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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Host-virus interactions in porcine reproductive and respiratory syndrome virus infection

Sorensen, George Edwin Peter January 2014 (has links)
Porcine reproductive and respiratory syndrome virus (PRRSV) is a rapidly evolving virus that has significant economic and welfare implications for the pig industry. Vaccination strategies have proved largely ineffective in controlling PRRSV, in some cases even reverting to virulence. An increasing body of evidence suggests a host genetic basis for PRRSV resistance so there is a need to examine the role of host genetics in a biologically relevant in vitro cell culture system. However, PRRSV research is inhibited by the current scarcity of suitable in vitro culture systems. With the aim of developing a convenient in vitro model, porcine bone marrow-derived macrophages (BMDM) were evaluated as a PRRSV cell culture system. BMDM were found to be highly permissive to Type I PRRSV and amenable to genetic manipulation. BMDM proved to be excellent cells for virus production, producing significantly higher titres of PRRSV than commonly used alternative cell types. Surprisingly, PRRSV entry into BMDM was found to be independent of both the prototypic PRRSV receptors, CD163 and CD169, providing further evidence for the existence of alternate PRRSV entry mechanisms in primary cell types. To explore the genetics of pig susceptibility to PRRSV, network-based analysis of host transcriptional datasets, following PRRSV challenge, revealed important differences in co-regulated gene pathways between samples from pigs with different PRRSV-permissiveness. These pathways included genes with important, recently characterised, anti-pathogen activities. The incorporation of network-based transcriptional analysis and published genetic variation data led to the identification of a member of the guanlyate binding protein family, GBP-1, as a candidate host gene involved in controlling PRRSV replication. Overexpression of GBP-1 in BMDM revealed a significant anti-PRRSV function for this protein. Further investigation of published genetic variation in GBP-1 suggested a potential role of this gene in PRRSV tolerance. The results presented in this thesis provide evidence for an alternate PRRSV entry pathway in a biologically relevant cell type. The discovery of a highly PRRSV-infectable cell type with potential for genetic manipulation adds a useful new tool to the area of PRRSV research. The identification of GBP-1 as a novel anti-viral protein with a significant inhibitory effect on PRRSV infection, together with genetic variation in this gene, prompts further research into the genetic basis for PRRSV resistance.
2

HOMINID: a framework for identifying associations between host genetic variation and microbiome composition

Lynch, Joshua, Tang, Karen, Priya, Sambhawa, Sands, Joanna, Sands, Margaret, Tang, Evan, Mukherjee, Sayan, Knights, Dan, Blekhman, Ran 08 November 2017 (has links)
Recent studies have uncovered a strong effect of host genetic variation on the composition of host-associated microbiota. Here, we present HOMINID, a computational approach based on Lasso linear regression, that given host genetic variation and microbiome taxonomic composition data, identifies host single nucleotide polymorphisms (SNPs) that are correlated with microbial taxa abundances. Using simulated data, we show that HOMINID has accuracy in identifying associated SNPs and performs better compared with existing methods. We also show that HOMINID can accurately identify the microbial taxa that are correlated with associated SNPs. Lastly, by using HOMINID on real data of human genetic variation and microbiome composition, we identified 13 human SNPs in which genetic variation is correlated with microbiome taxonomic composition across body sites. In conclusion, HOMINID is a powerful method to detect host genetic variants linked to microbiome composition and can facilitate discovery of mechanisms controlling host-microbiome interactions.
3

The Influence of Host Genetics on JCV and EBV Antibody Levels in Multiple Sclerosis Patients and Controls

Strid, Elin January 2012 (has links)
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), characterized by lesions formed due to demyelination. MS is a complex disease thought to be triggered by environmental factors in genetically predisposed individuals. The strongest associated susceptibility allele is HLA-DRB1*1501. Environmental factors include smoking, latitude and previous infection of Epstein-Barr virus (EBV), a common herpes virus. There is no cure for MS, but several inhibitor and symptomatic drugs. Tysabri® (natalizumab) is the most effective drug, but it may lead to progressive multifocal leukoencephalopathy (PML), a rare but often fatal disease caused by reactivation of JC virus. The aim of this thesis was to replicate previous findings from a genome-wide association study and to find host genetic factors influencing JCV seropositivity and EBNA1 IgG titers in Swedish MS patients and healthy controls. Samples from the EIMS and IMSE studies were genotyped by TaqMan® OpenArray™ PCR, an end-point SNP genotyping analysis. 1143 cases and 556 healthy controls were genotyped. Due to poor call rates, genotype data from an Immunochip study was added. A total of 3408 samples (1664 cases and 1744 controls) were analyzed. EBNA1 IgG antibodies were previously measured as a detection of EBV infection and increased MS risk, and JCV IgG antibodies were measured to find patients potentially at risk for PML. One significant result was found, gene 105 (p = 0.01674, OR 0.68, CI 95% 0.49-0.93), with a protective effect in MS. More significant results might have been found with better loading of the plate, or with a different genotyping method.
4

