Damian Krysan, MD, PhD

Portrait
Director, Division of Pediatric Infectious Disease
Professor of Pediatrics - Infectious Disease
Professor of Microbiology and Immunology

Contact Information

Primary Office
2040E ML
200 Hawkins Drive
Iowa City, IA 52242
319-356-2270

Education

BA, Chemistry, Grinnell College
Other, Medicine, University of South Dakota School of Medicine
PhD, Organic Chemistry, Northwestern University
MD, Medicine, University of Michigan
Postdoctoral Fellow, Department of Chemistry, Emory University
Internship, C.S. Mott Children's Hospital/ University of Michigan
Resident, C.S. Mott Children's Hospital/ University of Michigan
Fellow, University of Michigan, C.S. Mott Hospital

Licensure and Certifications

American Board of Pediatrics; Sub-board of Pediatric Infectious Disease
American Board of Pediatrics

Research Summary

The Krysan lab is interested in understanding how pathogenic fungi cause disease; how the host defends itself against these fungal pathogens; and how to develop new therapies for human fungal diseases. We use a combination of genetic, chemical-genetic, cell biological, and biochemical methods to investigate questions related to these topics. Currently, we are focused on three human fungal pathogens: Candida albicans, the most common human fungal pathogen; Cryptococcus neoformans, the most important cause of life-threatening fungal disease in those living with HIV/AIDS; and Aspergillus fumigatus, an important cause of mold infections in a range of patient populations. We have recently developed a set of genetic tools to probe the transcriptional networks that allow C. albicans to cause mucosal disease. In collaboration with Dr. Melanie Wellington, we are combining these tools with novel methods to directly image and assess C. albicans infections in mammals using confocal microscopy. Also, in collaboration with Dr. Wellington, we are investigating the role of the cytokines IL-1alpha/beta in the host response to C. albicans. Finally, we use high throughput screening approaches to identify novel antifungal small molecules. Highly active molecules are then evaluated in a pipeline of pre-clinical testing that leads to initial in vivo efficacy studies in mammalian models of candidiasis and cryptococcosis. Recently, our work has led to the initiation of a Phase II clinical trial to test the ability of tamoxifen to improve current therapy of cryptococcal meningitis in HIV/AIDS patients (NCT03112031).

Publications

Glazier, V. E., Murante, T., Koselny, K., Murante, D., Esqueda, M., Wall, G. A., Wellington, M., Hung, C. Y., Kumar, A. & Krysan, D. J. (2018). Systematic Complex Haploinsufficiency-Based Genetic Analysis of Candida albicans Transcription Factors: Tools and Applications to Virulence-Associated Phenotypes. G3 (Bethesda, Md.), 8(4), 1299-1314. PMID: 29472308.

Glazier, V. E., Krysan, D. J. (2018). Transcription factor network efficiency in the regulation of Candida albicans biofilms: it is a small world. Current genetics. PMID: 29318385.

Montoya, M. C., DiDone, L., Heier, R. F., Meyers, M. J. & Krysan, D. J. (2017). Antifungal Phenothiazines: Optimization, Characterization of Mechanism, and Modulation of Neuroreceptor Activity. ACS infectious diseases. PMID: 29058407.

Xie, J. L., Qin, L., Miao, Z., Grys, B. T., Diaz, J. C., Ting, K., Krieger, J. R., Tong, J., Tan, K., Leach, M. D., Ketela, T., Moran, M. F., Krysan, D. J., Boone, C., Andrews, B. J., Selmecki, A., Ho Wong, K., Robbins, N. & Cowen, L. E. (2017). The Candida albicans transcription factor Cas5 couples stress responses, drug resistance and cell cycle regulation. Nature communications, 8(1), 499. PMID: 28894103.

Glazier, V. E., Murante, T., Murante, D., Koselny, K., Liu, Y., Kim, D., Koo, H. & Krysan, D. J. (2017). Genetic analysis of the Candida albicans biofilm transcription factor network using simple and complex haploinsufficiency. PLoS genetics, 13(8), e1006948. PMID: 28793308.

Hwang, G., Liu, Y., Kim, D., Li, Y., Krysan, D. J. & Koo, H. (2017). Candida albicans mannans mediate Streptococcus mutans exoenzyme GtfB binding to modulate cross-kingdom biofilm development in vivo. PLoS pathogens, 13(6), e1006407. PMID: 28617874.

Krysan, D. J. (2017). The unmet clinical need of novel antifungal drugs. (Vols. 8). (2), pp. 135-137. Virulence. PMID: 28095189.

