Severity of Tuberculosis in Mice is Linked to Distal Chromosome 3 and Proximal Chromosome 9

Abstract

Genetic factors play a role in host response to infection with Mycobacterium tuberculosis, the number one infectious killer worldwide. Mice of the inbred strains I/St and A/Sn show significant differences in disease severity after intravenous injection of a lethal dose of the virulent human isolate M. tuberculosis H37Rv. Following challenge with H37Rv, only I/St mice have rapid body weight loss and short survival times. A genome wide analysis for linkage with body weight after M. tuberculosis H37Rv infection was done in (A/SnxI/St)F1xI/St mice. Among females, quantitative trait loci (QTLs) on chromosomes 9 and 3 were significantly linked to postinfection body weight (logarithm of the odds ratio [LOD] scores of 6.68 and 3.92, respectively). Suggestive linkages were found for QTLs on chromosomes 8 and 17 (LOD scores of 3.01 and 2.95, respectively). For males, QTLs on chromosomes 5 and 10 showed suggestive linkages (LOD scores of 3.03 and 2.31, respectively). These linkages can be used to identify candidate regions for tuberculosis susceptibility loci in the human genome.

Genetic control of susceptibility to infection with Mycobacterium tuberculosis in mice

“…Indeed, only two published studies document whole genome scans for QTLs that may affect host resistance to M. tuberculosis infection, 17,26 and the loci mapped in our study appear distinct from those mapped by these two groups. The Chr.1 Nramp1 locus plays a key role in host resistance against several intracellular infections in mice, including several mycobacterial species, 27 and NRAMP1 alleles have been associated with susceptibility to tuberculosis, 9 and leprosy in humans.…”

“…30 Finally, a locus (Tir3) which affects susceptibility to trypanosomiasis as measured by survival time was recently mapped in a BALB/c × C57Bl/6J cross to the distal part of Chr.1. 31 Lavebratt et al 17 We did not detect any linkage to chromosomes 5, 8, 9, 10 and 17 in our study. In addition, we did not observe any effect of sex on susceptibility to infection, and body weight at the time of death did not show any specific linkage in the (B6D2) F2 analyzed here, once data was regressed to account for gender of the animals.…”

“…At high power (i), some of the epithelioid macrophages can be seen to contain acidfast bacilli (arrows). 374,213,156,19,181,415,493,218,196,265,396,425,D11Mit226,19,20,349,194,39,67,224,103 109,145,206,541,150,361,221,209 D12Mit12,153,34,14,118,233,20 D2Mit1,32,367,61,91,436,164,401,225,311,200 D13Mit271,60,139,250,145,293,35 D3Mit176,306,69,241,51,72,156,106,17,128 D14Mit207, …”

“…[12][13][14][15][16] When studied, genetic control of susceptibility appeared multigenic, 14 including a recent study that suggested six chromosomal regions contributing to the reported difference between the A/Sn and I/St strains in M. tuberculosis infection-induced body weight loss. 17 Although a role for H-2 genes in genetic susceptibility (H-2k protective over H-2b) has been identified, 18,19 additional genes have yet to be identified.…”

Genetic regulation of host responses to Salmonella infection in mice

“…Now the future of mouse genetics in the study of host resistance to Salmonella and other infections is moving toward the identification of inbred mouse strains that show a complex mode of inheritance to specific pathogens for QTL gene identification. 19,20,[153][154][155][156][157][158][159][160] Dissection of the complex host response to Salmonella infection combined with the complete mouse genome sequence will contribute further to our understanding of the genetic control of host immunity.…”