Fetal bovine serum-triggered Titan cell formation and growth inhibition are unique to the Cryptococcus species complex

In the genus Cryptococcus, C. neoformans and C. gattii stand out by the number of virulence factors that allowed those fungi to achieve evolutionary success as pathogens. Among the factors contributing to cryptococcosis is a peculiar morphological transition to form giant (Titan) cells. Formation of Titans has been described in vitro. However, it remains unclear whether non-C. neoformans/non-C. gattii species are capable of titanisation. Based on a survey of several basidiomycetous yeasts, we propose that titanisation is unique to C. neoformans and C. gattii. In addition, we find that under in vitro conditions that induce titanisation, fetal bovine serum (FBS) possesses activity that inhibits growth of C. gattii and kills C. neoformans if incubation is conducted in the absence of 5% CO2. Moreover, lowering of pH or addition of an antioxidant, rescues growth in the presence of FBS and allows titanisation even in the absence of 5% CO2. Strikingly, acapsular mutants, cap10{Delta} and cap59{Delta}, show complete or partial reduction of titanisation, respectively and a partial resistance to growth inhibition imposed by the FBS. Our data implicate titanisation as a unique feature of C. neoformans and C. gattii and provide novel insights about the nature of this unusual morphological transition.