Genetic control of susceptibility to infection with Mycobacterium tuberculosis in mice

Lm, Mitsos; Lr, Cardon; Fortin, Anny; Ryan, Lynn; LaCourse, Ronald; Rj, North; Gros, Philippe

doi:10.1038/sj.gene.6363712

Cited by 98 publications

(91 citation statements)

References 37 publications

(59 reference statements)

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“…and aerosol challenge with MTB. 42,43 Position of peaks on the chromosome 7 found in our studies was almost identical, suggesting, firstly, that this locus plays an important role in pathogenesis of tuberculosis infection irrespective of route of the pathogen entry and, secondly, that this locus may represent an ancestral polymorphism shared in common between the C3H and DBA/2 inbred strains. This indicates that some of the genetic polymorphisms within those common loci are likely to be ancestral, that is, naturally arising in the wild and pre-existing in mice used for the generation of inbred strains.…”

Section: Chromosome 7 and 15 Locisupporting

confidence: 67%

Genetic architecture of tuberculosis resistance in a mouse model of infection

Yan

Kirby

et al. 2006

Genes Immun

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Tuberculosis remains a significant public health problem: one-third of the human population is infected with virulent Mycobacterium tuberculosis (MTB) and 10% of those are at risk of developing tuberculosis during their lifetime. In both humans and experimental animal models, genetic variation among infected individuals contributes to the outcome of infection. However, in immunocompetent individuals (the majority of patients), genetic determinants of susceptibility to tuberculosis remain largely unknown. Mouse models of MTB infection, allowing control of exposure and other potential environmental contributors, have proven extremely useful for examining this genetic component. In a cross of C3HeB/FeJ (susceptible) by C57BL/6J (resistant) inbred mouse strains, we have previously identified one major genetic locus, sst1, the susceptible allele of which did not confer an overt immunodeficiency, but rather specifically affected progression of lung tuberculosis. Having generated and tested the sst1 congenic strains, we have observed that this locus only partially explained the difference in susceptibility of the parental strains to MTB. We now present further studies controlling for the effect of the sst1, identify four additional tuberculosis susceptibility loci and characterize their effects by testing an independent cross, knockout or congenic mice.

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Section: Chromosome 7 and 15 Locisupporting

confidence: 67%

Genetic architecture of tuberculosis resistance in a mouse model of infection

Yan

Kirby

et al. 2006

Genes Immun

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“…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.…”

Section: Resultsmentioning

confidence: 99%

Genetic regulation of host responses to Salmonella infection in mice

Malo

2002

Genes Immun

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Salmonella spp are Gram-negative bacteria capable of infecting a wide range of host species, including humans, domesticated and wild mammals, reptiles, birds and insects. The outcome of an encounter between Salmonella and its host is dependent upon multiple factors including the host genetic background. To facilitate the study of the genetic factors involved in resistance to this pathogen, mouse models of Salmonella infection have been developed and studied for years, allowing identification of several genes and pathways that may influence the disease outcome. In this review, we will cover some of the genes involved in mouse resistance to Salmonella that were identified through the study of congenic mouse strains, cloning of spontaneous mouse mutations, use of site-directed mutagenesis or quantitative trait loci analysis. In parallel, the relevant information pertaining to genes involved in resistance to Salmonella in humans will be discussed.

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“…Because the ancestral parents are fully sequenced, the genotyped RI strains afford a powerful tool for identifying genes within QTLs and are particularly useful for mapping multiple and epistatic genetic effects underlying complex phenotypes, including those seen in infectious diseases. 22,47,[50][51][52] Among the different RI sets of mice, we found the BXD panel more suitable for us than other series (for example, the AXB set) as the BXD series is much larger, almost three-times more than used in any other series of experiments and because both parental strains (C57BL/ 6J and DBA/2J) have been fully sequenced, 30 and have been shown to differ in their response to many pathogens, 28,[53][54][55][56][57] …”

Section: Discussionmentioning

confidence: 98%

Susceptibility to severe streptococcal sepsis: use of a large set of isogenic mouse lines to study genetic and environmental factors

et al. 2007

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Variation in responses to pathogens is influenced by exposure history, environment and the host's genetic status. We recently demonstrated that human leukocyte antigen class II allelic differences are a major determinant of the severity of invasive group A streptococcal (GAS) sepsis in humans. While in-depth controlled molecular studies on populations of genetically wellcharacterized humans are not feasible, it is now possible to exploit genetically diverse panels of recombinant inbred BXD mice to define genetic and environmental risk factors. Our goal in this study was to standardize the model and identify genetic and nongenetic covariates influencing invasive infection outcomes. Despite having common ancestors, the various BXD strains (n strains ¼ 33, n individuals ¼ 445) showed marked differences in survival. Mice from all strains developed bacteremia but exhibited considerable differences in disease severity, bacterial dissemination and mortality rates. Bacteremia and survival showed the expected negative correlation. Among nongenetic factors, age -but not sex or weight -was a significant predictor of survival (P ¼ 0.0005). To minimize nongenetic variability, we limited further analyses to mice aged 40-120 days and calculated a corrected relative survival index that reflects the number of days an animal survived post-infection normalized to all significant covariates. Genetic background (strain) was the most significant factor determining susceptibility (Pp0.0001), thus underscoring the strong effect of host genetic variation in determining susceptibility to severe GAS sepsis. This model offers powerful unbiased forward genetics to map specific quantitative trait loci and networks of pathways modulating the severity of GAS sepsis.

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Genetic control of susceptibility to infection with Mycobacterium tuberculosis in mice

Cited by 98 publications

References 37 publications

Genetic architecture of tuberculosis resistance in a mouse model of infection

Genetic architecture of tuberculosis resistance in a mouse model of infection

Genetic regulation of host responses to Salmonella infection in mice

Susceptibility to severe streptococcal sepsis: use of a large set of isogenic mouse lines to study genetic and environmental factors

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