Ovoid cell is an inducible small-sized morphotype that enhances proliferation and antifungal drug tolerance in the human fungal pathogen Cryptococcus neoformans

Cryptococcus neoformans is the leading cause of fungal meningoencephalitis. Cellular heterogeneity during cryptococcal infection contributes to host adaptation and fungal pathogenesis. C. neoformans titan cells and seed cells represent enlarged and small-sized morphotypes, respectively, which exhibit distinct transcriptional profiles and can be induced by environmental factors. In this work, we describe a distinct small morphotype of C. neoformans, referred to as ovoid cells. The formation of ovoid cells is promoted by host-related conditions such as nutrient limitation and elevated CO2 levels, which was observed during the late stage of cryptococcal infection. In addition to their smaller size compared to typical yeast cells, ovoid cells highly express OSP1, a marker distinguishes ovoid cells from other small morphotypes, including seed cells and titanides. These cells exhibit an increased budding and proliferation rate, which is consistent with transcriptome data that ovoid cells upregulate cell cycle related genes. We further demonstrate that the glucose repression signaling pathway and the cAMP/PKA pathway are involved in ovoid cell formation in C. neoformans. Ovoid cells show reduced fungal virulence but enhanced tolerance under long-term fluconazole treatment, indicating their important role in the balancing virulence and antifungal tolerance within C. neoformans populations.