Aimless mutants of Cryptococcus neoformans: failure to disseminate

Abstract

The pathogenic fungus Cryptococcus neoformans exhibits a striking propensity to cause central nervous system (CNS) disease in people with HIV/AIDS. Given that cryptococcal infections are generally initiated by pulmonary colonization, dissemination requires that the fungus withstand phagocytic killing, cross the alveolar-capillary interface in the lung, survive in the circulatory system and breach the blood-brain barrier. We know little about the molecular mechanisms underlying dissemination, but there is a rapidly growing list of mutants that fail to cause CNS disease. These mutants reveal a remarkable diversity of functions and therefore illustrate the complexity of the cryptococcal-host interaction. The challenge now is to extend the analysis of these mutants to acquire a detailed understanding of each step in dissemination.

Figure 1

Dissemination of Cryptococcus across the lung and brain barriers. Cryptococcal cells infiltrate alveoli, passing through the interstitial space and capillary endothelial cells into the blood either as free cells or within alveolar macrophages. Cryptococcal cells traverse the blood-brain barrier to infect the central nervous system within macrophages by a Trojan horse mechanism, transcellularly by crossing though cells or by paracellular traversal between endothelial cells.

Figure 2

Interconnections between functions that influence virulence and/or dissemination in C. neoformans. The diversity of factors is shown to illustrate the involvement lipid and sugar metabolism, and trafficking and signaling components, as well as influences on the elaboration of virulence-related functions. For example, glucose is used to produce trehalose as well as acetyl-CoA, an important intermediate of lipid production. Lipid metabolism supports the formation of diacyl glycerol (DAG) which both affects the transcription of the antiphagocytic protein gene APP1 (Luberto et al., 2003), as well as a cascade of signaling molecules leading to the expression of proteins required for high temperature growth, cell wall integrity and melanin production, as well as other functions. The details for each function are provided in the text and in Table 1.