<i>Cryptococcus</i>: The once-sleeping giant is fully awake

In the late 19th century, Cryptococcus neoformans was recognized to be a pathogen of humans and animals, as well as a free-living yeast in the environment (reviewed in Casadevall & Perfect, 1998). However, for a long time afterwards, this fungus interested only a few investigators, in large part because cryptococcosis was a rare disease. Approximately half a century ago, the clinical use of corticosteroids to treat a variety of disease states led to the firm recognition that suppression of cell-mediated immunity was a major risk factor for cryptococcosis. Since then, the number of immunosuppressed persons has increased dramatically, largely due to the HIV epidemic. Worldwide, cryptococcosis ranks as one of the three common life-threatening opportunistic infections in persons with AIDS (Bicanic & Harrison, 2004). Other population groups with impaired T-cell function, particularly those receiving immunosuppression for solid organ transplants, have an up to 6% lifetime risk of developing clinically apparent cryptococcosis. Clearly, cryptococcosis has emerged from relative obscurity. This thematic issue is mainly an outgrowth of the 6th International Conference on Cryptococcus and Cryptococcosis, which was held in Boston, USA, June 24–28, 2005. The articles that follow are representative of the broad diversity of ongoing research in the field. It is worthwhile highlighting some of the exciting advances relating to Cryptococcus and cryptococcosis which have occurred over the past several years. The genome of C. neoformans was fully sequenced, revealing approximately 6500 predicted genes (Loftus, 2005). The genome is rich in transposons, which could help account for the observed phenotypic switching seen both in vitro and in vivo. Moreover, the transcriptome is abundant in alternatively spliced and antisense messages, indicating that double-stranded RNA likely serves as a general regulatory mechanism in the organism. Greater understanding of the genetic structure of C. neoformans strains has led to the elevation of C. neoformans var. gattii to species level. Serotype A and D isolates remain C. neoformans, while serotype B and C isolates are now classified as C. gattii (Kwon-Chung & Varma, 2006). Interestingly, infections due to C. gattii often afflict immunocompetent persons, whereas C. neoformans infects mainly those with impaired T-cell function. The recent availability of a draft genome sequence for C. gattii (http://www.bcgsc.ca/about/news/crypto_public) should facilitate studies seeking to elucidate the molecular basis for this disparity. Whereas C. neoformans is found in the environment worldwide, C. gattii was thought to be geographically restricted to tropical and subtropical regions. However, in 1999, a C. gattii epidemic affecting human and animal populations emerged on Vancouver Island, Canada. A hypervirulent clone accounts for the majority of the fungal isolates. This clone appears to have descended from two α mating-type parents (Fraser, 2005). Cryptococcus has the capacity to undergo sexual reproduction between partners of both the same and opposite mating types (Lin, 2005). Cryptococcus is unique among medically important fungi in its possession of a capsule, which has long been recognized as the organism's major virulence factor. Whereas four serotypes based upon capsular structure have been recognized, recent data suggest considerable heterogeneity in the molecular composition of the major capsular component, glucuronoxylomannan, even among individual strains (Coenjaerts, 2006; McFadden, 2006). A myriad of other putative cryptococcal virulence factors have been described, perhaps most notably melanin production and phospholipase activity. Interesting approaches to identifying novel virulence factors have employed models of cryptococcosis in species of flies, worms and ameba (London, 2006). Aided mainly by the sequencing of the genome, progress has been made defining the proteomics and glycomics of Cryptococcus. A large family of serine- and threonine-rich mannoproteins has been described that appear to be important in cell wall assembly and contribute to the immunogenicity of the fungus (Levitz & Specht, 2006). Many of the genes predicted to be involved in chitin and chitosan synthesis have been identified and knocked out (Banks, 2005). Their gene products, and other glycosyltransferases involved in cell wall and capsule synthesis, make attractive drug targets as most do not have mammalian homologs (Banks, 2005; Klutts, 2006). Morbidity and mortality remain high in cryptococcosis, and a critical challenge will be to develop novel treatments based upon advances in genomics, proteomics and glycomics. An innovative approach to improving outcomes by determining optimal combinations of existing antifungal drugs was described (Brouwer, 2004). Patients with AIDS and cryptococcal meningitis were randomized to different antifungal combinations and the rate of clearance of Cryptococcus from the cerebrospinal fluid measured. Amphotericin B plus flucytosine was the most rapidly fungicidal regimen in vivo. Sit back, relax and enjoy the excellent articles in this thematic issue. However, I caution you to keep your seat belt fastened as further exciting developments in this rapidly advancing field loom on the horizon. The giant is no longer sleeping!

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