BACKGROUND: Trypanosoma brucei brucei infects livestock, with severe effects in horses and dogs. Mouse strains differ greatly in susceptibility to this parasite. However, no genes controlling these differences were mapped. METHODS: We studied the genetic control of survival after T. b. brucei infection using recombinant congenic (RC) strains, which have a high mapping power. Each RC strain of BALB/c-c-STS/A (CcS/Dem) series contains a different random subset of 12.5% genes from the parental "donor" strain STS/A and 87.5% genes from the "background" strain BALB/c. Although BALB/c and STS/A mice are similarly susceptible to T. b. brucei, the RC strain CcS-11 is more susceptible than either of them. We analyzed genetics of survival in T. b. brucei-infected F(2) hybrids between BALB/c and CcS-11. CcS-11 strain carries STS-derived segments on eight chromosomes. They were genotyped in the F(2) hybrid mice and their linkage with survival was tested by analysis of variance. RESULTS: We mapped four Tbbr (Trypanosoma brucei brucei response) loci that influence survival after T. b. brucei infection. Tbbr1 (chromosome 3) and Tbbr2 (chromosome 12) have effects on survival independent of inter-genic interactions (main effects). Tbbr3 (chromosome 7) influences survival in interaction with Tbbr4 (chromosome 19). Tbbr2 is located on a segment 2.15 Mb short that contains only 26 genes. CONCLUSION: This study presents the first identification of chromosomal loci controlling susceptibility to T. b. brucei infection. While mapping in F(2) hybrids of inbred strains usually has a precision of 40-80 Mb, in RC strains we mapped Tbbr2 to a 2.15 Mb segment containing only 26 genes, which will enable an effective search for the candidate gene. Definition of susceptibility genes will improve the understanding of pathways and genetic diversity underlying the disease and may result in new strategies to overcome the active subversion of the immune system by T. b. brucei.

Laboratory of Molecular and Cellular Immunology Institute of Molecular Genetics Academy of Sciences of the Czech Republic Prague Czech Republic

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Aksoy S, Gibson WC, Lehane MJ. Interactions between tsetse and trypanosomes with implications for the control of trypanosomiasis. Adv Parasitol. 2003;53:1–83. PubMed

Vanhamme L, Paturiaux-Hanocq F, Poelvoorde P, Nolan DP, Lins L, et al. Apolipoprotein L-I is the trypanosome lytic factor of human serum. Nature. 2003;422:83–87. PubMed

Wheeler RJ. The trypanolytic factor-mechanism, impacts and applications. Trends Parasitol. 2010;26:457–464. PubMed

Lai DH, Hashimi H, Lun ZR, Ayala FJ, Lukes J. Adaptations of Trypanosoma brucei to gradual loss of kinetoplast DNA: Trypanosoma equiperdum and Trypanosoma evansi are petite mutants of T. brucei. Proc Natl Acad Sci U S A. 2008;105:1999–2004. PubMed PMC

Vincendeau P, Bouteille B. Immunology and immunopathology of African trypanosomiasis. An Acad Bras Cienc. 2006;78:645–665. PubMed

Tabel H, Wei G, Shi M. T cells and immunopathogenesis of experimental African trypanosomiasis. Immunol Rev. 2008;225:128–139. PubMed

Masocha W, Amin DN, Kristensson K, Rottenberg ME. Differential invasion of Trypanosoma brucei brucei and lymphocytes into the brain of C57BL/6 and 129Sv/Ev mice. Scand J Immunol. 2008;68:484–491. PubMed

Marcello L, Barry JD. Analysis of the VSG gene silent archive in Trypanosoma brucei reveals that mosaic gene expression is prominent in antigenic variation and is favored by archive substructure. Genome Res. 2007;17:1344–1352. PubMed PMC

Rickman WJ, Cox HW. Immunologic reactions associated with anemia, thrombocytopenia, and coagulopathy in experimental African trypanosomiasis. J Parasitol. 1980;66:28–33. PubMed

Coller SP, Mansfield JM, Paulnock DM. Glycosylinositolphosphate soluble variant surface glycoprotein inhibits IFN-gamma-induced nitric oxide production via reduction in STAT1 phosphorylation in African trypanosomiasis. J Immunol. 2003;171:1466–1472. PubMed

