K.J. Kwon-Chung, Ph.D.

Chief, Molecular Microbiology Section
Senior Investigator 

Description of Research Program

The program of the Molecular Microbiology Section is focused on the pathobiology of Cryptococcus neoformans and Aspergillus fumigatus, two of the most common and serious fungal pathogens that primarily affect immunocompromised patients. Both C. neoformans and A. fumigatus are environmental pathogens that cause serious systemic disease upon inhalation. C. neoformans causes meningoencephalitis, and A. fumigatus causes invasive pulmonary aspergillosis; both are fatal unless treated. The fatality rate of these diseases is high even if treated with the most effective antimycotic agents currently available.

Cryptococus neoformans Lifecycle

Researchers have cloned and characterized many genes that are essential for C. neoformans to produce an extracellular polysaccharide capsule, which is the major virulence factor causing central nervous system (CNS) infection. These studies are the first to have met the Molecular Koch's Postulates applied to fungal pathogenicity. By using the human brain microvascular endothelial cells (HBMEC) as an in vitro model of the blood-brain barrier (BBB), investigators have found that yeast cells of C. neoformans cross the BBB transcellularly and that Cps1p, one of the capsule-associated proteins, plays a significant role in the association of yeast cells and endothelial cells. Numerous insertional mutants have been constructed that fail to associate with HBMEC and are being characterized in order to identify the genetic factors of C. neoformans required for invasion of the brain. Researchers also have discovered that the cryptococcal homologs of mammalian SREBP/SCP play an important role in oxygen sensing and are required to produce fulminating CNS infection in mice. These studies will allow the identification of potential targets for prevention and/or therapeutic intervention.

By disrupting a global regulator, TUP1, researchers have discovered that there are fundamental biological differences between MATalpha and MATa strains of C. neoformans and that the gene deletant secreted a novel peptide which functions as a density-dependent, quorum-sensing compound.  Investigators are pursuing the pathobiological significance of the peptide from A. fumigatus.

Aspergillus fumigatus, the most common cause of invasive aspergillosis can be differentiated from those morphologically similar species by producing gliotoxin, a potent mycotoxin that is known to be proapoptotic and immunosuppressive in vitro. Researchers have disrupted the gliP gene which encodes a non-ribosomal peptide synthase essential for the biosynthesis of gliotoxin from A. fumigatus. The resulting gliP knockout strain that produces no gliotoxin was significantly less virulent than the wild type in mice immunosuppressed by corticosteroids. This study confirmed that the mycotoxin plays a role in pathogenesis of aspergillosis.

Awards

International Society of Human and Animal Mycology Award, Lucille George's Award, Medical Mycological Society of Americas Award (Rhoda Benham Award), NIH Director's Award, Distinguished Scholar Award - Ewha Woman University, Sung-Ji Award - Korean National Academy of Science, Compatriot Scholar Award - Korea

Memberships

• American Society for Microbiology
• International Society of Human and Animal Mycology
• Mycological Society of America
• Medical Mycological Society of Americas

Editorial Boards

• Revisita Iberoamericana de Mycologia

Research Group Members

Front row, left to right: Taneisha Jones, Susham Ingavale, June Kwon-Chung, Hyeseung Lee, Janyce Sugui. Back row: Edward Sionov, Ashok Varma, Yun Chang

Selected Publications

(View list in PubMed)

Chang YC, Stins MF, et al. Cryptococcal yeast cells invade the central nervous system via transcellular penetration. Infect Immun. 2004. 72: 4985-4995.

Lee, H., Chang, Y.C. and Kwon-Chung, K.J.: TUP1 reveals biological differences between MATa and MATa strains of Cryptococcus neoformans. Mol. Microbiol. 2005. 55:1222-1232.

Chang, Y.C., Jong, A., Huang, S., Zerfa, P. and Kwon- Chung K.J.: CPS1, a homolog of Streptococcus pneumoniae type 3 polysaccharide synthase gene is important for thepathobiology of Cryptococcus neoformans. Infect. Immun. 2006. 74:3930-3938.

Chang, Y.C.: Bien, C.M., Lee, H., Espenshade, P.J. and Kwon-Chung, K.J.: Sre1p, a regulator of oxygen sensing and sterol homeostasis, is required for virulence in Cryptococcus neoformans. Mol. Microbiol. 2007. 64:614-628.

Lee, H., Chang, Y.C. and Kwon-Chung, K.J.: TUP1 disruption in Cryptococcus neoformans uncovers a peptide-mediated density-dependent growth phenomenon that mimics quorum sensing. Mol. Microbiol. 2007. 64:591-601.

Sugui, J. A., Pardo, J., Chang, Y.C., Zarember, K.A. Nardone, G., Galvez, E.M., Mullbacher, A., Gallin, J., Simon, M. and Kwon-Chung, K.J.: Gliotoxin is a virulence factor of Aspergillus fumigatus: gliP deletion attenuates virulence in mice immunosuppressed with hydrocortisone. Eukaryot. Cell 2007. 6:1486-1496.

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