It’s what's on the menu that counts

Though it may not seem obvious, fungi are the sister group to animals on the tree of life. Unlike bacteria, which are an entirely different part of the tree of life, fungi are nestled in with eukaryotes close to humans and other animals. Because of that they share a lot of common biological pathways. To treat a fungal infection successfully, without eliciting undue harm to its human host, one needs to find out what makes them different from animals.

A collaborative team of researchers, led by those at the Broad Institute, searched for such differences for a particular group of pathogenic fungi, called Paracoccidioides. These fungi most commonly found in Venezuela and Brazil cause pulmonary infections called paracoccidioidomycoses in otherwise very healthy people. As part of research sponsored by the National Institute of Allergy and Infectious Diseases, Broad researchers are investigating this pathogen and two others that share a common lifecycle that includes two forms. Known as dimorphic fungi for their ability to grow in filamentous form in soil and in yeast form after infection in humans, they cause respiratory illnesses classified as neglected tropical diseases. Dimorphic fungi are the most common causes of pulmonary infection due to fungal infection in otherwise healthy hosts.

Researchers have known that the shift in growth form is temperature-related but they wanted to know if the Paracoccidioides genome would surrender any hints about how the fungi have adapted to grow in people. To do so, the team sequenced the genome of three Paracoccidioides strains, the first time this has been done. By comparing the genomes of these fungi to others with a similar lifestyle, and looking for differences between them, researchers found two important clues. Paracoccidioides genomes and other dimorphic fungi contain many more regions coding for protein-degrading enzymes (proteases) than carbohydrate-degrading enzymes compared to related fungi such as Aspergilli. “This shift suggests that the proteases might be an adaptation important for growth of these fungi in the human host,” explains Christina Cuomo, leader of the fungal genome analysis group at the Broad Institute. This work is published in a paper in the current issue of PLoS Genetics.

To confirm that the genome results were predictive of real-life growth preferences, the team grew isolates of a Paracoccidioides body-double called Uncinocarpus on different proteins and carbohydrates to see what it preferred. (Uncinocarpus is a close relative of Paracoccidioides but it is nonpathogenic and therefore safer to work with).

The results show that the Paracoccidioides mimic grew very well on many of the amino acids and peptides but not as well on the carbohydrates suggesting a dietary preference for proteins over carbohydrates. “From that we conclude that this preference may be what gives Paracoccidioides its ability to grow on animal hosts and become invasive pathogens,” says Christina.

Looking deeper, the team found a genome innovation specific to the Paracoccidioides species: many extra copies of a gene for a fungal-specific kinase enzyme. “While we don’t yet know the function of these kinases, patterns in their sequences near the predicted active site give clues as to what the kinases might bind to,” says lead author Chris Desjardins, a bioinformatics specialist at the Broad. The unexpectedly large number of gene copies could indicate that modification of these enzyme targets is a potentially important activity for this pathogen.

As part of its work on dimorphic fungi, the Broad team has recently sequenced the genomes for two other fungi – Blastomyces and Histoplasma – in attempts to learn more about their growth adaptations. This work was supported through the NIAID-funded Broad Institute Genome Sequencing Center for Infectious Disease