Cryptococcus neoformans (Cn) is a fungal pathogen, commonly found in urban environments (Tampieri, 2006) that primarily affects immunocompromised individuals through inhalation of spores. In healthy individuals Cn infection is usually cleared, or can remain in a latent form for prolonged periods of time. However, in individuals with impaired immune function, the infection may spread to the central nervous system (CNS), causing life-threatening meningitis (Casadevall & Perfect, 1998; Hull & Heitman, 2002). Thus, the disease is relatively common in AIDS patients. A recent study shows that the prevalence of cryptococcosis has declined with the increasing availability of highly active retroviral therapy (HAART) to treat HIV (Lortholary et al., 2006; Mirza et al., 2003). However, the disease continues to be a problem for those with limited access to HAART, especially in the developing world (Banerjee et al., 2001; Marques et al., 2000). Another group of individuals who are susceptible to cryptococcosis are organ transplant recipients receiving immunosuppressive therapy (Husain et al., 2001; Vilchez et al., 2002). However, cryptococcosis is not limited to immunocompromised persons, as shown by the recent outbreak in Vancouver among healthy individuals (Hoang et al., 2004).
Cn is a basidiomycete that normally grows as a haploid-budding yeast. Opposite mating types exist and Cn can undergo sexual reproduction and meiosis to produce spores (Idnurm et al., 2005). Cn strains manifest antigenic differences that allow them to be grouped into five different serotypes (A, B, C, D, and an AD hybrid) as well as different varieties. C. neoformans var. neoformans includes serotypes D and AD while var. grubii includes serotype A and var. gatti includes serotypes B and C. Cn var. neoformans and var. grubii are responsible for the majority of clinical infections in immunocompromised hosts while var. gatti causes disease primarily in immunocompetent hosts (Casadevall & Perfect, 1998; Fraser et al., 2005). Since there are considerable genetic differences among the varieties, it has been suggested that they should be considered separate species (Kwon-Chung & Varma, 2006).
The Cn genome is 19 Mb and contains 6572 genes on 14 chromosomes. Ten percent of the genes have no homologs among sequenced fungi. Some of the key features found in analyzing the genome are a large amount of transposons and
K. Kavanagh (ed.), New Insights in Medical Mycology. © Springer 2007
Figure 6.1 Diagram illustrating a Cn cell and the various factors that contribute to virulence in this fungus. The polysaccharide capsule (blue) is the main virulence factor. It varies on both a macroscopic and molecular level. See text for details on each of these factors
alternative splice variants (Loftus et al., 2005). The genome sequences of the serotype D strains JEC21 and B3501, the serotype A strain H99 and the serotype B strain WM276 involved in the Vancouver outbreak are available through a variety of sources including NCBI, Stanford University (http://www-sequence.stanford. edu/group/C.neoformans/), Oklahoma University (http://www.genome.ou.edu/ cneo.html), Duke University (http://fungal.genome.duke.edu/), Broad Institute (http://www.broad.mit.edu/annotation/genome/cryptococcus_neoformans/Home. html), and Canada's Michael Smith Genome Sciences Centre (http://www.bcgsc. ca/project/cryptococcus).
There are three major sections in this chapter. We first introduce all of the virulence factors of Cn and the factors that affect and regulate virulence (Figure 6.1). Next, we describe the host immune response to Cn. Finally, we discuss possible new treatments for cryptococcosis in patients and future directions of research on Cn.
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