F-038. Inheritance of Resistance versus Susceptibility Patterns to Cryptococcus neoformans Infection in a Mouse Model

G-H. Chen1, D. A. McNamara1, Y. Hernandez1, K. C. Tompkins2, G. B. Huffnagle1, G. B. Toews1,2, M. A. Olszewski2,1;
1Univ. of Michigan, Ann Arbor, MI, 2VA Med. Ctr., Ann Arbor, MI.

Background: Resistance/susceptibility to C. neoformans infections vary in different inbred mouse strains. We investigated patterns of inheritance of anti-cryptococcal resistance. Methods: Resistant BALB/c mice, susceptible C57BL/6 mice and their first generation offspring, F1 mice, were infected intratracheally with C. neoformans (104 CFU). Parameters of clearance and immunological response were evaluated. Results: BALB/c mice progressively cleared cryptococcal infection in the lungs, had no CNS dissemination, and showed type 1 (T1)-skewed immune response with a T1 cytokine profile, limited and self-resolving lung pathology, and minimal IgE accumulation. C57BL/6 mice developed a chronic infection, fungemia and some CNS dissemination. These mice showed a T2-skewed immune response with persistent pulmonary eosinophilia, a T2 shifted cytokine profile, systemic IgE accumulation and severe lung pathology. F1 mice demonstrated intermediate clearance/dissemination patterns compared to parental strains; however, at some time-points they differed only from C57BL/6. F1 mice also showed intermediate patterns of immune polarization and intermediate lung pathology. Differential outcomes of the immune responses between mouse strains were consistent with differences in numbers/frequencies of CD4+ and CD8+ T cells. Furthermore, frequencies of activated (CD40high, CD80high and CD86high) dendritic cells in pulmonary lymphonodes were greater in BALB/c mice compared with C57BL/6 mice and intermediate in F1 mice. The detected differences in early induction of IL-12, IFN-γ, IL-4 and TNF-α but not IL-10 in the lungs, could be a source of subsequent differences in polarization of immune response and anti-cryptococcal resistance. Conclusions: Although intermediately resistant, F1 mice can clear the infection. These data are consistent with a complex inheritance of the anti-cryptococcal resistance pattern with some elements of dominance passed down from the resistant BALB/c mice. Differential early cytokine induction and subsequent differential activation of dendritic cells in the regional nodes is most likely responsible for observed differences in immune response polarization.