Author(s): Ormerod KL, Morrow CA, Chow EW, Lee IR, Arras SD,
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Abstract The opportunistic fungal pathogen Cryptococcus neoformans is a leading cause of mortality amongst the HIV/AIDS population, and is known for frequently causing life-threatening relapse. To investigate the potential contribution of in-host microevolution to persistence and relapse we have analyzed two serial isolates obtained from an AIDS patient who suffered an initial and relapse episode of cryptococcal meningoencephalitis. Despite being identical by multilocus sequence typing, the isolates differ phenotypically, exhibiting changes in key virulence factors, nutrient acquisition, metabolic profiles and ability to disseminate in an animal model. Whole genome sequencing uncovered a clonal relationship, with only a few unique differences. Of these, two key changes are expected to explain the phenotypic differences observed in the relapse isolate: loss of a predicted AT-rich interaction domain protein, and changes in copy number of the left and right arms of chromosome 12. Gene deletion of the predicted transcriptional regulator produced changes in melanin, capsule, carbon source utilization and dissemination in the host, consistent with the phenotype of the relapse isolate. In addition, the deletion mutant displayed altered virulence in the murine model. The observed differences suggest the relapse isolate evolved subsequent to penetration of the central nervous system and may have gained dominance following the administration of antifungal therapy. These data reveal the first molecular insights into how the Cryptococcus neoformans genome changes during infection of humans and the manner in which microevolution progresses in this deadly fungal pathogen.
This article was published in G3 (Bethesda)
and referenced in Fungal Genomics & Biology