Lack of an atypical PDR transporter generates an immunogenic Cryptococcus neoformans strain that drives a dysregulated and lethal immune response in murine lungs.

Cryptococcus neoformans is an opportunistic fungal pathogen responsible for >150,000 deaths every year with a mortality rate as high as 81%. This high medical burden is due, in part, to an incomplete understanding of its pathogenesis. In a previous study, we identified a cryptococcal atypical ATP-binding cassette (ABC) pleiotropic drug resistance (PDR) transporter, PDR6, that affected antifungal resistance and host interactions. Here, we follow-up on the role of PDR6 in cryptococcal virulence. In vivo, mice infected with the pdr6Δ strain display altered symptomatology and disease progression. Specifically, we observed a significant increase in the innate immune cell populations in the pdr6Δ-infected mice when compared to their WT-infected littermates. Furthermore, quantification of pulmonary cytokines/chemokines revealed a robust increase of pro-inflammatory cytokines in mice infected with the pdr6Δ mutant strain. Despite the documented sensitivity of the pdr6Δ strain to azole antifungal drugs, the treatment of pdr6Δ-infected animals with antifungals did not affect survival, yet treatment with a corticosteroid significantly extended survival, highlighting the importance of a balanced/controlled host immune response. Results with mice that mount opposing immune responses supports out hypothesis that the pdr6Δ strain induces a hyper-inflammatory immune response, and that the mice succumb to immune-dependent tissue damage rather than the fungal burden. This altered immune response is driven, in part, by changes in the mutant's surface. Taken together, this study provides insights regarding cryptococcal pathogenesis and highlights additional functions of PDR-type ABC transporters in pathogenic fungi.