Exploring host genetic differences in gastrointestinal microbiota and homeostasis, through the production of fecal miRNA

Horne, Rachael January 2018 (has links)
Research has shown that our gut microbiota confers many beneficial functions, including aiding the development of the immune system, metabolism, modulating stress reactivity and behaviour. The diverse population of the gut microbiota has been shown to be heterogeneous between individuals, with host genetic factors emerging as a contributor to gut microbiota composition. Recent work suggests that microRNA may act as a mediator of communication between the host and resident gut microbiota. Here we explore host genetic differences in gut microbiota composition and fecal miRNA profiles in two inbred mouse strains BALB/C and C57BL/6, in relation to gastrointestinal homeostasis. Furthermore, we evaluate the role of host genetics in response to perturbation of the gut microbiota using broad-spectrum antibiotic treatment. Distinct differences in the gut microbiota composition evaluated by fecal 16s rRNA gene sequencing between BALB/c and C57BL/6 mice were found with notable significant differences in genera Prevotella, Alistipes, Akkermansia and Ruminococcus. Significant host genetic differences were also observed in fecal miRNA profiles evaluated using the nCounter Nanostring platform. A BLASTn analysis was used to identify conserved fecal miRNA target regions in bacterial metagenomes, which identified numerous bacterial gene targets. Of those miRNA targets that were conserved in our dataset, 14 significant correlations were found between fecal miRNA and predicted taxa relative abundance. Treatment with broad-spectrum antibiotics for a period of 2 weeks resulted in BALB/c mice exhibiting a decrease in barrier permeability while C56BL/6 barrier permeability remained unchanged, demonstrating a host-specific physiological response to antibiotics at the gastrointestinal barrier. Differential response to antibiotics was also observed in the expression of barrier regulating genes in both host strains. Individual taxa were found to respond differentially by host strain, with Parabacteroides and Bacteroides associating with changes in barrier function. Together these findings suggest that host genetics play a role in determining the host-microbe relationship in both healthy homeostatic conditions and altered microbial conditions. / Thesis / Master of Science (MSc)
5

Investigating candidate genes identified by genome-wide studies of granulomatous diseases in susceptibility to tuberculosis: ANXA11 and the CADM family

