The hypervirulent Type-1/Type-17 phenotype of Cryptococcus neoformans clinical isolates is specific to A/J mice

Cryptococcus neoformans is a fungal pathogen that causes cryptococcal meningitis in immunocompromised individuals. Both host- and pathogen-specific factors are known to affect patient outcome, and recent studies showed that strain-specific differences in C. neoformans clinical isolates can influence virulence in A/J mice. However, it is unclear how the immunologic and genetic background of inbred mouse strains affects disease outcome during C. neoformans infection. In this study, we show that a hypervirulent phenotype is dependent on the host immune response and mouse genetic background. A/J mice intranasally infected with the hypervirulent isolates, UgCl247, UgCl422, and UgCl236, have increased neutrophil and T-cell recruitment when compared with infection with the reference strain KN99α. In addition, the cytokine profile of the hypervirulent isolates in A/J mice had a profound IFNγ and IL-17 response, and lung resident CD4 T-cells isolated from A/J mice expressed significantly increased Th1 (CXCR3, Tbet) and Th17 (RORγT) markers compared with KN99α infection. Intriguingly, when C57BL/6J mice were infected with these isolates, the hypervirulent phenotype was not evident, and all isolates had virulence comparable to the KN99α control. The immune response in C57BL/6J mice was also nearly identical in response to infections with the hypervirulent isolates and the KN99α control strain. Finally, we determined that the hypervirulent phenotype in A/J mice is not caused by known genetic mutations in the A/J inbred mouse background. Overall, this study demonstrates that an inbred mouse inhalation model can be used to identify host- and pathogen-specific factors that affect C. neoformans disease progression.