Cellular differentiation, mating, and filamentous growth are regulated in many fungi by environmental and nutritional signals. For example, in response to nitrogen limitation, diploid cells of the yeast Saccharomyces cerevisiae undergo a dimorphic transition to filamentous growth referred to as pseudohyphal differentiation. Yeast filamentous growth is regulated, in part, by two conserved signal transduction cascades: a mitogen-activated protein kinase cascade and a G-protein regulated cyclic AMP signaling pathway. Related signaling cascades play an analogous role in regulating mating and virulence in the plant fungal pathogen Ustilago maydis and the human fungal pathogens Cryptococcus neoformans and Candida albicans. We review here studies on the signaling cascades that regulate development of these and other fungi. This analysis illustrates both how the model yeast S. cerevisiae can serve as a paradigm for signaling in other organisms and also how studies in other fungi provide insights into conserved signaling pathways that operate in many divergent organisms.

Signal Transduction Cascades Regulating Fungal Development and Virulence

Cryptococcus neoformans is a major cause of fungal meningoencephalitis in immunocompromised patients. Despite recent advances in the genetics and molecular biology of C. neoformans, and improved techniques for molecular epidemiology, aspects of the ecology, population structure, and mode of reproduction of this environmental pathogen remain to be established. Application of recent insights into the life cycle of C. neoformans and its different ways of engaging in sexual reproduction under laboratory conditions has just begun to affect research on the ecology and epidemiology of this human pathogenic fungus. The melding of these disparate disciplines should yield rich dividends in our understanding of the evolution of microbial pathogens, providing insights relevant to diagnosis, treatment, and prevention.

The Biology of the Cryptococcus neoformans Species Complex

Cryptococcus neoformans is a human-pathogenic fungus that has evolved into three distinct varieties that infect most prominently the central nervous system. A sexual cycle involving haploid cells of a and alpha mating types has been reported for two varieties (C. neoformans var. neoformans, serotype D, and C. neoformans var. gattii, serotypes B and C), yet the vast majority of infections involve a distinct variety (C. neoformans var. grubii, serotype A) that has been thought to be clonal and restricted to the alpha mating type. We recently identified the first serotype A isolate of the a mating type which had been thought to be extinct (strain 125.91). Here we report that this unusual strain can mate with a subset of pathogenic serotype A strains to produce a filamentous dikaryon with fused clamp connections, basidia, and viable recombinant basidiospores. One meiotic segregant mated poorly with the serotype A reference strain H99 but robustly with a crg1 mutant that lacks a regulator of G protein signaling and is hyperresponsive to mating pheromone. This meiotic segregant was used to create congenic a and alpha mating type serotype A strains. Virulence tests with rabbit and murine models of cryptococcal meningitis showed that the serotype A congenic a and alpha mating type strains had equivalent virulence in animal models, in contrast to previous studies linking the alpha mating type to increased virulence in congenic serotype D strains. Our studies highlight a role for sexual recombination in the evolution of a human fungal pathogen and provide a robust genetic platform to establish the molecular determinants of virulence.

Sexual Cycle of Cryptococcus neoformans var. grubii and Virulence of Congenic a and α Isolates

Cryptococcus neoformans and Cryptococcus gattii are closely related pathogenic fungi that cause pneumonia and meningitis in both immunocompromised and immunocompetent hosts and are a significant global infectious disease risk. Both species are found in the environment and are acquired via inhalation, leading to an initial pulmonary infection. The infectious propagule is unknown but is hypothesized to be small desiccated yeast cells or spores produced by sexual reproduction (opposite- or same-sex mating). Here we characterize the morphology, germination properties, and virulence of spores. A comparative morphological analysis of hyphae and spores produced by opposite-sex mating, same-sex mating, and self-fertile diploid strains was conducted by scanning electron microscopy, yielding insight into hyphal/basidial morphology and spore size, structure, and surface properties. Spores isolated by microdissection were found to readily germinate even on water agarose medium. Thus, nutritional signals do not appear to be required to stimulate spore germination, and as-yet-unknown environmental factors may normally constrain germination in nature. As few as 500 CFU of a spore-enriched infectious inoculum (∼95% spores) of serotype A C. neoformans var. grubii were fully virulent (100% lethal infection) in both a murine inhalation virulence model and the invertebrate model host Galleria mellonella. In contrast to a previous report on C. neoformans var. neoformans, spores of C. neoformans var. grubii were not more infectious than yeast cells. Molecular analysis of isolates recovered from tissues of infected mice (lung, spleen, and brain) provides evidence for infection and dissemination by recombinant spore products. These studies provide a detailed morphological and physiological analysis of the spore and document that spores can serve as infectious propagules.

Spores as Infectious Propagules of Cryptococcus neoformans

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.

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

Gene Disruption by Biolistic Transformation in Serotype D Strains of Cryptococcus neoformans

On the origins of congenic MATalpha and MATa strains of the pathogenic yeast Cryptococcus neoformans.

Cryptococcus neoformans was first recognized as a human pathogen over 100 years ago when it was independently isolated from a patient with a tibial infection and from environmental sources (peach juice). This basidiomycete has subsequently been isolated from most regions of the world, causing a significant number of lethal infections each year, especially in AIDS patients. Originally described as a yeast-like fungus causing human and animal infections, C. neoformans is now known to undergo morphological transitions that are important for its survival and dissemination. Some of the signaling pathways that control yeast and hyphal morphogenesis in this organism are also central regulators of its pathogenesis.

Morphogenesis of Cryptococcus neoformans.

Molecular analysis of the cryptococcus neoformans ade2 gene, a selectable marker for transformation and gene disruption

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Gene Disruption by Biolistic Transformation in Serotype D Strains of Cryptococcus neoformans

On the origins of congenic MATalpha and MATa strains of the pathogenic yeast Cryptococcus neoformans.

Morphogenesis of Cryptococcus neoformans.

Molecular analysis of the cryptococcus neoformans ade2 gene, a selectable marker for transformation and gene disruption