Multigenic Control of Disease Severity after VirulentMycobacterium tuberculosisInfection in Mice

Abstract

Following challenge with virulent Mycobacterium tuberculosis, mice of the I/St inbred strain exhibit shorter survival time, more rapid body weight loss, higher mycobacterial loads in organs, and more severe lung histopathology than mice of the A/Sn strain. We previously performed a genome-wide scan for quantitative trait loci (QTLs) that control the severity of M. tuberculosis-triggered disease in [(A/Sn ؋ I/St) F1 ؋ I/St] backcross-1 (BC1) mice and described several QTLs that are significantly or suggestively linked to body weight loss. In the present study we expanded our analysis by including the survival time phenotype and by genotyping 406 (A/Sn ؋ I/St) F2 mice for the previously identified chromosomal regions of interest. The previously identified 12-cM-wide QTL on distal mouse chromosome 3 was designated tbs1 (tuberculosis severity 1); the location of the QTL on proximal chromosome 9 was narrowed to a 9-cM interval, and this QTL was designated tbs2. Allelic variants of the tbs2 locus appeared to be involved in control of both body weight loss and survival time. Also, the data strongly suggested that a QTL located in the vicinity of the H-2 complex on chromosome 17 is involved in control of tuberculosis in mice of both genders, whereas the tbs1 locus seemed to have an effect on postinfection body weight loss in female mice. Interestingly, these loci appeared to interact with each other, which suggests that there might be a basic genetic network for the control of intracellular parasites. Overall, linkage data reported here for F2 mice are in agreement with, and add to, our previous findings concerning the control of M. tuberculosis-triggered disease in the BC1 segregation.Identification of genes and their alleles that confer resistance and/or susceptibility to tuberculosis (TB) provides deep insight into basic mechanisms of immunity and pathology. Variations in NRAMP1 (5) and/or NRAMP1-linked loci on human chromosome 2q35 (8), VDR (3, 27), and class II HLA genes (6, 7) were shown to be linked to or associated with susceptibility to TB in humans. However, linkage and association results vary between studies, which may be due to the genetic control being polygenic and ethnicity dependent and to the absence of clearly delineated phenotypes (4, 24).Mouse models of TB have proved to be valuable for studies of antimycobacterial immunity and of the genetic control of susceptibility and resistance (16). For example, the Nramp1 gene, which has provided great insight in our understanding of macrophage-mycobacterium relationships, was first discovered in a mouse model of susceptibility to Mycobacterium bovis BCG (9, 28). Numerous inbred mouse strains have been tested to determine their survival times after challenge with virulent Mycobacterium tuberculosis (1,17,20). Among these strains, I/StSnEgYCit (I/St) mice display the shortest survival time, while A/SnYCit (A/Sn) mice survive significantly longer. In addition, I/St mice display more severe and rapid disease progression than A/Sn mice in terms of body weight los...

Sex differences in the genetic architecture of susceptibility to Cryptococcus neoformans pulmonary infection

“…This genomic region has been associated with susceptibility to various models of pulmonary infection including Chlamydia pneumoniae 58,59 and Mycobacterium tuberculosis. 60,61 One previous report of female H-2 congenic C57BL/10 strains bearing the H-2 k/k haplotype also demonstrated an increased cryptococcal burden in the liver 39 days following infection. 12,16 In the current study, segregation of the H-2 k/k (CBA/J) and C57BL/6J (H-2 b/b ) haplotypes was observed in our CBAB6F2 intercross population and the peak LOD score positions of the Cnes2 and Cnes3 lie proximal and distal to the H-2 region of chromosome 17, respectively.…”

Complex genetic control of susceptibility to Mycobacterium bovis (Bacille Calmette-Guérin) infection in wild-derived Mus spretus mice

“…17 QTL detected herein overlaps the major histocompatibility locus, a region that contains many genes regulating early (innate) and late phase (acquired immunity) of host response to infection with mycobacteria including M. bovis (BCG) (herein), and M. tuberculosis. 23,24 The effect of Chr. 17 on host response to M. tuberculosis has recently been attributed to a functional polymorphism in the tumor necrosis factor-a gene, 25 suggesting a possible modifying effect of this pleitropic proinflammatory cytokine on Nramp1-mediated resistance.…”

Genetic architecture of tuberculosis resistance in a mouse model of infection

“…Association of tuberculosis susceptibility with MHC polymorphisms have been previously reported both in humans 30 and in a mouse model of infection. 31,32 In mice, different alleles at specific H-2 loci affected survival after i.v. infection with virulent MTB, the level of delayed type hypersensitivity (DTH), T cell proliferative response to mycobacterial antigens, and efficacy of antituberculosis vaccination with live attenuated Mycobacterium bovis (BCG), 31 production of IFN-g by mycobacteria-specific T cells, 33,34 as well as production of mycobacteria-specific antibodies.…”