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Molecular and Cellular Biology, May 2001, p. 3179-3191, Vol. 21, No. 9
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.9.3179-3191.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Cyclic AMP-Dependent Protein Kinase Controls Virulence of the Fungal Pathogen Cryptococcus neoformans

Cletus A. D'Souza,1 J. Andrew Alspaugh,1,2 Changli Yue,1 Toshiaki Harashima,1,3 Gary M. Cox,2,4 John R. Perfect,2,4 and Joseph Heitman1,2,3,4,5,*

Departments of Genetics,1 Medicine,2 Microbiology,4 and Pharmacology and Cancer Biology,5 and Howard Hughes Medical Institute,3 Duke University Medical Center, Durham, North Carolina 27710

Received 3 November 2000/Returned for modification 5 December 2000/Accepted 29 January 2001

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

* Corresponding author. Mailing address: Department of Genetics, 322 CARL Bldg., Duke University Medical Center, Research Dr., Durham, NC 27710. Phone: (919) 684-2824. Fax: (919) 684-5458. E-mail: heitm001{at}duke.edu.

Molecular and Cellular Biology, May 2001, p. 3179-3191, Vol. 21, No. 9
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.9.3179-3191.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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