Glass, Elizabeth

Knott, Sara

Leach, Richard Jonathan

2011-08-01T09:53:20Z

2011-08-01T09:53:20Z

2011-06-27

Infectious disease is an important issue for animal breeders, farmers and governments. Solutions to control infectious disease are needed and research focused on the genetic loci determining variation in immune-related traits has the potential to deliver solutions. The primary aim of this thesis is to discover regions of the bovine genome which influence the immune response post immunisation. To accomplish this two types of immunising agents, a Foot-and-Mouth Disease Virus (FMDV) peptide (FMDV15) and a commercial vaccine for Bovine Respiratory Syncytial Virus (BRSV), were used to immunise the second generation (F2 and backcrosses) of the Roslin Bovine Genome (RoBoGen) herd, a Charolais Holstein cross population. The FMDV15 peptide consisted of two sections of the VP1 protein located on the FMDV capsid, together encompassing the major neutralising antibody sites that are known to be immunogenic. Protection against FMDV is generally believed to relate to the levels of neutralising antibody and has been correlated with IgG1 and IgG2 levels as well as interferon- . In addition it has been shown that T cell responses also play a role in protection against FMDV. Thus all of these were used as phenotypic measurements post immunisation to the FMDV15 peptide. The BRSV vaccine used was an attenuated live vaccine. Protective mechanisms against BRSV infection include IgA, IgG1, IgG2 and IgM BRSV-specific antibodies and antibody titres particularly those of the IgG isotypes are considered to be correlates of protection. Thus, IgG1 and IgG2 antibody levels were measured post vaccination with the BRSV vaccine. All phenotypes were measured across time, and allowed analysis of the primary and secondary adaptive immune responses. Both agents caused considerable variation in the phenotypes measured post immunisation, with significant responses detected two weeks post immunisation. REstricted Maximum Likelihood (REML) analysis attributed much of this variation to sire, highlighting the heritable component, and environmental effects. Significant positive correlations were detected across time within each trait for both the FMDV and BRSV responses. The FMDV and BRSV antibody levels also correlated with each other at later time points, suggesting that there may be animals which are genetically predisposed to be high or low responders in general. Initially a linkage mappingapproach was followed using 165 microsatellite markers, which detected 77 QTL in response to the FMDV peptide and 27 QTL in response to the BRSV vaccine. There were some overlapping QTL, for example QTL which spanned the Major Histocompatibility Complex. Further analysis was conducted by developing a Perl scripted program which genotyped the RoBoGen herd in two ways; 1) Single Nucleotide Polymorphism(s) (SNP) were genotyped within the confidence intervals of the previously discovered QTL and 2) SNP were genotyped via a candidate gene approach. Association study methodology, accounting for relationship stratification via principal components of the genetic relationship matrix, was used to detect significant SNP, in response to both the FMDV peptide and the BRSV vaccine. Twenty significant SNP associations were discovered across 19 traits, with some SNP located in genes with known biological relevance to an immune response, such as the Toll-Like Receptors (TLR), TLR4 and TLR8. This thesis has detected regions of the genome which are significantly associated with the immune responses elicited by two different agents, suggesting similar pathway(s)/gene(s) may be used in defence of multiple pathogens. Once regions of significance were detected, further analysis using SNP markers identified significant, non-synonymous SNP that were associated with the immunising agents. The novel markers discovered in this study may aid breeding for resistance to disease via marker assisted selection. In addition, they may also have highlighted new targets for vaccinologists to develop ‘next generation’ vaccines.

http://hdl.handle.net/1842/5018

en

The University of Edinburgh

Leach, R. J., Craigmile, S.C., Knott, S. A., Glass, E. J. Quantitative trait loci for variation in immune response to a Foot-and-Mouth disease peptide. BMC Genet, 2010. 11(1): 107

Hadjipavlou, G., Hemani, G., Leach, R., Louro, B., Nadaf, J., Rowe, S., de Koning, D. J. Extensive QTL and Association analyses of the QTLMAS2009 data. BMC proceedings, 2010. 4(Suppl 1):S11.

Leach, R. J., Craigmile, S.C., Jann, O.C., Glass, E. J. Locating SNPs in the bovine genome associated with variation in the immune response. The 9th World Congress on Genetics Applied to Livestock Production, 2010. Paper number: 486.

Glass, E. J., Baxter, R., Leach, R. and Taylor, G. Bovine viral diseases. The role of host genetics. Chapter in “Breeding for Disease Resistance in Farm Animals” pages 88-141. 3rd edition (2010). Edited by S. C. Bishop., R. F. E. Axford., J. B. Owen and F. W. Nicholas, CAB International.

genetics

vaccination

QTL

FMDV

BRSV

Genetics of bovine vaccination

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy