Functionally distinct regions of the locus Leishmania major response 15 control IgE or IFN & gamma, level in addition to skin lesions

0575020 - ÚMG 2024 RIV CH eng J - Článek v odborném periodiku
Krayem, Imtissal - Sohrabi, Yahya - Havelková, Helena - Gusareva, Elena - Strnad, Hynek - Čepičková, Marie - Volková, Valeriya - Kurey, Irina - Vojtíšková, Jarmila - Svobodová, M. - Demant, P. - Lipoldová, Marie
Functionally distinct regions of the locus Leishmania major response 15 control IgE or IFN & gamma, level in addition to skin lesions.
Frontiers in Immunology. Roč. 14, Aug (2023), č. článku 1145269. ISSN 1664-3224. E-ISSN 1664-3224
Grant CEP: GA ČR GA16-22346S; GA MZd NV19-05-00457
Institucionální podpora: RVO:68378050
Klíčová slova: Leishmania major * susceptibility to infection * quantitative trait locus * advanced intercross line * recombinant mapping * bioinformatics analysis * fine mapping * functional heterogeneity
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 7.3, rok: 2022
Způsob publikování: Open access
https://www.frontiersin.org/articles/10.3389/fimmu.2023.1145269/full

Leishmaniasis, a disease caused by parasites of Leishmania spp., endangers more than 1 billion people living in endemic countries and has three clinical forms: cutaneous, mucocutaneous, and visceral. Understanding of individual differences in susceptibility to infection and heterogeneity of its pathology is largely lacking. Different mouse strains show a broad and heterogeneous range of disease manifestations such as skin lesions, splenomegaly, hepatomegaly, and increased serum levels of immunoglobulin E and several cytokines. Genome-wide mapping of these strain differences detected more than 30 quantitative trait loci (QTLs) that control the response to Leishmania major. Some control different combinations of disease manifestations, but the nature of this heterogeneity is not yet clear. In this study, we analyzed the L. major response locus Lmr15 originally mapped in the strain CcS-9 which carries 12.5% of the genome of the resistant strain STS on the genetic background of the susceptible strain BALB/c. For this analysis, we used the advanced intercross line K3FV between the strains BALB/c and STS. We confirmed the previously detected loci Lmr15, Lmr18, Lmr24, and Lmr27 and performed genetic dissection of the effects of Lmr15 on chromosome 11. We prepared the interval-specific recombinant strains 6232HS1 and 6229FUD, carrying two STS-derived segments comprising the peak linkage of Lmr15 whose lengths were 6.32 and 17.4 Mbp, respectively, and analyzed their response to L. major infection. These experiments revealed at least two linked but functionally distinct chromosomal regions controlling IFN & gamma, response and IgE response, respectively, in addition to the control of skin lesions. Bioinformatics and expression analysis identified the potential candidate gene Top3a. This finding further clarifies the genetic organization of factors relevant to understanding the differences in the individual risk of disease.
Trvalý link: https://hdl.handle.net/11104/0346209