Cryptococcus neoformans Kin1 protein kinase homologue, identified through a Caenorhabditis elegans screen, promotes virulence in mammals

doi:10.1111/j.1365-2958.2004.04310.x

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Wiley InterScience

Molecular Microbiology

Volume 54 Issue 2, Pages 407 - 419

Published Online: 6 Sep 2004

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Cryptococcus neoformans Kin1 protein kinase homologue, identified through a Caenorhabditis elegans screen, promotes virulence in mammals

Eleftherios Mylonakis ¹ , Alexander Idnurm ² , Roberto Moreno ¹ , Joseph El Khoury ^1,3,4 , James B. Rottman ⁵ , Frederick M. Ausubel ^6,7 , Joseph Heitman ^2,8,9,10 and Stephen B. Calderwood ^1,11*

¹ Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 02114, USA.
² Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
³ Center for Immunology and Inflammatory Diseases, and
⁴ Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵ Archemix Corporation, Cambridge, MA 02139, USA.
⁶ Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
⁷ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
⁸ Division of Infectious Diseases,
⁹ Department of Medicine, and
¹⁰ Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
¹¹ Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115, USA.

Correspondence to *E-mail scalderwood@partners.org; Tel. (+1) 617 726 3811; Fax (+1) 617 726 7416.

Summary

Cryptococcal infections are a global cause of significant morbidity and mortality. Recent studies support the hypothesis that virulence of Cryptococcus neoformans may have evolved via survival selection in environmental hosts, such as amoebae and free-living nematodes. We used killing of the nematode Caenorhabditis elegans by C. neoformans as an assay to screen a library of random C. neoformans insertion mutants. Of 350 mutants tested, seven were identified with attenuated virulence that persisted after crossing the mutation back into a wild-type strain. Genetic analysis of one strain revealed an insertion in a gene homologous to Saccharomyces cerevisiae KIN1, which encodes a serine/threonine protein kinase. C. neoformans kin1 mutants exhibited significant defects in virulence in murine inhalation and haematogenous infection models and displayed increased binding to alveolar and peritoneal macrophages. The kin1 mutant phenotypes were complemented by the wild-type KIN1 gene. These findings show that the C. neoformans Kin1 kinase homologue is required for full virulence in disparate hosts and that C. elegans can be used as a substitute host to identify novel factors involved in fungal pathogenesis in mammals.