Inbred SJL mice recapitulate human resistance to Cryptococcus infection due to differential immune activation

Cryptococcosis remains a significant threat to human health. While the popular C57BL/6J mouse model of cryptococcosis has some advantages, there are some serious shortcomings that limit the ability of researchers to address the disease. Since humans are resistant to environmental cryptococcal infection until rendered immunodeficient while C57BL/6J mice are innately susceptible, we screened 15 inbred mouse strains for resistance to Cryptococcus infection. The SJL/J mouse strain was unusually resistant to several virulent strains of Cryptococcus while the closely related FVB/J strain was susceptible. The infection pathobiology in SJL/J mice and susceptible mice was similar for the first 7-10 days then markedly diverged toward pathogen clearance. Interferon-gamma (IFN-gamma) expression was critical for SJL/J resistance while tumor necrosis factor-alpha was also important. Both CD4 and CD8 T cells produced IFN-gamma and were collectively critical. While IL-17 and associated cytokines were expressed in SJL/J mice, IL-17 inhibition did not affect the outcome of infection. Unlike the C57BL/6J, infected SJL/J mice failed to express Th2/atopy-type cytokines even when rendered susceptible by IFN-gamma blockade or infection with an alternative fatal cryptococcal strain virulent in SJL/J. These data suggest that the atopic-type response typically associated with the C57BL/6J model is not critical for susceptibility. The productive immune response in SJL/J mice resulted in immune memory that protected mice from reinfection. The SJL/J cryptococcal resistance phenotype was associated with a strong genetic linkage from regions located in chromosomes 2 and 11 suggesting strain-specific modifiers contribute to disease severity. Thus, SJL/J mice are an exciting alternative animal model for cryptococcal pathobiology.