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Infection and Immunity, July 2005, p. 3842-3850, Vol. 73, No. 7
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.7.3842-3850.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Galleria mellonella as a Model System To Study Cryptococcus neoformans Pathogenesis

Eleftherios Mylonakis,1* Roberto Moreno,1 Joseph B. El Khoury,1,3,4 Alexander Idnurm,5 Joseph Heitman,5,6,7,8 Stephen B. Calderwood,1,9 Frederick M. Ausubel,2,10 and Andrew Diener2

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

Received 27 November 2004/ Returned for modification 7 January 2005/ Accepted 26 January 2005

Evaluation of Cryptococcus neoformans virulence in a number of nonmammalian hosts suggests that C. neoformans is a nonspecific pathogen. We used the killing of Galleria mellonella (the greater wax moth) caterpillar by C. neoformans to develop an invertebrate host model system that can be used to study cryptococcal virulence, host immune responses to infection, and the effects of antifungal compounds. All varieties of C. neoformans killed G. mellonella. After injection into the insect hemocoel, C. neoformans proliferated and, despite successful phagocytosis by host hemocytes, killed caterpillars both at 37°C and 30°C. The rate and extent of killing depended on the cryptococcal strain and the number of fungal cells injected. The sequenced C. neoformans clinical strain H99 was the most virulent of the strains tested and killed caterpillars with inocula as low as 20 CFU/caterpillar. Several C. neoformans genes previously shown to be involved in mammalian virulence (CAP59, GPA1, RAS1, and PKA1) also played a role in G. mellonella killing. Combination antifungal therapy (amphotericin B plus flucytosine) administered before or after inoculation was more effective than monotherapy in prolonging survival and in decreasing the tissue burden of cryptococci in the hemocoel. The G. mellonella-C. neoformans pathogenicity model may be a substitute for mammalian models of infection with C. neoformans and may facilitate the in vivo study of fungal virulence and efficacy of antifungal therapies.

* Corresponding author. Mailing address: Division of Infectious Diseases, Massachusetts General Hospital, Gray-Jackson 504, 55 Fruit St., Boston, MA 02114. Phone: (617) 726-3812. Fax: (617) 726-7416. E-mail: emylonakis{at}partners.org.

Editor: T. R. Kozel

Infection and Immunity, July 2005, p. 3842-3850, Vol. 73, No. 7
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.7.3842-3850.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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