Adaptation of Cryptococcus neoformans to mammalian hosts: integrated regulation of metabolism and virulence

Abstract

The basidiomycete fungus Cryptococcus neoformans infects humans via inhalation of desiccated yeast cells or spores from the environment. In the absence of effective immune containment, the initial pulmonary infection often spreads to the central nervous system to result in meningoencephalitis. The fungus must therefore make the transition from the environment to different mammalian niches that include the intracellular locale of phagocytic cells and extracellular sites in the lung, bloodstream, and central nervous system. Recent studies provide insights into mechanisms of adaptation during this transition that include the expression of antiphagocytic functions, the remodeling of central carbon metabolism, the expression of specific nutrient acquisition systems, and the response to hypoxia. Specific transcription factors regulate these functions as well as the expression of one or more of the major known virulence factors of C. neoformans. Therefore, virulence factor expression is to a large extent embedded in the regulation of a variety of functions needed for growth in mammalian hosts. In this regard, the complex integration of these processes is reminiscent of the master regulators of virulence in bacterial pathogens.

Fig 1

Regulatory factors that influence expression of two major virulence factors, melanin and capsule. The GATA factors Cir1, Gat201, and Gat1, along with Tup1, show a reciprocal regulation of capsule and melanin. As described in the text and Table 1, many of the regulators directly or indirectly influence the expression of iron uptake functions, including Cir1, Gat201, Nrg1, Rim101, Sre1, Tup1, and Cuf1 (blue background). In addition, Cir1, Rim101, Sre1, Tup1, and Cuf1 influence copper homeostasis (gray background). However, as also indicated in Table 1, these factors influence the expression of genes in many other functional categories. The impact on capsule and melanin is shown for all of the factors in the serotype A background, based on the phenotypes of the corresponding mutants. The photographs show a highly melanized colony of C. neoformans grown on medium containing l-3,4-dihydroxyphenylalanine (∼4 mm in diameter) and a cell stained for capsule polysaccharide with India ink (∼10 μm in diameter).