Salie, Muneeb 12 1900 (has links)
Thesis (MScMedSc (Biomedical Sciences))--University of Stellenbosch, 2010. / Thesis presented in partial fulfilment of the requirements for the degree Master of Medical Science (Human Genetics) at the University of Stellenbosch. / Bibliography / ENGLISH ABSTRACT: The infectious disease tuberculosis (TB) remains the leading cause of death worldwide by a single infectious agent, despite significant advances in biomedical sciences. The idea that host genetics plays a role in the development of disease was proposed by Haldane in 1949. The observation that only 10% of immunocompetent individuals develop disease while others are able to successfully contain it, further suggests that host genetics plays an important role. TB is thus a complex disease, with the causative bacterium, Mycobacterium tuberculosis, host genetic factors and environment all contributing to the development of disease. To date several genes have been implicated in TB susceptibility, albeit with small effect. Genome-wide association studies (GWAS) offer the means to identify novel susceptibility variants and pathways through their ability to interrogate polymorphisms throughout the genome without being limited by our understanding of the immune processes involved in TB infection and disease progression. TB and sarcoidosis are both granulomatous diseases, and we therefore hypothesized that the genes and their associated variants identified in recent GWAS conducted in West Africa for TB, and Germany for sarcoidosis, could alter susceptibility to TB in the South African Coloured (SAC) population. In the sarcoidosis GWAS, ANXA11 was shown to alter susceptibility to sarcoidosis; whereas in the TB GWAS, CADM1 was found to alter susceptibility to TB. This study tested the association with TB of 16 polymorphisms in 5 potential TB host susceptibility genes in the SAC population. A well designed case-control study was employed, using the TaqMan® genotyping system to type the various polymorphisms. Any polymorphism that was found to be significantly associated with susceptibility to TB was then subjected to further analysis to determine the functional effect of the polymorphism. Promoter methylation patterns were also investigated in ANXA11 as another mechanism to elucidate its role in TB susceptibility. A 3’ UTR ANXA11 polymorphism was found to be strongly associated with susceptibility to TB, including 3 haplotypes. The gene expression analysis identified differential transcriptional levels between individual with the different genotypes, with individuals homozygous for the A-allele exhibiting a 1.2-fold increase in gene expression relative to those homozygous for the G-allele. Methylation analysis however found no differences between cases and controls. In addition, 16 novel polymorphisms were also identified, 15 of which occurred in the 3’UTR of ANXA11. The mechanism of action of ANXA11 in TB susceptibility is hypothesised to be in the area of endocytosis, autophagy or apoptosis. A weak association was noted with one of the 5’ UTR polymorphisms of CADM3, which did not hold up to further analysis in the GWAS study, and no functional work was therefore done. This work facilitates our understanding of the role of host genetics in susceptibility to TB and adds to the growing amount of information available. Proper understanding of the role that host genetics plays in TB susceptibility could result in better treatment regimens and prediction of individuals who are at a greater risk of developing TB, a disease that still kills millions of individuals annually. / AFRIKAANSE OPSOMMING: Tuberkulose is verantwoordelik vir meer sterftes as enige ander aansteeklike siekte, ten spyte van die voortuitgang wat die Biomediese Wetenskappe tans beleef. In 1949 het Haldane voorgestel dat die genetiese samestelling van die gasheer ‘n rol speel in vatbaarheid vir aansteeklike siektes. Vir tuberkulose word hierdie aanname gesteun deur die feit dat slegs 10% van individue wat geïnfekteer word aktiewe simptome ontwikkel, terwyl 90% die siekte suksesvol sal afweer. Tuberkulose is dus ‘n komplekse siekte wat veroorsaak word deur Mycobacterium tuberculosis, maar wat beïnvloed word deur genetiese sowel as omgewingsfaktore. Verskeie gene is al geïdentifiseer wat ‘n rol speel in vatbaarheid vir tuberkulose, tog is hul invloed betreklik klein. Genoom-wye assosiasiestudies (GWAS) bied unieke geleenthede vir die identifisering van nuwe polimorfismes wat genetiese vatbaarheid kan beïnvloed. Hierdie tegniek kan die hele genoom fynkam, sonder dat enige vooropgestelde idees oor die immuunrespons teen tuberkulose ‘n invloed sal hê. Tuberkulose en sarkoïdose is albei siektes wat die vorming van granulomas veroorsaak. Verskeie gene met hul geassosieerde variante is geïdentifiseer in ‘n onlangse GWAS, wat gefokus het op populasies in Wes-Afrika en Duitsland. Ons hipotese was dat die polimorfismes wat in hierdie studie geïdentifiseer is, ‘n invloed kan hê op genetiese vatbaarheid vir TB in die Suid-Afrikaanse Kleurlingbevolking (SAK). Die sarkoïdose GWAS het bevind dat ANXA11 vatbaarheid vir die siekte beïnvloed, terwyl CADM1 in die tuberkulose GWAS geïdentifiseer is. Die studie het die assosiasie tussen 16 variante en tuberkulose vatbaarheid ondersoek in die SAK populasie. Die variante strek oor 5 potensiële tuberkulose vatbaarheidsgene. Goedbeplande pasiënt-kontrole assosiasiestudies is gedoen en die polimorfismes is gegenotipeer deur gebruik te maak van die TaqMan® genotiperingsisteem. Enige polimorfisme wat beduidend met tuberkulose geassosieer was, is verder geanaliseer om die moontlike funksionele invloed daarvan te bepaal. Promotormetileringspatrone van ANXA11 is ook geanaliseer, om ‘n addisionele meganisme in tuberkulose vatbaarheidheid te ondersoek. Na genotipering van die polimorfismes is ‘n 3’ UTR ANXA11 variant geïdentifiseer wat beduidend met tuberkulose vatbaarheid geassosieer was. Drie haplotipes is ook geïdentifiseer. Geenuitdrukkingsanalise het aangedui dat verskille in transkripsie vlakke voorkom in individue met verskillende genotipes. Individue wat homosigoties was vir die A-alleel het ‘n verhoging van 1.2 in geenuitdrukking gehad, relatief tot individue wat homosigoties was vir die G-alleel. Metileringsanalise het egter geen verskil aangedui tussen pasiënte en kontroles nie. Addisioneel, is 16 nuwe variante ontdek, waarvan 15 in die 3’UTR van ANXA11 geleë was. Die meganisme waarmee ANAX11 genetiese vatbaarheid vir tuberkulose beïnvloed, blyk in die area van endositose, apoptose of outofagie, te wees. ‘n Swak assosiasie is gevind vir ‘n 5’ UTR variant van CADM3 en is nie verder opgevolg in die GWAS nie. Gevolglik is geen funksionele studies op hierdie polimorfisme gedoen nie. Hierdie studie dra by tot ons kennis oor die rol wat die genetiese samestelling van die gasheer speel in vatbaarheid vir tuberkulose. Indien die rol van mensgenetika in tuberkulose vatbaarheid korrek verstaan word, kan behandeling van die siekte verbeter word en kan individue wat ‘n hoër risiko loop om tuberkulose te ontwikkel geïdentifiseer word.

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