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Strong Epistasis in Genetics of Leishmaniasis - Identification of Genes and Mechanisms
Krayem, Imtissal ; Lipoldová, Marie (advisor) ; Černá, Marie (referee) ; Krulová, Magdaléna (referee)
Leishmaniasis, a disease caused by Leishmania parasites, ranks as the leading neglected tropical disease in terms of morbidity and mortality. Genotype of the infected organism is an important factor that influences susceptibility to and manifestations of this disease. To study human disease using mouse models, several strains are required, which could collectively exhibit different human pathophysiology. In the current thesis, we investigated the genetic influence on resting levels of immune cells in mice, because these resting levels could influence susceptibility to many of clinical disorders, including infectious diseases; and we performed a systematic review of the role of host genetics and cytokines in Leishmania infections. Moreover, we employed systems genetics to map genes causing susceptibility to leishmaniasis, and to identify additional mechanisms controlling response to Leishmania parasites. Also, we fine mapped the locus Leishmania major response 15 (Lmr15) in order to functionally characterize its role and to identify novel potential candidate genes regulating the response to L. major. Finally, we show a novel role of guanylate binding proteins 2b and 5 in the resistance to L. major. Strain B10.O20 carrying 3.6% of O20-derived genes on the C57BL/10 genetic background, on chromosomes...
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