Journal Article

A Multi-Host Approach for the Systematic Analysis of Virulence Factors in Cryptococcus neoformans

Athanasios Desalermos, Xiaojiang Tan, Rajmohan Rajamuthiah, Marios Arvanitis, Yan Wang, Dedong Li, Themistoklis K. Kourkoumpetis, Beth Burgwyn Fuchs and Eleftherios Mylonakis

in The Journal of Infectious Diseases

Published on behalf of Infectious Diseases Society of America

Published in print September 2014 | ISSN: 0022-1899
Published online September 2014 | e-ISSN: 1537-6613 | DOI: https://dx.doi.org/10.1093/infdis/jiu441

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A multi-host approach was followed to screen a library of 1201 signature-tagged deletion strains of Cryptococcus neoformans mutants to identify previously unknown virulence factors. The primary screen was performed using a Caenorhabditis elegansC. neoformans infection assay. The hits among these strains were reconfirmed as less virulent than the wild type in the insect Galleria mellonella–C. neoformans infection assay. After this 2-stage screen, and to prioritize hits, we performed serial evaluations of the selected strains, using the C. elegans model. All hit strains identified through these studies were validated in a murine model of systemic cryptococcosis. Twelve strains were identified through a stepwise screening assay. Among them, 4 (CSN1201, SRE1, RDI1, and YLR243W) were previously discovered, providing proof of principle for this approach, while the role of the remaining 8 genes (CKS101, CNC5600, YOL003C, CND1850, MLH3, HAP502, MSL5, and CNA2580) were not previously described in cryptococcal virulence. The multi-host approach is an efficient method of studying the pathogenesis of C. neoformans. We used diverse model hosts, C. elegans, G. mellonella, and mice, with physiological differences and identified 12 genes associated with mammalian infection. Our approach may be suitable for large pathogenesis screens.

Keywords: Cryptococcus neoformans; Caenorhabditis elegans; Galleria mellonella; pathogenesis; model host; virulence

Journal Article.  4913 words.  Illustrated.

Subjects: Infectious Diseases ; Immunology ; Public Health and Epidemiology ; Microbiology