VARCAL - Roles of the Candida albicans variome in its interaction with the human host

Overview

Project Summary

It is estimated that Candida albicans infections result on an average of 250,000 to 400,000 deaths per year. This high mortality is the result of nonspecific symptomatology of these infections, difficulties in early and speedy detection of the fungus, increasing resistance to antifungals, aging and increased immunosuppression of the human population. Therefore, it is urgent to increase knowledge about the biology and pathogenesis of infectious fungi to decrease both mortality and morbidity.
Despite the high level of infections, high mortality and associated morbidity, about half of the human population is colonized asymptomatically by C. albicans. Only in circumstances of weakened immune system, hormonal dysregulation, trauma or dysbiosis, can C. albicans take advantage of its commensalism to invade and cause human infection. This is due to the fungus' ability to colonize and survive in various human niches/tissues and to effectively interact and escape human phagocytes. The fact that C. albicans and humans have a common history suggests that they are very well adapted to each other and that the genetic, evolutionary and molecular basis of this adaptation can be unraveled. However, its asexual reproduction, its almost constitutive diploidy, the instability of its genome, somewhat atypical patterns of genomic recombination and clonal accumulation of mutations, complicate the understanding of the genetic and evolutionary biology of this fungus.
In this project we will uncover the genetic diversity of a large population of clinical C. albicans strains and will elucidate the role of such diversity in its colonization and interaction with the human immune system. We have a long track record on the study of genetics, the genome and evolution of C. albicans and other fungi, particularly of its adaptation to a natural change of identity of the CUG codon from leucine to serine, which unveiled of the CTG clade and contributed to understand the biology and evolution of several pathogenic fungi of the sub-phylum Saccharomycotina. We have also participated in the sequencing of the genomes of pathogenic fungi, and contributed to increase the knowledge about fluconazole resistance
pathways through NGS sequencing and genomics bioinformatics approaches. As a whole, the expertise thus acquired constitutes a very solid base of knowledge to tackle the challenges of this project.
We propose the hypothesis that the evolutionary markers present in the genome of C. albicans can be captured and used to identify the genetic variants associated with the adaptation of this fungus to its host, either as a commensal or as a pathogen. To achieve this, a consortium was established between the Genomic Medicine group, of the Aveiro Institute of Biomedicine (iBiMED), and the Medical Microbiology group of CNC/UC, which has a collection of more than 500 clinical isolates of C. albicans, associated clinical data, and methodologies to study their interaction with macrophages.

Main Goals

These strains will be sequenced to:

1) map the genetic and epigenetic variability (variome) of C. albicans populations,

2) identify genetic and epigenetic variants associated with adaptation to multiple human niches and macrophages,

3) identify strains with high virulence levels, and

4) develop methods to stratify patients based on the pathogenicity of the infecting strain.

We aim to contribute, in this way, to the implementation of Personalized Medicine programs for fungal infections.

Project Details