Functionally distinct regions of the locus Leishmania major response 15 control IgE or IFNγ level in addition to skin lesions

Frontiers in Immunology

Immunology

Hynek Strnad¹  Peter Demant²  Milena Svobodová³  Elena S. Gusareva⁴  Jarmila Vojtíšková⁴  Imtissal Krayem⁴  Marie Čepičková⁴  Iryna Kurey⁴  Helena Havelková⁴  Valeryia Volkova⁴  Marie Lipoldová⁵  Yahya Sohrabi⁶ 

[1] Department of Genomics and Bioinformatics, Institute of Molecular Genetics of The Czech Academy of Sciences, Prague, Czechia;Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States;Department of Parasitology, Faculty of Science, Charles University, Prague, Czechia;Laboratory of Molecular and Cellular Immunology, Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czechia;Laboratory of Molecular and Cellular Immunology, Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czechia;Department of Medical Genetics, Third Faculty of Medicine, Charles University, Prague, Czechia;Laboratory of Molecular and Cellular Immunology, Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czechia;Department of Medical Genetics, Third Faculty of Medicine, Charles University, Prague, Czechia;Department of Cardiology I-Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital Münster, Westfälische Wilhelms-Universität, Münster, Germany;

关键词: Leishmania major;    susceptibility to infection;    quantitative trait locus;    advanced intercross line;    recombinant mapping;    bioinformatics analysis;    fine mapping;    functional heterogeneity;   

DOI  :  10.3389/fimmu.2023.1145269

 received in 2023-01-15, accepted in 2023-05-02,  发布年份 2023

来源: Frontiers

【 摘 要 】

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 IFNγ 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.

【 授权许可】

Unknown   
Copyright © 2023 Krayem, Sohrabi, Havelková, Gusareva, Strnad, Čepičková, Volkova, Kurey, Vojtíšková, Svobodová, Demant and Lipoldová