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  Genome-wide mapping of gene-microbiota interactions in susceptibility to epidermolysis bullosa acquisita

Srinivas, G. (2013). Genome-wide mapping of gene-microbiota interactions in susceptibility to epidermolysis bullosa acquisita. PhD Thesis, University of Lübeck, Lübeck.

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 Urheber:
Srinivas, Girish1, Autor           
Ibrahim, S., Gutachter
Solbach, W., Gutachter
Franke, A., Gutachter
Affiliations:
1Guest Group Evolutionary Genomics, Max Planck Institute for Evolutionary Biology, Max Planck Society, ou_1445638              

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 Zusammenfassung: The skin is in constant contact with the environment and serves a critical barrier function, yet provides a range of niches to inhabiting microbial communities. A multitude of interactions between the skin microbiota, host and environment contribute to community structure and its potential contribution to changes in health status is well known. Susceptibility to chronic inflammatory diseases is determined by the interaction of immunogenetic and environmental risk factors. In particular, resident microbial communities as environmental factors are the subject of intense scrutiny due to numerous observations of differences in community composition or structure are of primary etiological importance or secondary to the altered inflammatory environment remains largely unknown. Epidermolysis bullosa acquisita (EBA) is a chronic skin blistering disease of autoimmune origin characterized by antibodies to type VII collagen (COL7). This study provides experimental evidence for host gene-microbiota interactions contributing to disease risk in a mouse immunization model of EBA. By using an advanced intercross mouse population, genetic loci contributing to variability in the skin microbiota were simultaneously identified along with susceptibility to EBA and their overlap. QTL mapping of the skin microbiota with susceptibility to EBA demonstrates the involvement of host gene-microbe interactions in disease. Furthermore, treating the abundances of individual bacterial species as covariates with disease lead to the discovery of a novel disease locus. The majority of the identified covariate taxa were characterized by a reduction in abundance being associated with increased disease risk. This provides evidence of a primary role for individual bacterial species abundances in disease susceptibility and underscores their importance in protection from disease. Interestingly, in a parallel study in this thesis, mice that did not develop clinical disease showed a higher diversity in their skin microbial communities before disease induction. This further demonstrates the importance of skin community in predictive of EBA disease outcome. Thus, further characterization of these putative probiotic species or species assemblages offers promising potential for preventative and therapeutic treatment development.

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Sprache(n): eng - English
 Datum: 2013-10-292013
 Publikationsstatus: Erschienen
 Seiten: IX, 131 S.
 Ort, Verlag, Ausgabe: Lübeck : University of Lübeck
 Inhaltsverzeichnis: Table of Contents
Acknowledgements .......................................................................................................... I
Declaration of Author’s Contribution ......................................................................... II
List of Figures ................................................................................................................ V
List of Tables .............................................................................................................. VIII
Summary ....................................................................................................................... IX
1. Introduction ................................................................................................................. 1
1.1 Skin microbiota ..................................................................................................................... 2
1.1.1 Skin microbiota characterization ......................................................................................... 3
1.1.2 Factors influencing skin microbiota composition ............................................................... 6
1.1.3 Skin microbiota association with health and disease .......................................................... 7
1.2 Autoimmunity and Autoimmune diseases ......................................................................... 8
1.2.1 Why study Autoimmune diseases? ...................................................................................... 8
1.2.2 Autoimmune skin blistering diseases .................................................................................. 9
1.3 Epidermolysis Bullosa Acquisita ....................................................................................... 10
1.3.1 Mouse models to study EBA ............................................................................................. 11
1.3.2 Genetics of EBA ................................................................................................................ 13
1.4 Scope of the thesis ............................................................................................................... 15
2 Materials and Methods .............................................................................................. 19
2.1 Generation of a four way advanced intercross lines ....................................................... 19
2.2 SJL/J mice ........................................................................................................................... 19
2.3 Recombinant peptides ........................................................................................................ 20
2.4 Induction of experimental EBA and observation protocol ............................................. 20
2.5 Genomic DNA extraction for genotyping ......................................................................... 21
2.6 G4 population genotyping .................................................................................................. 21
2.7 Bacterial DNA extraction and 16S rRNA gene pyrosequencing .................................... 22
2.8 454 pyrosequencing data analysis ..................................................................................... 23
2.8.1 Pre-processing steps .......................................................................................................... 23
2.8.2 OTU determination ............................................................................................................ 24
2.8.3 Sequence alignment ........................................................................................................... 25
2.8.4 Normalization using rarefaction method ........................................................................... 26
2.8.5 Alpha diversity analysis .................................................................................................... 27
2.8.6 Beta diversity analysis ....................................................................................................... 29
2.8.7 Indicator species analysis .................................................................................................. 30
2.8.8 Taxonomy classification .................................................................................................... 31
2.9 Data preparation for QTL analysis .................................................................................. 32
2.10 Core measurement microbiota ........................................................................................ 32
2.11 QTL analysis ..................................................................................................................... 33
2.11.1 Model selection ............................................................................................................... 35
2.11.2 QTL mapping .................................................................................................................. 36
3. Results ........................................................................................................................ 40
3.1 Skin bacterial diversity ....................................................................................................... 40
3.1.1 Microbial communities in healthy and EBA afflicted individuals .................................... 45
3.1.1.1 Alpha diversity ................................................................................................................ 46
3.1.1.2 Beta diversity .................................................................................................................. 49
3.1.1.3 Indicator species analysis ................................................................................................ 51
3.2 Skin microbiota role in EBA susceptibility ...................................................................... 54
3.3 Factors influencing skin microbiota .................................................................................. 59
3.3.1 Cage .................................................................................................................................. 59
3.3.2 Family ............................................................................................................................... 60
3.4 QTL analysis of skin microbiota ....................................................................................... 60
3.4.1 Effects of immunization on QTL mapping ........................................................................ 62
3.5 Genetics association of EBA ............................................................................................... 64
3.6 Genetics and skin microbiota interaction ......................................................................... 64
4. Discussion ................................................................................................................... 71
5. Bibliography .............................................................................................................. 80
6. Appendices ................................................................................................................. 95
6.1 Appendix A – Additional figures ....................................................................................... 95
6.2 Appendix B – Additional tables ....................................................................................... 104
7. Scientific achievements during doctoral research ................................................ 122
8. Affidavit ................................................................................................................... 125
9. Copyright Statement ............................................................................................... 126
10. Index ....................................................................................................................... 131
 Art der Begutachtung: -
 Identifikatoren: Anderer: Diss/12500
 Art des Abschluß: Doktorarbeit

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