A new cystic fibrosis study, showing a high-resolution picture of the fungal microbiome of cystic fibrosis patients’ lungs, has identified a genetic basis for pathogen adaptation in a fungus exposed to bacteria. The study, entitled “Global Analysis of the Fungal Microbiome in Cystic Fibrosis Patients Reveals Loss of Function of the Transcriptional Repressor Nrg1 as a Mechanism of Pathogen Adaptation,” was recently published in the journal PLOS Pathogens.
Cystic fibrosis (CF) is a genetic disease affecting various organs, but mostly the lungs, and is characterized by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The CFTR mutations result in regular infective pulmonary exacerbations with opportunistic pathogens, including the fungus Candida albicans. The presence of this fungus in CF patients is well-associated with deterioration in lung function; however, the understanding of the species and population dynamics of this fungus is still in its early stages.
Candida albicans is a particularly well-adapted fungus with the ability to change its form depending on its microenvironments, which makes it extremely harmful. The fungus is a frequent resident of the human microbiome, and is especially common in the lungs of cystic fibrosis patients. In a healthy individual, Candida albicans does not induce infection; but in individuals suffering from debilitating conditions such as HIV, organ transplantation, cancer chemotherapy, or cystic fibrosis, whose immune systems are compromised, this opportunistic fungal pathogen can be very dangerous. The health threat is particularly alarming since there are no reliable anti-fungal drugs to fight Candida albicans.
“Fungi have a staggering impact on human health, infecting billions of people around the world and killing 1.5 million every year — that’s in the range of tuberculosis and malaria,” said Leah Cowen, senior study author and a University of Toronto Molecular Genetics professor, in the news release.
For this study, the research team analyzed 89 mucus samples from 28 cystic fibrosis patients, using both high-throughput genetic sequencing as well as culture-based analysis. As expected, Candida albicans genome was prevalent. Surprisingly, this fungus changed form into its stringy shape without any environmental signal. Usually, this transformation, called filamentation, does not occur spontaneously but is triggered by the presence of certain substances, such as blood. To understand this transformation, the researchers sequenced the genomes of these samples and found that all genomes but one had mutations in a common factor, called NRG1, a gene known to inhibit the shape change.
Dr. Cowen said that NRG1 gene makes a protein that functions as a brake on filamentation. She added that the fungi with the genetic mutations were not able to inhibit the filamentation process (the formation of long strings).
To understand why the fungi developed these mutations, the researchers analyzed neighboring pathogens. In cystic fibrosis patients, the airways are infected with other opportunistic pathogens, such as the bacterium Pseudomonas aeruginosa, and certain bacteria secrete molecules to prevent the fungus from changing into its stringy shape. As a result, the researchers exposed the mutated fungus to bacterial pathogens — their rivals — and found that the fungus did not change from its stringy form. The researchers believe that these are strategies developed by fungus and are important for their survival when in contact with bacterial populations.
Dr. Cowen said they believe that the interaction between bacteria and fungus may be the explanation for these observations. “It may be a great defense mechanism for Candida. These fungi have essentially learned to ignore the bacteria,” she concluded.
The research team is currently pursuing studies into the impact of fungal pathogens in cystic fibrosis patients and wants to better understand the role of fungi in a variety of other conditions.