Variation in Host Resistance to Blastomyces dermatitidis: Potential Use of Genetic Reference Panels and Advances in Immunophenotyping of Diverse Mouse Strains

Host genetic determinants that underpin variation in susceptibility to systemic fungal infection are poorly understood. Genes responsible for complex traits can be identified by correlating variation in phenotype with allele in founder strains of wild mice with known genetic variation, assembled in genetic reference panels. In this work, we describe wide natural variation in both primary and acquired resistance to experimental pulmonary blastomycosis in eight founder strains, including 129, A/J, BL/6, CAST, NOD, NZO, PWK, and WSB of the Collaborative Cross collection, and the inbred DBA strain. These differences in susceptibility across strains were accompanied by sharp differences in the accumulation and function of immune cells in the lungs. Immune perturbations were mapped by identifying reagents that phenotypically mark immune cell populations in the distinct strains of mice. In particular, we uncovered marked differences between BL/6 and DBA/2 mouse strains in the development of acquired resistance. Our findings highlight the potential value in using genetic reference panels of mice, and particularly the BXD (recombinant inbred strains of mice from a cross of C57BL/6J and DBA/2J mice) collection harboring a cross between resistant BL/6 and susceptible DBA/2 mice, for unveiling genes linked with host resistance to fungal infection. IMPORTANCE Host genetic variation significantly impacts vulnerability to infectious diseases. While host variation in susceptibility to fungal infection with dimorphic fungi has long been recognized, genes that underpin this variation are poorly understood. We used a collection of seven mouse strains that represent nearly 90% of the genetic variation in mice to identify genetic variability among the strains in resistance to pulmonary infection with the dimorphic fungus Blastomyces dermatitidis. We analyzed differences between the strains in innate resistance by infecting naive mice and in acquired resistance by infecting vaccinated mice. We identified extreme variations in both innate and acquired resistance among the strains. In particular, we found sharp differences between C57BL/6 and DBA/2 strains in the ability to acquire vaccine-induced resistance. We also identified commercial reagents that allowed the phenotyping of immune cells from this strain collection of mice. Because there are additional mice harboring a genetic cross of the C57BL/6 and DBA/2 strains (BXD collection), such mice will permit future investigations to identify the genes that underlie differences in the ability to acquire resistance to infection.