Phenotypic switching in Cryptococcus neoformans results in changes in cellular morphology and glucuronoxylomannan structure

Cryptococcus neoformans strains exhibit variability in their capsular polys accharide, cell morphology, karyotype, and virulence, but the relationship between these variables is poorly understood. A hypovirulent C. neoformans 24067A isolate, which usually produces smooth (SM) colony types, was found to undergo phenotypic switching and to produce wrinkled (WR) and pseudohyph al (PH) colony types at frequencies of approximately 10(-4) to 10(-5) when plated on Sabouraud agar. Cells from these colony types had large polysacch aride capsules and PW morphology, respectively. Scanning electron microscop y showed that different colony types were the result of altered cellular pa cking in the colony. Phenotypic switching was associated with quantitative and qualitative changes in capsular polysaccharide. Specifically, the glucu ronoxylomannan (GXM) of the WR polysaccharide differed in the proportion of structural reporter groups and in increased xylose residue content linked at the 4 to 0 position. The? relative virulence of the colony types was WR > PH > SM, as measured by CFU in rat lungs after intratracheal infection. K aryotype instability was observed in strain 24067A and involved primarily t wo chromosomes. Colonies with an alternative colony type exhibited more kar yotype changes, which did not revert to the original karyotype in reverted colonies. In summary, this study revealed that phenotypic switching in C. n eoformans (i) can produce WR colonies consisting of cells with either large capsule or PH morphology, (ii) is associated with production of structural ly different GXM, (iii) is commonly associated with karyotype changes, (iv) can produce cells of PR morphology, and (v) can increase the virulence of a strain. Hence, phenotypic switching is an adaptive mechanism linked to vi rulence that can generate cell types with very different biological charact eristics.