title: Genetic control of susceptibility to Candida albicans in SM/J mice.
abstract: In the immunocompromised host, invasive infection with the fungal pathogen Candida albicans is associated with high morbidity and mortality. Sporadic cases in otherwise normal individuals are rare, and they are thought to be associated with genetic predisposition. Using a mouse model of systemic infection with C. albicans, we identified the SM/J mouse strain as unusually susceptible to infection. Genetic linkage studies in informative [C57BL/6JxSM/J]F2 mice identified a major locus on distal chromosome 15, given the appellation Carg5, that regulates C. albicans replication in SM/J mice. Cellular and molecular immunophenotyping experiments, as well as functional studies in purified cell populations from SM/J and C57BL/6J, and in [C57BL/6JxSM/J]F2 mice fixed for homozygous or heterozygous Carg5 alleles, indicate that Carg5-regulated susceptibility in SM/J is associated with a complex defect in the myeloid compartment of these mice. SM/J neutrophils express lower levels of Ly6G, and importantly, they show significantly reduced production of reactive oxygen species in response to stimulation with fMLF and PMA. Likewise, CD11b(+)Ly6G(-)Ly6C(hi) inflammatory monocytes were present at lower levels in the blood of infected SM/J, recruited less efficiently at the site of infection, and displayed blunted oxidative burst. Studies in F2 mice establish strong correlations between Carg5 alleles, Ly6G expression, production of serum CCL2 (MCP-1), and susceptibility to C. albicans. Genomic DNA sequencing of chromatin immunoprecipitated for myeloid proinflammatory transcription factors IRF1, IRF8, STAT1 and NF-κB, as well as RNA sequencing, were used to develop a "myeloid inflammatory score" and systematically analyze and prioritize potential candidate genes in the Carg5 interval.
authors: Biochemistry Department, McGill University, Montreal, Quebec H3G 0B1, Canada; Complex Traits Group, McGill University, Montreal, Quebec H3G 0B1, Canada;
authors: Irena
authors: I
authors: Radovanovic
authors: Complex Traits Group, McGill University, Montreal, Quebec H3G 0B1, Canada; Department of Human Genetics, McGill University, Montreal, Quebec H3G 0B1, Canada; and.
authors: Vicki
authors: V
authors: Leung
authors: Biochemistry Department, McGill University, Montreal, Quebec H3G 0B1, Canada; Complex Traits Group, McGill University, Montreal, Quebec H3G 0B1, Canada;
authors: Alexandra
authors: A
authors: Iliescu
authors: Biochemistry Department, McGill University, Montreal, Quebec H3G 0B1, Canada; Complex Traits Group, McGill University, Montreal, Quebec H3G 0B1, Canada;
authors: Silayuv E
authors: SE
authors: Bongfen
authors: National Research Council-Biotechnology Research Institute, Montreal, Quebec H4P 2R2, Canada.
authors: Alaka
authors: A
authors: Mullick
authors: Biochemistry Department, McGill University, Montreal, Quebec H3G 0B1, Canada; Complex Traits Group, McGill University, Montreal, Quebec H3G 0B1, Canada;
authors: David
authors: D
authors: Langlais
authors: Biochemistry Department, McGill University, Montreal, Quebec H3G 0B1, Canada; Complex Traits Group, McGill University, Montreal, Quebec H3G 0B1, Canada; philippe.gros@mcgill.ca.
authors: Philippe
authors: P
authors: Gros
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000096:biosynthesis / Q000235:genetics; D002177:Candidiasis / Q000235:genetics* / Q000276:immunology* / Q000382:microbiology; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000097:blood; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000276:immunology / Q000382:microbiology; D005260:Female; D020022:Genetic Predisposition to Disease; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics; D016130:Immunophenotyping; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D009504:Neutrophils / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D061251:Primary Cell Culture; D012097:Repressor Proteins / Q000235:genetics; D013045:Species Specificity; D013172:Spores, Fungal / Q000235:genetics / Q000254:growth & development / Q000276:immunology
chemical_list: D000950:Antigens, Ly; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; C480309:Ly6G antigen, mouse; D008565:Membrane Proteins; D012097:Repressor Proteins; C490015:Tmbim6 protein, mouse; C077048:Hnrnpab protein, mouse