growth and reproduction of the parasite. To test this prediction, I examine behavioral thermoregulation in two strains of the snail Biomphalaria glabrata, one resistant to, and one susceptible to, the parasite Schistosoma mansoni. The preferred temperature of infected snails drops five weeks after exposure to the parasite. I propose the hypothesis that pathogen-induced host defense responses result in altered host behaviors and enhanced predation. In particular, I examine the effects of the acute phase response (a physiological response whose symptoms include fever, reduced activity and malaise) on antipredatory behavior in bullfrog (Rana catesbeiana) tadpoles. This host response is associated with the preliminary stages of infection with many pathogens yet its behavioral effects have received little attention. I find that the stereotypical effects of the acute phase response can lead to increased predation. I suggest that altered behaviors may afford some parasites a potential pathway to their next host. I examine the behavioral effects of a yeast, Candida spp., a single-host parasite species in its natural host, the red-legged frog (Rana aurora). Infected tadpoles exhibit the same behavioral modifications that are noted in bacteria injected bullfrog tadpoles. These results suggest that some altered behaviors may occur due to a host response to infection and not due to parasitic manipulation. / Graduation date: 1993

The autoimmune diseases embody a diverse range of common human conditions that are caused by a loss of self-tolerance in the host immune system to a specific organ or tissue type. Approximately 5% of the general population are affected by autoimmune diseases which include type 1 diabetes (T1D), rheumatoid arthritis (RA) and Graves disease (GD). The majority of the autoimmune diseases are multifactorial in origin, brought about by a combination of both environmental and genetic factors. Numerous susceptibility loci have been identified for each autoimmune disease and a number of these loci have been shown to be shared amongst the autoimmune diseases. The fine-mapping of susceptibility loci to the underlying disease genes remains the current challenge facing complex disease genetics. This project aimed to further characterise the autoimmune disease susceptibility locus IDDM6 on chromosome 18q12-21. This was achieved by using a comparative mapping approach that incorporates the study of genetic association in human autoimmune disease alongside the consomic mapping of the orthologous region in the non-obese diabetic (NOD) mouse model of autoimmunity. Deleted in colorectal carcinomas (DCC) provided a strong candidate gene at IDDM6 and the resident R201G polymorphism was identified as a functional candidate A potential mechanism for the R201G polymorphism involvement in T1D aetiology was identified where the polymorphism may affect the ability of DCC to induce apoptosis in vitro. However, no evidence for R201G association could be detected in autoimmune disease case-control datasets from the New Zealand (NZ) population (T1D n = 428, RA n = 730, autoimmune thyroid disease n = 192 (AITD); versus n = 1246 healthy controls). In addition, no evidence for R201G involvement in T1D could be provided in a transmission disequilibrium test (TDT) incorporating 382 affected sib-pair families (54.2% transmission; P = 0.15). Significant association of R201G with GD was detected in a United Kingdom (UK) dataset (P = 0.002) from the Newcastle population (423 cases vs. 393 controls) but this was not replicated in an additional dataset from the UK Birmingham population (731 cases vs 668 controls; P = 0.81). It was concluded that the R201G polymorphism may encode susceptibility to GD but is unlikely to be the sole aetiological variant that accounts for the linkage previously observed at IDDM6 in autoimmune disease. To further investigate DCC as a positional candidate at IDDM6, five SNPs were selected from a 100 kb window surrounding a DCC-resident microsatellite that had previously been associated with T1D, called "88,21". The five SNPs were genotyped in the NZ T1D dataset, and the ascertainment of estimated haplotypes in this dataset revealed association of a rare haplotype with T1D, called haplotype H (3.31% cases vs 1.17% controls; P = 0.0044), in addition to global association of all haplotypes (P = 0.018). Haplotype H was also associated in an independent case-control dataset from the UK comprised of 400 T1D subjects and 443 healthy controls (P = 0.038). Maximum support for association of haplotype H was extended when both the UK and NZ T1D datasets were combined (P = 0.0017). Association of haplotype H could not be verified in a family-based test for association using the 382 UK T1D families (P = 0.40). However, the inclusion of the DCC SNPs in a TDT analysis of the published DCC-resident microsatellites "88,21" and "55,26", that had been used to identify IDDM6, extends support for the previously-associated 2-10 haplotype (2-10 refers to the published allele nomenclature at "88,21" and "55,26" respectively; 2-10-haplotype A; 59.6% T; P = 0.0058). There was no evidence for association of the five SNPs with RA or AITD when using either individual SNP analyses or estimated haplotypes in the NZ datasets. A similar lack of association was reported for the UK Newcastle GD dataset. Taken together, these data further support DCC, or a nearby gene, as conferring susceptibility to T1D. The human genetic data that supports IDDM6 involvement in autoimmune disease is further strengthened by consomic mapping of the orthologous region in mouse, using the non-obese diabetic mouse (NOD) model of autoimmune disease. In this thesis, the first evidence for a diabetes and thyroiditis susceptibility locus on mouse chromosome 18 is presented, which have been designated Idd21 and Sat1 respectively. This was achieved by using a chromosome-replacement strain with chromosome 18 derived from the diabetes-resistant Biozzi ABH strain on a diabetes-susceptible NOD genome, called NOD.ABH[Chr�⁸]. Mouse chromosome 18 contains orthology to both IDDM6 and the rat diabetes-susceptibility locus Iddm3. The NOD.ABH[Chr�⁸] mice showed a dramatic and significant reduction in diabetes incidence (30% of females were affected by 7 months of age versus 85% in NOD; P <0.0001) and that of thyroiditis (15.5% at 12 months compared to 37.4% in NOD; P <0.002). The comparative mapping of the chromosome 18 autoimmune susceptibility locus IDDM6 in human and mouse presented in this thesis provides further support for this locus. This research also clearly defines the next steps required to fine-map IDDM6 to the underlying disease genes, especially in regard to the DCC gene.

