ИСТИНА

Tuberculosis (TB) pathogenesis is multistage, highly complex sequence of events, with many cell types involved. Allelic variants of genes determining the spectrum of natural genetic resistance to Mycobacterium tuberculosis (MTB) can be identified using forward genetic approaches, i.e., from the phenotype to gene. Mouse models of MTB infection for genetic mapping of resistance/susceptibility loci were applied by three teams of researchers. In each study, a different combination of inbred mice was used as resistant and susceptible partners for linkage analysis. Regardless of parental combinations, all three groups reported complex, polygenic control of host resistance to TB. Our group, in collaboration with groups from Canada and Sweden, used TB-resistant A/Sn and TB-susceptible I/St mice, backcross 1 and F2 segregation, and the whole genome SSLP-mapping approaches. We identified three QTL on chromosomes 3, 9 and 17. The latter QTL is located within the region containing the mouse major histocompatibility complex (Н2). After tuberculosis infection, mice of the I/St inbred strain exhibit shorter survival time, rapid body weight loss, higher mycobacterial loads in organs, and a more severe lung histopathology compared to yet another TB-resistant strain, C57BL/6. We have established a big panel of MHC-congenic recombinant mouse strains which differ at small segments of the chromosome 17 transferred from TB-susceptible I/St mice onto genetic background of TB-resistant C57BL/6 mice. Assessment of TB-related phenotypes allowed to narrow the location of the QTL to the 33.9 – 34.5 Mbp interval. This region is proximal to the H2-Ea gene and thus does not contain “classical” immunologically active distal MHC genes H2-D, L and, importantly, TNF-a. The segment mapped in our study contains 35 structural genes with different functions. Sequencing of candidates is in progress; positional cloning of 15 genes accomplished so far provided many polymorphisms of potential significance differentiating I/St and C57BL/6 mice.