Diffley P. Trypanosomal surface coat variant antigen causes polyclonal lymphocyte activation. J Immunol. 1983;131:1983–1986. PubMed

Darji A, Beschin A, Sileghem M, Heremans H, Brys L, et al. In vitro simulation of immunosuppression caused by Trypanosoma brucei: active involvement of gamma interferon and tumor necrosis factor in the pathway of suppression. Infect Immun. 1996;64:1937–1943. PubMed PMC

Courtin D, Jamonneau V, Mathieu JF, Koffi M, Milet J, et al. Comparison of cytokine plasma levels in human African trypanosomiasis. Trop Med Int Health. 2006;11:647–653. PubMed

Black SJ, Sendashonga CN, Lalor PA, Whitelaw DD, Jack RM, et al. Regulation of the growth and differentiation of Trypanosoma (Trypanozoon) brucei brucei in resistant (C57BL/6) and susceptible (C3H/He) mice. Parasite Immunol. 1983;5:465–478. PubMed

van Velthuysen ML, Veninga A, Bruijn JA, de Heer E, Fleuren GJ. Susceptibility for infection-related glomerulopathy depends on non-MHC genes. Kidney Int. 1993;43:623–629. PubMed

Magez S, Truyens C, Merimi M, Radwanska M, Stijlemans B, et al. P75 tumor necrosis factor-receptor shedding occurs as a protective host response during African trypanosomiasis. J Infect Dis. 2004;189:527–539. PubMed

Gershon RK, Kondo K. Deficient production of a thymus-dependent high affinity antibody subset in mice (CBA/N) with an X-linked B lymphocyte defect. J Immunol. 1976;117:701–702. PubMed

Gasbarre LC, Finerty JF, Louis JA. Non-specific immune responses in CBA/N mice infected with Trypanosoma brucei. Parasite Immunol. 1981;3:273–282. PubMed

Kemp SJ, Iraqi F, Darvasi A, Soller M, Teale AJ. Localization of genes controlling resistance to trypanosomiasis in mice. Nat Genet. 1997;16:194–196. PubMed

Iraqi F, Clapcott SJ, Kumari P, Haley CS, Kemp SJ, et al. Fine mapping of trypanosomiasis resistance loci in murine advanced intercross lines. Mamm Genome. 2000;11:645–648. PubMed

Goodhead I, Archibald A, Amwayi P, Brass A, Gibson J, et al. A comprehensive genetic analysis of candidate genes regulating response to Trypanosoma congolense infection in mice. PLoS Negl Trop Dis . 2010;4:e880. PubMed PMC

Nganga JK, Soller M, Iraqi FA. High resolution mapping of trypanosomosis resistance loci Tir2 and Tir3 using F12 advanced intercross lines with major locus Tir1 fixed for the susceptible allele. BMC Genomics. 2010;11:394. PubMed PMC

Graefe SE, Meyer BS, Muller-Myhsok B, Ruschendorf F, Drosten C, et al. Murine susceptibility to Chagas' disease maps to chromosomes 5 and 17. Genes Immun. 2003;4:321–325. PubMed

Demant P, Hart AA. Recombinant congenic strains--a new tool for analyzing genetic traits determined by more than one gene. Immunogenetics. 1986;24:416–422. PubMed

Van Wezel T, Lipoldová M, Demant, Editors: Malcolm S P, Goodship J. Genotype to Phenotype second edition. Oxford: BIOS Scientific Publishers Ltd; 2001. Identification of disease susceptibility genes (modifiers) in mouse models: cancer and infectious diseases. pp. 107–129.

