DNA mutations mediate microevolution between host-adapted forms of the pathogenic fungus Cryptococcus neoformans

Area of Science:

• Mycology
• Pathogen Biology
• Evolutionary Genetics

Background:

• Cryptococcosis is caused by Cryptococcus neoformans, acquired environmentally.
• Environmental predator interactions may select for fungal virulence.
• C. neoformans can switch from yeast to pseudohyphal forms, affecting virulence.

Purpose of the Study:

• Investigate the genetic control of the yeast-pseudohyphal morphological switch in C. neoformans.
• Determine the role of DNA mutation versus epigenetic control in this phenotypic switch.
• Understand the implications of this microevolutionary process for cryptococcosis pathogenesis.

Main Methods:

• Induction of yeast-to-pseudohyphal transition under in vitro and co-incubation conditions.
• Genetic analysis to identify mutations in pseudohyphal strains.
• Phenotypic characterization of wild-type and mutant strains.
• Murine models of cryptococcosis to assess virulence of different morphotypes.

Main Results:

• The yeast-pseudohyphal switch is controlled by DNA mutations in RAM pathway genes, not epigenetic factors.
• High rates of pseudohyphal strain isolation are linked to large RAM genes and a hypermutator phenotype.
• RAM mutants exhibit varied outcomes in mice: clearance, asymptomatic carriage, or reversion to virulent yeast forms.

Conclusions:

• DNA mutation is a key driver of microevolution in C. neoformans, influencing its pathogenic potential.
• The RAM pathway is critical for regulating morphological transitions and virulence.
• Understanding these microevolutionary mechanisms is vital for managing cryptococcosis.