Letters to Nature

Nature 412, 83-86 (5 July 2001) | doi:10.1038/35083594; Received 9 February 2001; Accepted 8 May 2001

The glyoxylate cycle is required for fungal virulence

Michael C. Lorenz & Gerald R. Fink

  1. Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA

Correspondence to: Gerald R. Fink Correspondence and requests for materials should be addressed to G.R.F. (e-mail: Email: fink@wi.mit.edu).

Candida albicans, a normal component of the mammalian gastrointestinal flora, is responsible for most fungal infections in immunosuppressed patients. Candida is normally phagocytosed by macrophages and neutrophils, which secrete cytokines and induce hyphal development in this fungus1, 2. Neutropenic patients, deficient in these immune cells, are particularly susceptible to systemic candidiasis3, 4. Here we use genome-wide expression profiles of the related yeast Saccharomyces cerevisiae to obtain a signature of the events that take place in the fungus on ingestion by a mammalian macrophage. Live S. cerevisiae cells isolated from the phagolysosome are induced for genes of the glyoxylate cycle, a metabolic pathway that permits the use of two-carbon compounds as carbon sources. In C. albicans, phagocytosis also upregulates the principal enzymes of the glyoxylate cycle, isocitrate lyase (ICL1) and malate synthase (MLS1). Candida albicans mutants lacking ICL1 are markedly less virulent in mice than the wild type. These findings in fungi, in conjunction with reports that isocitrate lyase is both upregulated and required for the virulence of Mycobacterium tuberculosis 5, 6, demonstrate the wide-ranging significance of the glyoxylate cycle in microbial pathogenesis.