Johne�s disease in ruminants is caused by the pathogenic bacterium Mycobacterium avium subspecies paratuberculosis. An experimental infection model in sheep was developed as a prelude to the testing of new vaccines and the development of improved diagnostic assays for Johne�s disease. The final challenge model developed used four doses of 10⁹ viable organisms given at two to three day intervals. Gross and microscopic lesions were found in a high proportion of sheep (80%) at ten months post challenge. There was considerable variation in immune responses from animals challenged with different strains of M. paratuberculosis. Sheep challenged with a low passage laboratory culture of strain (W) M. paratuberculosis, produced strong lymphocyte transformation responses and Interferon gamma (IFN-γ) production at two months post challenge. Subsequent necropsy and culture from intestinal tissues showed only a low level of infection (25%). In comparison a primary tissue isolate of M. paratuberculosis (JD3) resulted in higher (60-90%) infection rates in orally challenged animals. The immune profile from these animals showed very little reactivity for the first three months post challenge, after which IFN-γ production could be detected. Antibody production and lymphocyte transformation response could not be measured until at least seven months post challenge. Sheep challenged with the primary tissue isolate instilled directly into the tonsil resulted in equivalent levels of Johne�s disease to those obtained with oral challenge. However, intratonsillar challenge resulted in higher levels of immune reactivity than oral challenge. The proprietary Johne�s vaccines; NeoparsecTM and GudairTM and an Aqueous vaccine were tested in sheep. The immunological reactions of the sheep to these vaccines showed some variations between the two separate studies, with the NeoparasecTM and GudairTM vaccines evoking high levels of CMI and humoral reactivity within two months of vaccination. Detailed immunological examination of gut associated lymphoid tissues were carried out on subgroups of animals that were either vaccinated or non-vaccinated and went on to develop disease or were immune to experimental challenge. The results showed that the diseased animals examined had multibacillary lesions and strong CMI and humoral responses. There were decreased proportions of CD4⁺, CD8⁺ and CD25⁺ T cells in peripheral blood and gut associated lymphatics of diseased animals compared with the immune or unchallenged subgroups. Profiles from the immune subgroups showed a stronger lymphocyte transformation response than case matched diseased animals. Tissues from immune animals showed increased proportions of B cells above those seen in diseased or unchallenged animals. This study has resulted in the development of a robust experimental sheep model in which Johne�s disease occurs in a high proportion of challenged animals. Critical time points for the establishment of infection or disease have been determined. It can be used in the future to evaluate protective efficacy of vaccines or to critically chart immunological profiles that are associated with infection, disease or protective immunity. Considerable research is needed to develop improved diagnostic tests to identify patterns of immunity during the early stages of infection or while the animal has subclinical disease.

Bibliography: leaves 183-228 / x, 228 leaves, [8] leaves of plates : ill. (1 col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Microbiology and Immunology, 1989

Copies of author's previously published articles inserted / Includes bibliographical references / [ix], 261, [101] leaves, [4] leaves of plates : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Microbiology and Immunology, 1992

Includes a list of publications co-authored by the author during the preparation of this thesis. / Thesis amendments in back leaf / Includes bibliographical references (leaves 123-168). / [14], 168 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / The studies described concentrate on the cloning and characterisation of the two Drosophila caspases, DRONC and DECAY / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 2001

Typescript (photocopy) / xii, 186, xxxvii leaves, [4] leaves of col. plates : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Microbiology, 1982

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv., 2002. / Härtill 4 uppsatser.

Mémoire (M.Ress.Renouv.)-- Université du Québec à Chicoutimi, 1992. / Résumé disponible sur Internet. CaQCU Bibliogr.: f. 69-73. Document électronique également accessible en format PDF. CaQCU