Strain-Specific Differences in the Genetic Control of Two Closely Related Mycobacteria

The host response to mycobacterial infection depends on host and pathogen genetic factors. Recent studies in human populations suggest a strain specific genetic control of tuberculosis. To test for mycobacterial-strain specific genetic control of susceptibility to infection under highly controlled experimental conditions, we performed a comparative genetic analysis using the A/J- and C57BL/6J-derived recombinant congenic (RC) mouse panel infected with the Russia and Pasteur strains of Mycobacterium bovis Bacille Calmette Guérin (BCG). Bacillary counts in the lung and spleen at weeks 1 and 6 post infection were used as a measure of susceptibility. By performing genome-wide linkage analyses of loci that impact on tissue-specific bacillary burden, we were able to show the importance of correcting for strain background effects in the RC panel. When linkage analysis was adjusted on strain background, we detected a single locus on chromosome 11 that impacted on pulmonary counts of BCG Russia but not Pasteur. The same locus also controlled the splenic counts of BCG Russia but not Pasteur. By contrast, a locus on chromosome 1 which was indistinguishable from Nramp1 impacted on splenic bacillary counts of both BCG Russia and Pasteur. Additionally, dependent upon BCG strain, tissue and time post infection, we detected 9 distinct loci associated with bacillary counts. Hence, the ensemble of genetic loci impacting on BCG infection revealed a highly dynamic picture of genetic control that reflected both the course of infection and the infecting strain. This high degree of adaptation of host genetics to strain-specific pathogenesis is expected to provide a suitable framework for the selection of specific host-mycobacteria combinations during co-evolution of mycobacteria with humans

Genetic Interactions between Chromosomes 11 and 18 Contribute to Airway Hyperresponsiveness in Mice

We used two-dimensional quantitative trait locus analysis to identify interacting genetic loci that contribute to the native airway constrictor hyperresponsiveness to methacholine that characterizes A/J mice, relative to C57BL/6J mice. We quantified airway responsiveness to intravenous methacholine boluses in eighty-eight (C57BL/6J X A/J) F2 and twenty-seven (A/J X C57BL/6J) F2 mice as well as ten A/J mice and six C57BL/6J mice; all studies were performed in male mice. Mice were genotyped at 384 SNP markers, and from these data two-QTL analyses disclosed one pair of interacting loci on chromosomes 11 and 18; the homozygous A/J genotype at each locus constituted the genetic interaction linked to the hyperresponsive A/J phenotype. Bioinformatic network analysis of potential interactions among proteins encoded by genes in the linked regions disclosed two high priority subnetworks - Myl7, Rock1, Limk2; and Npc1, Npc1l1. Evidence in the literature supports the possibility that either or both networks could contribute to the regulation of airway constrictor responsiveness. Together, these results should stimulate evaluation of the genetic contribution of these networks in the regulation of airway responsiveness in humans

Systemic Toll-Like Receptor Stimulation Suppresses Experimental Allergic Asthma and Autoimmune Diabetes in NOD Mice

BackgroundInfections may be associated with exacerbation of allergic and autoimmune diseases. Paradoxically, epidemiological and experimental data have shown that some microorganisms can also prevent these pathologies. This observation is at the origin of the hygiene hypothesis according to which the decline of infections in western countries is at the origin of the increased incidence of both Th1-mediated autoimmune diseases and Th2-mediated allergic diseases over the last decades. We have tested whether Toll-like receptor (TLR) stimulation can recapitulate the protective effect of infectious agents on allergy and autoimmunity. Methods and Findings Here, we performed a systematic study of the disease-modifying effects of a set of natural or synthetic TLR agonists using two experimental models, ovalbumin (OVA)-induced asthma and spontaneous autoimmune diabetes, presenting the same genetic background of the non obese diabetic mouse (NOD) that is highly susceptible to both pathologies. In the same models, we also investigated the effect of probiotics. Additionally, we examined the effect of the genetic invalidation of MyD88 on the development of allergic asthma and spontaneous diabetes. We demonstrate that multiple TLR agonists prevent from both allergy and autoimmunity when administered parenterally. Probiotics which stimulate TLRs also protect from these two diseases. The physiological relevance of these findings is further suggested by the major acceleration of OVA-induced asthma in MyD88 invalidated mice. Our results strongly indicate that the TLR-mediated effects involve immunoregulatory cytokines such as interleukin (IL)-10 and transforming growth factor (TGF)-β and different subsets of regulatory T cells, notably CD4+CD25+FoxP3+ T cells for TLR4 agonists and NKT cells for TLR3 agonists. Conclusions/Significance These observations demonstrate that systemic administration of TLR ligands can suppress both allergic and autoimmune responses. They provide a plausible explanation for the hygiene hypothesis. They also open new therapeutic perspectives for the prevention of these pathologies

Biological effects and clinical efficacy of a topical Toll-like receptor 7 agonist in seasonal allergic rhinitis: a parallel group controlled phase IIa study.

The purpose of the study was to examine effects of pre-treatment with a Toll-like receptor 7 (TLR7) agonist (AZD8848) in allergic rhinitis and to evaluate clinical effects of two dosing regimens