Genetic control of resistance to experimental infection with virulentMycobacterium tuberculosis

Abstract

Over 2 billion people are estimated to be infected with virulent Mycobacterium tuberculosis, yet fewer than 10% progress to clinical tuberculosis within their lifetime. Twin studies and variations in the outcome of tuberculosis infection after exposure to similar environmental risks suggest genetic heterogeneity among individuals in their susceptibility to disease. In a mouse model of tuberculosis, we have established that resistance and susceptibility to virulent M. tuberculosis is a complex genetic trait. A new locus with a major effect on tuberculosis susceptibility, designated sst1 (susceptibility to tuberculosis 1), was mapped to a 9-centimorgan (cM) interval on mouse chromosome 1. It is located 10 -19 cM distal to a previously identified gene, Nramp1, that controls the innate resistance of mice to the attenuated bacillus Calmette-Gué rin vaccine strain. The phenotypic expression of the newly identified locus is distinct from that of Nramp1 in that sst1 controls progression of tuberculosis infection in a lung-specific manner. Mice segregating at the sst1 locus exhibit marked differences in the growth rates of virulent tubercle bacilli in the lungs. Lung lesions in congenic sst1-susceptible mice are characterized by extensive necrosis and unrestricted extracellular multiplication of virulent mycobacteria, whereas sst1-resistant mice develop interstitial granulomas and effectively control multiplication of the bacilli. The resistant allele of sst1, although powerful in controlling infection, is not sufficient to confer full protection against virulent M. tuberculosis, indicating that other genes located outside of the sst1 locus are likely also to be important for controlling tuberculosis infection.

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.…”

Toll-like receptors and their role in experimental models of microbial infection

“…Nevertheless, extensive in vitro data implicating TLR2 in the recognition of mycobacterial lipoarabinomannan, 31 a soluble tuberculosis factor, 22 whole Mycobacterium avium, 71 and Mycobacterium tuberculosis 72,73 strongly suggest that one or more TLRs participate in mycobacterial host defense. Published genetic analyses of experimental mycobacterial infection among different strains of inbred mice have identified significant QTL for tuberculosis susceptibility (sst1) on mouse chromosome 1 74 as well as resistance (Trl1-3) on mouse chromosomes 1, 3, and 7. 75 TLR5 is located on chromosome 1 but is unlikely to be a candidate gene for either the susceptibility or resistance phenotypes since it maps distal to both candidate intervals.…”

Lung carcinogenesis induced by chronic tuberculosis infection: the experimental model and genetic control

“…We have showed that in addition to DNA-damaging reactive oxygen and nitrogen species, the MTB-infected macrophages produce a most potent member of the epidermal growth factor family epiregulin, which may serve as a paracrine growth factor at the initial steps of tumorigenesis. We also identified a powerful genetic modifier of MTB-induced lung tumorigenesis in our model: the genetic locus sst1 (Kramnik et al, 2000), which specifically controls tissue damage and TB progression in the lungs.…”