Cryptococcus gattii comparative genomics and transcriptomics: a NIH/NIAID White Paper

Cryptococcus gattii is an emerging global pathogen. Recent reports suggest that C. gattii cryptococcosis is more common in immunocompetent as well as HIV-infected AIDS patients than earlier estimated. An ongoing outbreak of C. gattii in Vancouver, Canada, and the US Pacific Northwest has heightened public health awareness in North America. We have few clues as to what causes emergence or re-emergence of highly pathogenic strains, why C. gattii split up from its sibling pathogen C. neoformans, why it thrives in trees instead, and why immunocompetent individuals are vulnerable to this pathogen? C. gattii comprises of four distinct lineages, but the information on the genome of C. gattii is inadequate and unrepresentative as it is limited to two strains, R265 and WM276, which are MATα, serotype B, genotype VGII/VGI from Canada and Australia, respectively. There is a wide gap in knowledge about the genomes of VGIII and VGIV strains, serotype C strains, and MATa strains. The geographical representation is inadequate in the absence of strains from California, South America, Asia, and Africa. Additional obstacles to work with this pathogen are the following: (a) complex molecular typing schemes and (b) lack of functional genomics analyses. We propose to complete genome sequencing of 12 reference strains by next-generation sequencing technology and to map their transcriptomes by RNA-Seq technology. This effort would lead to new resources for the scientific community including (1) insight from additional C. gattii genomes to anchor future research studies, (2) validation of single-nucleotide polymorphisms (SNPs) for molecular typing to improve epidemiology studies, and (3) transcript analyses from strains under relevant pathogenic and non-pathogenic conditions to accelerate the discovery of proteins for diagnostics, drug targets, and vaccines.