Comparative Genomics of Serial Isolates of Cryptococcus neoformans Reveals Gene Associated With Carbon Utilization and Virulence

Ormerod, Kate L., Morrow, Carl A., Chow, Eve W. L., Lee, I. Russel, Arras, Samantha D. M., Schirra, Horst Joachim, Cox, Gary M., Fries, Bettina C. and Fraser, James A. (2013) Comparative Genomics of Serial Isolates of Cryptococcus neoformans Reveals Gene Associated With Carbon Utilization and Virulence. G3: Genes, Genomes, Genetics, 3 4: 675-686. doi:10.1534/g3.113.005660


Author Ormerod, Kate L.
Morrow, Carl A.
Chow, Eve W. L.
Lee, I. Russel
Arras, Samantha D. M.
Schirra, Horst Joachim
Cox, Gary M.
Fries, Bettina C.
Fraser, James A.
Title Comparative Genomics of Serial Isolates of Cryptococcus neoformans Reveals Gene Associated With Carbon Utilization and Virulence
Journal name G3: Genes, Genomes, Genetics   Check publisher's open access policy
ISSN 2160-1836
Publication date 2013-04-01
Year available 2013
Sub-type Article (original research)
DOI 10.1534/g3.113.005660
Open Access Status DOI
Volume 3
Issue 4
Start page 675
End page 686
Total pages 12
Place of publication Bethesda, MD United States
Publisher Genetics Society of America
Collection year 2014
Language eng
Formatted abstract
The opportunistic fungal pathogen Cryptococcus neoformans is a leading cause of mortality among the human immunodeficiency virus/acquired immunodeficiency syndrome population and is known for frequently causing life-threatening relapses. To investigate the potential contribution of in-host microevolution to persistence and relapse, we have analyzed two serial isolates obtained from a patient with acquired immunodeficiency syndrome 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 the 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 use, 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.
Keyword Microevolution
Fungal Pathogenesis
Cryptococcosis
Relapse
Candida-Albicans
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Chemistry and Molecular Biosciences
Centre for Advanced Imaging Publications
 
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