Cyclic AMP-dependent protein kinase controls virulence of the fungal pathogen Cryptococcus neoformans

Cryptococcus neoformans is an opportunistic fungal pathogen that infects th e human central nervous system. This pathogen elaborates two specialized vi rulence factors: the antioxidant melanin and an antiphagocytic immunosuppre ssive polysaccharide capsule. A signaling cascade controlling mating and vi rulence was identified. The PKA1 gene encoding the major cyclic AMP (cAMP)- dependent protein kinase catalytic subunit was identified and disrupted. pk a1 mutant strains were sterile, failed to produce melanin or capsule, and w ere avirulent. The PKR1 gene encoding the protein kinase A (PKA) regulatory submit was also identified and disrupted. pkr1 mutant strains overproduced capsule and were hypervirulent in animal models of cryptococcosis. pkr1 pk a1 double mutant strains exhibited phenotypes similar to that of pka1 mutan ts, providing epistasis evidence that the Pka1 catalytic subunit functions downstream of the Pkr1 regulatory subunit. The PKA pathway was also shown t o function downstream of the G alpha protein Gpa1 and to regulate cAMP prod uction by feedback inhibition. These findings define a G alpha protein-cAMP -PKA signaling pathway regulating differentiation and virulence of a human fungal pathogen.