Mucor circinelloides and Rhizopus oryzae are the most prevalent causal agents of the deadly fungal infection, mucormycosis, which is an emerging disease in immunocompromised patients and the second most common fungal infection in both hematopoietic malignancy patients and transplant recipients. However, considerably less is known about the virulence of these species compared to other fungal pathogens. This study focuses on the genetics of sexual development and pathogenicity of two zygomycete species complexes. In the studies proposed for M. circinelloides, we will investigate the roles of three genes that encode a triose phosphate transporter homolog, HMG domain protein, and RNA helicase in the syntenic sex locus of three related Mucor sub-species. The expression patterns of these genes during sexual development will be investigated. Disruption mutants of each gene and isogenic strains will be generated to test their roles in sexual development. Our recent studies found evidence that the sex locus may be involved in spore size and virulence of M. circinelloides, in which (-) isolates produce more virulent larger spores when compared to (+) isolates. We will investigate how genes in the syntenic sex locus are involved in spore size determination and virulence in three host models: cultured macrophages, the wax moth Galleria mellonella, and the mouse. In parallel, in the studies proposed for R. oryzae, we will establish a typing system to classify R. oryzae and R. delemar that are two sub-species in the R. oryzae complex. The two sub-species will be discriminated at high resolution based on MLST and lactate dehydrogenase gene sequences. Our preliminary studies indicate that R. oryzae is sexual and saprobic, whereas R. delemar is infertile under laboratory conditions and may be more virulent. We will also further test sexuality of the two sub-species as well as virulence in the wax moth and the mouse to investigate links between sexuality and virulence. Understanding the life cycles and detailed phylogeny of these pathogens will greatly enhance our knowledge to develop new drug targets and diagnostic typing approaches, and may provide the means to control human pathogenic zygomycetes.

Public Health Relevance

Mucormycosis is an opportunistic fungal infection recently recognized as emerging cause of infectious disease with a high mortality rate. However, little is known about the relationship of sexual reproduction to pathogenesis in the zygomycetes compared to other fungal pathogens. This project will provide insight to develop novel drug targets, typing methodology to assign species causing infection, and information that can be applied to control zygomycete infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI085331-01A1
Application #
7990472
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Duncan, Rory A
Project Start
2010-05-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
1
Fiscal Year
2010
Total Cost
$234,000
Indirect Cost
Name
Duke University
Department
Genetics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Lee, Soo Chan; Li, Alicia; Calo, Silvia et al. (2015) Calcineurin orchestrates dimorphic transitions, antifungal drug responses and host-pathogen interactions of the pathogenic mucoralean fungus Mucor circinelloides. Mol Microbiol 97:844-65
Lee, Soo Chan; Sun, Sheng; Heitman, Joseph (2014) Unseen sex in ancient virgin fungi. New Phytol 201:3-5
Lee, Soo Chan; Billmyre, R Blake; Li, Alicia et al. (2014) Analysis of a food-borne fungal pathogen outbreak: virulence and genome of a Mucor circinelloides isolate from yogurt. MBio 5:e01390-14
Lee, Soo Chan; Heitman, Joseph (2014) Sex in the Mucoralean fungi. Mycoses 57 Suppl 3:18-24
Lee, Soo Chan; Li, Alicia; Calo, Silvia et al. (2013) Calcineurin plays key roles in the dimorphic transition and virulence of the human pathogenic zygomycete Mucor circinelloides. PLoS Pathog 9:e1003625
Ni, Min; Feretzaki, Marianna; Sun, Sheng et al. (2011) Sex in fungi. Annu Rev Genet 45:405-30
Li, Charles H; Cervantes, Maria; Springer, Deborah J et al. (2011) Sporangiospore size dimorphism is linked to virulence of Mucor circinelloides. PLoS Pathog 7:e1002086
Lee, Soo Chan; Corradi, Nicolas; Doan, Sylvia et al. (2010) Evolution of the sex-related locus and genomic features shared in microsporidia and fungi. PLoS One 5:e10539
Gryganskyi, Andrii P; Lee, Soo Chan; Litvintseva, Anastasia P et al. (2010) Structure, function, and phylogeny of the mating locus in the Rhizopus oryzae complex. PLoS One 5:e15273
Lee, Soo Chan; Ni, Min; Li, Wenjun et al. (2010) The evolution of sex: a perspective from the fungal kingdom. Microbiol Mol Biol Rev 74:298-340