Demant P, Lipoldová M, Svobodová M. Resistance to Leishmania major in mice. Science. 1996;274:1392a. PubMed

Lipoldová M, Svobodová M, Krulová M, Havelková H, Badalová J, et al. Susceptibility to Leishmania major infection in mice: multiple loci and heterogeneity of immunopathological phenotypes. Genes Immun. 2000;1:200–206. PubMed

Havelková H, Badalová J, Svobodová M, Vojtíšková J, Kurey I, et al. Genetics of susceptibility to leishmaniasis in mice: four novel loci and functional heterogeneity of gene effects. Genes Immun. 2006;7:220–233. PubMed

Lipoldová M, Demant P. Genetic susceptibility to infectious disease: lessons from mouse models of leishmaniasis. Nat Rev Genet. 2006;7:294–305. PubMed

Vladimirov V, Badalová J, Svobodová M, Havelková H, Hart AA, et al. Different genetic control of cutaneous and visceral disease after Leishmania major infection in mice. Infect Immun. 2003;71:2041–2046. PubMed PMC

Banus HA, van Kranen HJ, Mooi FR, Hoebee B, Nagelkerke NJ, et al. Genetic control of Bordetella pertussis infection: identification of susceptibility loci using recombinant congenic strains of mice. Infect Immun. 2005;73:741–747. PubMed PMC

Stassen AP, Groot PC, Eppig JT, Demant P. Genetic composition of the recombinant congenic strains. Mamm Genome. 1996;7:55–58. PubMed

Tripodis N, Demant P. Three-dimensional patterns of lung tumor growth: association with tumor heterogeneity. Exp Lung Res. 2001;27:521–531. PubMed

Lander ES, Schork NJ. Genetic dissection of complex traits. Science. 1994;265:2037–2048. PubMed

Kurey I, Kobets T, Havelková H, Slapničková M, Quan L, et al. Distinct genetic control of parasite elimination, dissemination, and disease after Leishmania major infection. Immunogenetics. 2009;61:619–633. PubMed PMC

Frankel WN, Schork NJ. Who's afraid of epistasis? Nat Genet. 1996;14:371–373. PubMed

Hanotte O, Ronin Y, Agaba M, Nilsson P, Gelhaus A, et al. Mapping of quantitative trait loci controlling trypanotolerance in a cross of tolerant West African N'Dama and susceptible East African Boran cattle. Proc Natl Acad Sci U S A. 2003;100:7443–7448. PubMed PMC

Havelková H, Badalová J, Demant P, Lipoldová M. A new type of genetic regulation of allogeneic response. A novel locus on mouse chromosome 4, Alan2 controls MLC reactivity to three different alloantigens: C57BL/10, BALB/c and CBA. Genes Immun. 2000;1:483–487. PubMed

Lipoldová M, Svobodová M, Havelková H, Krulová M, Badalová J, et al. Mouse genetic model for clinical and immunological heterogeneity of leishmaniasis. Immunogenetics. 2002;54:174–183. PubMed

Shockley KR, Churchill GA. Gene expression analysis of mouse chromosome substitution strains. Mamm Genome. 2006;17:598–614. PubMed

Li R, Lyons MA, Wittenburg H, Paigen B, Churchill GA. Combining data from multiple inbred line crosses improves the power and resolution of quantitative trait loci mapping. Genetics. 2005;169:1699–1709. PubMed PMC

Moen CJ, Stoffers HJ, Hart AA, Westerhoff HV, Demant P. Simulation of the distribution of parental strains' genomes in RC strains of mice. Mamm Genome. 1997;8:884–889. PubMed

Badalová J, Svobodová M, Havelková H, Vladimirov V, Vojtíšková J, et al. Separation and mapping of multiple genes that control IgE level in Leishmania major infected mice. Genes Immun. 2002;3:187–195. PubMed

Gusareva ES, Havelková H, Blažková H, Kosařová M, Kučera P, et al. Mouse to human comparative genetics reveals a novel immunoglobulin E-controlling locus on Hsa8q12. Immunogenetics. 2009;61:15–25. PubMed

Alexander J, Irving K, Snider H, Satoskar A Editors: Klein SL, Roberts CW. Heildelberg, Dordrecht, London, New York: 2010. Sex hormones of host responses against parasites. pp. 147–186.

