A significant variation in susceptibility to tuberculosis among immunocompetent individuals is partially explained by genetic heterogeneity within the host population. However, precise mechanisms of the genetic control of anti-tuberculosis immunity are unknown. We employ a mouse experimental model of tuberculosis for the genetic analysis of the naturally occurring variation in tuberculosis resistance among immunocompetent inbred mouse strains to identify and isolate genes important for determining susceptibility to this infection. We have previously mapped the sstl locus, which controls progression of pulmonary tuberculosis early after infection. Using the sst1-resistant congenic mice we mapped six new quantitative trait loci (QTL) that control variation in tuberculosis resistance among the sstl-resistant hosts. Functional expression of some of those loci is sstl-dependent. We will study the new loci and characterize their possible interactions using genotype-assisted breeding and advanced backcross-intercross progeny testing in order to narrow candidate intervals and establish conditions for their further genetic dissection. We will generate a set of congenic strains by transferring new candidate QTLs on a C3H background and dissect those loci into smaller chromosomal segments to facilitate positional cloning. Using new congenic strains we will study cells that form lung granulomas in resistant and susceptible animals. Identify correlates of tuberculosis resistance and susceptibility at molecular level and establish proxy phenotypes for each locus that can be used as surrogate biomarkers for predicting genetic susceptibility in segregating populations. Identification of molecules encoded in QTLs will help explain critical functional differences conferred by the genetic polymorphisms on mechanisms of host resistance to tuberculosis at both systemic and lung-specific levels.
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