Stochasticity and Bet Hedging Drive Cryptococcal Capsule Dynamics

Cryptococcus neoformans and related species are major human pathogens that cause cryptococcosis, a disease with high mortality and morbidity despite antifungal therapy. Pathogenic Cryptococcus spp. cells express a polysaccharide capsule, which is the most important virulence factor. In this study we analyzed the distribution of capsule sizes for several strains from Cryptococcus spp. and found that they follow stochastic dynamics, with a heavy right-hand tail distribution, favoring larger capsules. The distribution for each strain is remarkably stable despite repeated perturbation of culture conditions including media refreshment, time, and macrophage ingestion. Growth in macrophages resulted in different capsule distributions, observed in vitro, with a suggestion of different polysaccharide-like materials formed or utilized in the resident phagosome. We propose that the stability in capsule size distributions represents a capsulestat mechanism for the population. An emergent property whereby individual cells manifest capsule size variation emanating from random effects on individual capsule assembly steps. This distribution balances between cells with large capsules that are less susceptible to a variety of environmental stresses at the price of slower replication, increased size, and increased energy requirements and cells with smaller, less protective capsules that reproduce faster. Thus, Cryptococcus spp. populations establish a bet hedging strategy that can enhance the viability of the population as conditions change at the cost of optimal short-term growth.