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* Centre for the Study of Host Resistance, Department of Biochemistry, McGill University, Montréal, Québec, Canada; and
Trudeau Institute, Saranac Lake, NY 12983
The genetic control of susceptibility to tuberculosis in DBA/2J and C57BL/6J mice is complex and influenced by at least four tuberculosis resistance loci (Trl1-Trl4). To further study the Trl3 and Trl4 loci, we have created congenic mouse lines D2.B6-Chr7 and D2.B6-Chr19, in which resistant B6-derived portions of chromosome 7 (Chr.7) and chromosome 19 (Chr.19) overlapping Trl3 and Trl4, respectively, were independently introgressed onto susceptible D2 background. Transfer of B6-derived Trl3 chromosome 7 segment significantly increased resistance of D2 mice, as measured by reduced pulmonary microbial replication at day 70, and increased host survival following aerosol infection. However, transfer of B6-derived chromosome 19 (Trl4) onto D2 mice did not increase resistance by itself and does not improve on the protective effect of chromosome 7. Further study of the protective effect of Trl3 in D2.B6-Chr7 mice indicates that it does not involve modulation of timing or magnitude of Th1 response in the lung, as investigated by measuring the number of Ag-specific, IFN-
-producing CD4+ and CD8+ T cells. Rather, Trl3 appears to affect the intrinsic ability of activated macrophages to restrict intracellular mycobacterial replication in an NO synthase 2-independent fashion. Microarray experiments involving parental and congenic mouse lines identified a number of genes in the Trl3 interval on chromosome 7 the level of expression of which before infection or in response to Mycobacterium tuberculosis infection is differentially regulated in a parental haplotype-dependent fashion. This gene list represents a valuable entry point for the identification and prioritization of positional candidate genes for the Trl3 effect on chromosome 7.
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1 This work was supported by Grant AI035237 (to P.G.) and Grant AI069161 (to R.J.N.) from National Institute of Allergy and Infectious Diseases, National Institutes of Health. P.G. is a James McGill Professor of Biochemistry and a Distinguished Scientist of the Canadian Institutes of Health Research. J.-F.M. is supported by a fellowship from the Fonds de Recherche en Santé du Québec.
2 Address correspondence and reprint requests to Dr. Philippe Gros, Department of Biochemistry, McGill University, Bellini Building, 3649 Promenade Sir William Osler, Room 370, Montréal, Québec H3G 0B1, Canada. E-mail address: philippe.gros{at}mcgill.ca
3 Abbreviations used in this paper: TB, tuberculosis; MST, mean survival time; NOS, NO synthase; QTL, quantitative trait locus.
4 The online version of this article contains supplemental material.
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