title: Susceptibility to progressive Cryptococcus neoformans pulmonary infection is regulated by loci on mouse chromosomes 1 and 9.
abstract: Genetic factors that regulate the pathogenesis of pneumonia caused by the fungus Cryptococcus neoformans are poorly understood. Through a phenotypic strain survey we observed that inbred C3H/HeN mice develop a significantly greater lung fungal burden than mice of the resistant CBA/J strain 4 weeks following intratracheal infection with C. neoformans ATCC 24067. The aim of the present study was to characterize the inflammatory response of C3H/HeN mice following C. neoformans pulmonary infection and to identify genetic loci that regulate host defense. Following cryptococcal infection, C3H/HeN mice demonstrated a Th2 immune response with heightened airway and tissue eosinophilia, goblet cell metaplasia, and significantly higher lung interleukin-5 (IL-5) and IL-13 protein expression relative to CBA/J mice. Conversely, CBA/J mice exhibited greater airway and tissue neutrophilia that was associated with significantly higher pulmonary expression of gamma interferon, CXCL10, and IL-17 proteins than C3H/HeN mice. Using the fungal burden at 4 weeks postinfection as a phenotype, genome-wide quantitative trait locus (QTL) analysis among 435 segregating (C3H/HeN × CBA/J)F2 (C3HCBAF2) hybrids identified two significant QTLs on chromosomes 1 (Cnes4) and 9 (Cnes5) that control susceptibility to cryptococcal pneumonia in an additive manner. Susceptible C3H/HeN mice carry a resistance allele at Cnes4 and a susceptibility allele at Cnes5. These studies reveal additional genetic complexity of the host response to C. neoformans that is associated with divergent patterns of pulmonary inflammation.
authors.affiliation: Centre for the Study of Host Resistance, McGill University, Montreal, Quebec, Canada.
authors.forename: Scott F
authors.initials: SF
authors.lastname: Carroll
authors.forename: Erin I
authors.initials: EI
authors.lastname: Lafferty
authors.forename: Adam
authors.initials: A
authors.lastname: Flaczyk
authors.forename: T Mary
authors.initials: TM
authors.lastname: Fujiwara
authors.forename: Robert
authors.initials: R
authors.lastname: Homer
authors.forename: Kenneth
authors.initials: K
authors.lastname: Morgan
authors.forename: J C
authors.initials: JC
authors.lastname: Loredo-Osti
authors.forename: Salman T
authors.initials: ST
authors.lastname: Qureshi
mesh_terms: D000818:Animals; D033481:Chromosomes, Mammalian / Q000235:genetics*; D003453:Cryptococcosis / Q000235:genetics* / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D003455:Cryptococcus neoformans / Q000472:pathogenicity*; D016207:Cytokines / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008172:Lung Diseases, Fungal / Q000235:genetics* / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008808:Mice, Inbred CBA; D040641:Quantitative Trait Loci / Q000235:genetics*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D016207:Cytokines