Yeretssian G, Doiron K, Shao W, Leavitt BR, Hayden MR, et al. Gender differences in expression of the human caspase-12 long variant determines susceptibility to Listeria monocytogenes infection. Proc Natl Acad Sci U S A. 2009;106:9016–9020. PubMed PMC

Greenblatt HC, Rosenstreich DL. Trypanosoma rhodesiense infection in mice: sex dependence of resistance. Infect Immun. 1984;43:337–340. PubMed PMC

Brownstein DG, Gras L. Chromosome mapping of Rmp-4, a gonad-dependent gene encoding host resistance to mousepox. J Virol. 1995;69:6958–6964. PubMed PMC

Lundberg P, Welander P, Openshaw H, Nalbandian C, Edwards C, et al. A locus on mouse chromosome 6 that determines resistance to herpes simplex virus also influences reactivation, while an unlinked locus augments resistance of female mice. J Virol. 2003;77:11661–11673. PubMed PMC

Butterfield RJ, Roper RJ, Rhein DM, Melvold RW, Haynes L, et al. Sex-specific quantitative trait loci govern susceptibility to Theiler's murine encephalomyelitis virus-induced demyelination. Genetics. 2003;163:1041–1046. PubMed PMC

Carroll SF, Loredo Osti JC, Guillot L, Morgan K, Qureshi ST. Sex differences in the genetic architecture of susceptibility to Cryptococcus neoformans pulmonary infection. Genes Immun. 2008;9:536–545. PubMed

Min-Oo G, Lindqvist L, Vaglenov A, Wang C, Fortin P, et al. Genetic control of susceptibility to pulmonary infection with Chlamydia pneumoniae in the mouse. Genes Immun. 2008;9:383–388. PubMed

Schuurhof A, Bont L, Siezen CL, Hodemaekers H, van Houwelingen HC, et al. Interleukin-9 polymorphism in infants with respiratory syncytial virus infection: an opposite effect in boys and girls. Pediatr Pulmonol. 2010;45:608–613. PubMed

Gamper CJ, Agoston AT, Nelson WG, Powell JD. Identification of DNA methyltransferase 3a as a T cell receptor-induced regulator of Th1 and Th2 differentiation. J Immunol. 2009;183:2267–2276. PubMed PMC

Dagenais TR, Freeman BE, Demick KP, Paulnock DM, Mansfield JM. Processing and presentation of variant surface glycoprotein molecules to T cells in African trypanosomiasis. J Immunol. 2009;183:3344–3355. PubMed PMC

Catania A. The melanocortin system in leukocyte biology. J Leukoc Biol. 2007;81:383–392. PubMed

Bicknell AB. The tissue-specific processing of pro-opiomelanocortin. J Neuroendocrinol. 2008;20:692–699. PubMed

Tasken K, Stokka AJ. The molecular machinery for cAMP-dependent immunomodulation in T-cells. Biochem Soc Trans. 2006;34:476–479. PubMed

Xu J, Wu RC, O'Malley BW. Normal and cancer-related functions of the p160 steroid receptor co-activator (SRC) family. Nat Rev Cancer. 2009;9:615–630. PubMed PMC

Schleifer KW, Mansfield JM. Suppressor macrophages in African trypanosomiasis inhibit T cell proliferative responses by nitric oxide and prostaglandins. J Immunol. 1993;151:5492–5503. PubMed

Dorshkind K, Montecino-Rodriguez E. Fetal B-cell lymphopoiesis and the emergence of B-1-cell potential. Nat Rev Immunol. 2007;7:213–219. PubMed

Dutra WO, Colley DG, Pinto-Dias JC, Gazzinelli G, Brener Z, et al. Self and nonself stimulatory molecules induce preferential expansion of CD5+ B cells or activated T cells of chagasic patients, respectively. Scand J Immunol. 2000;51:91–97. PubMed

Onah DN, Hopkins J, Luckins AG. Increase in CD5+ B cells and depression of immune responses in sheep infected with Trypanosoma evansi. Vet Immunol Immunopathol. 1998;63:209–222. PubMed

Buza J, Sileghem M, Gwakisa P, Naessens J. CD5+ B lymphocytes are the main source of antibodies reactive with non-parasite antigens in Trypanosoma congolense-infected cattle. Immunology. 1997;92:226–233. PubMed PMC

Taft RJ, Pang KC, Mercer TR, Dinger M, Mattick JS. Non-coding RNAs: regulators of disease. J Pathol. 2010;220:126–139. PubMed

Roy MF, Riendeau N, Loredo-Osti JC, Malo D. Complexity in the host response to Salmonella typhimurium infection in AcB and BcA recombinant congenic strains. Genes Immun. 2006;7:655–666. PubMed

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