A hyper-immunogenic and slow-growing fungal strain induces a murine granulomatous response to cryptococcal infection

Many successful pathogens cause latent infections, remaining dormant within the host for years but retaining the ability to reactivate to cause symptomatic disease. The human opportunistic pathogen Cryptococcus neoformans is a ubiquitous yeast that establishes latent pulmonary infections in immunocompetent individuals upon fungal inhalation from the environment. These latent infections are frequently characterized by granulomas, or foci of chronic inflammation, that contain dormant cryptococcal cells. Immunosuppression causes these granulomas to break down and release viable fungal cells that proliferate, disseminate, and eventually cause lethal cryptococcosis. This course of C. neoformans dormancy and reactivation is understudied due to limited models, as chronic pulmonary granulomas do not typically form in most mouse models of cryptococcal infection. Here, we report that a previously characterized Cryptococcus-specific gene which is required for host-induced cell wall remodeling, MAR1, inhibits murine granuloma formation. Specifically, the mar1Δ loss-of-function mutant strain induces mature pulmonary granulomas at sites of infection dormancy in mice. Our data suggest that the combination of reduced fungal burden and increased immunogenicity of the mar1Δ mutant strain stimulates a host immune response that contains viable fungi within granulomas. Furthermore, we find that the mar1Δ mutant strain has slow growth and hypoxia resistance phenotypes, which may enable fungal persistence within pulmonary granulomas. Together with the conventional primary murine infection model, latent murine infection models will advance our understanding of cryptococcal disease progression and define fungal features important for persistence in the human host.