Study takes aim at opportunistic human pathogens

Esophageal tissue infected with Candida (shown in black).A Candida infection of the esophagus, with the invading fungi stained in black.
Image courtesy of the Centers for Disease Control and Prevention

A strong immune system is like an invisible shield, fending off multiple invaders that might otherwise threaten health. Yet cracks in that shield create opportunities for pathogens to take hold, including various species of Candida, a group of fungi related to the otherwise harmless baker’s yeast. Now, new insights into these “opportunists” and how they evade the immune system come from an international effort to decode and analyze the genomes of six Candida species. The research, which appears in the May 24 online issue of Nature, significantly extends the arsenal of genomic information on these organisms and offers some initial clues about what makes some fungi pathogenic and others not.

“Most of what we know about Candida comes from the study of a single species, C. albicans,” said Christina Cuomo, a senior author of the study and a research scientist at the Broad Institute. “But there are at least six other species that together account for nearly half of all Candida infections. Our work is a key step toward deepening our knowledge of these medically important fungi.”

Together with their colleagues, Cuomo and co-senior author Manolis Kellis chose six additional Candida species for whole genome sequencing. These include established and emerging pathogens (C. tropicalis, C. parapsilosis, L. elongisporus, C. guilliermondii, and C. lusitaniae) as well a second strain of C. albicans. To help interpret the information within these genomes, the researchers compared them to eleven previously sequenced fungal genomes, illuminating a broad spectrum of biological and evolutionary diversity. The paper signifies one of the largest comparative genomics studies to date, involving a total of 17 fungal species and spanning more than 500 million years of evolution.

The team’s analyses led to several key findings about Candida genomes and the fundamental elements contained therein. For example, many diploid Candida species, which carry two complete sets of chromosomes, harbor unusually large regions in which both DNA copies are exactly identical (or “homozygous”), suggesting recent recombination events during normal growth or reproductive cycles. The researchers’ comparative methods also helped refine the number of actual genes in the C. albicans genome, adding 91 new genes and removing more than 200 misidentified genes. In addition, complementary studies revealed that some Candida species lack genes controlling reproduction, raising questions about the process and its genetic controls.

Yet perhaps the most significant of the new findings, from the standpoint of human health, involves genes associated with Candida virulence. Because the researchers compared the genomes of both pathogenic and non-pathogenic fungi, they were able to identify groups of genes that track with species’ capacities to cause disease. Matthew Rasmussen, a MIT graduate student and co-author of the study, conducted analyses that highlighted 21 gene families enriched in pathogenic Candida species from among the more than 9,000 Candida gene families. These genes function in processes ranging from cell wall formation and cell adhesion to fungal growth and extracellular transport, as well as several novel families whose roles remain unclear. In addition to interesting biology, these findings suggest potential new therapeutic approaches.

Although future work is needed to extend the findings of this “phylogenomic” approach, the work of Cuomo, Kellis and their collaborators is a critical first step to fully dissect the molecular underpinnings of opportunistic fungal infections.

The work described here is part of the Fungal Genome Initiative at the Broad Institute and was funded by the National Human Genome Research Institute and the National Institute of Allergy and Infectious Diseases among other organizations. Researchers from the Broad Institute who contributed to this research include Bruce Birren, Christina Cuomo, Manfred Grabherr, Manolis Kellis, Chinnappa Kodira, Michael Lin, Sharadha Sakthikumar, and Qiandong Zeng, and members of the Broad Institute’s Genome Sequencing Platform.

Paper(s) cited

Butler G. et al. Evolution of pathogenicity and sexual reproduction in eight Candida genomes. Nature DOI 10.1038/nature08064