Blanchard, C., Brooks, L., Ebsworth-Mojica, K., Didione, L., Wucher, B., Dewhurst, S., Krysan, D., Dunman, P. M. & Wozniak, R. A. (2016). Zinc Pyrithione Improves the Antibacterial Activity of Silver Sulfadiazine Ointment. mSphere, 1(5). PMID: 27642637.

Krysan, D. J. (2016). Challenges in the development of novel anticryptococcal agents. (Vols. 8). (12), pp. 1375-7. Future medicinal chemistry. PMID: 27485948.

Saputo, S., Norman, K. L., Murante, T., Horton, B. N., Diaz Jde, L., DiDone, L., Colquhoun, J., Schroeder, J. W., Simmons, L. A., Kumar, A. & Krysan, D. J. (2016). Complex Haploinsufficiency-Based Genetic Analysis of the NDR/Lats Kinase Cbk1 Provides Insight into Its Multiple Functions in Candida albicans. Genetics, 203(3), 1217-33. PMID: 27206715.

Koselny, K., Green, J., Favazzo, L., Glazier, V. E., DiDone, L., Ransford, S. & Krysan, D. J. (2016). Antitumor/Antifungal Celecoxib Derivative AR-12 is a Non-Nucleoside Inhibitor of the ANL-Family Adenylating Enzyme Acetyl CoA Synthetase. ACS infectious diseases, 2(4), 268-280. PMID: 27088128.

Hartland, K., Pu, J., Palmer, M., Dandapani, S., Moquist, P. N., Munoz, B., DiDone, L., Schreiber, S. L. & Krysan, D. J. (2016). High-Throughput Screen in Cryptococcus neoformans Identifies a Novel Molecular Scaffold That Inhibits Cell Wall Integrity Pathway Signaling. ACS infectious diseases, 2(1), 93-102. PMID: 26807437.

Forbes, L., Ebsworth-Mojica, K., DiDone, L., Li, S. G., Freundlich, J. S., Connell, N., Dunman, P. M. & Krysan, D. J. (2015). A High Throughput Screening Assay for Anti-Mycobacterial Small Molecules Based on Adenylate Kinase Release as a Reporter of Cell Lysis. PloS one, 10(6), e0129234. PMID: 26098625.

Butts, A., Martin, J. A., DiDone, L., Bradley, E. K., Mutz, M. & Krysan, D. J. (2015). Structure-activity relationships for the antifungal activity of selective estrogen receptor antagonists related to tamoxifen. PloS one, 10(5), e0125927. PMID: 26016941.

Brown JCS,, Nelson, J., VanderSluis, B., Deshpande, R., Butts, A., Kagan, S., Polacheck, I., Krysan, D. J., Myers, C. L. & Madhani, H. D. (2014). Unraveling the biology of a fungal meningitis pathogen using chemical genetics. Cell, 159(5), 1168-1187. PMID: 25416953.

Perlmutter, J. I., Forbes, L. T., Krysan, D. J., Ebsworth-Mojica, K., Colquhoun, J. M., Wang, J. L., Dunman, P. M. & Flaherty, D. P. (2014). Repurposing the antihistamine terfenadine for antimicrobial activity against Staphylococcus aureus. Journal of medicinal chemistry, 57(20), 8540-62. PMID: 25238555.

Saputo, S., Kumar, A. & Krysan, D. J. (2014). Efg1 directly regulates ACE2 expression to mediate cross talk between the cAMP/PKA and RAM pathways during Candida albicans morphogenesis. Eukaryotic cell, 13(9), 1169-80. PMID: 25001410.

Falsetta, M. L., Klein, M. I., Colonne, P. M., Scott-Anne, K., Gregoire, S., Pai, C. H., Gonzalez-Begne, M., Watson, G., Krysan, D. J., Bowen, W. H. & Koo, H. (2014). Symbiotic relationship between Streptococcus mutans and Candida albicans synergizes virulence of plaque biofilms in vivo. Infection and immunity, 82(5), 1968-81. PMID: 24566629.

Butts, A., Koselny, K., Chabrier-Roselló, Y., Semighini, C. P., Brown, J. C., Wang, X., Annadurai, S., DiDone, L., Tabroff, J., Childers, Jr, W. E., Abou-Gharbia, M., Wellington, M., Cardenas, M. E., Madhani, H. D., Heitman, J. & Krysan, D. J. (2014). Estrogen receptor antagonists are anti-cryptococcal agents that directly bind EF hand proteins and synergize with fluconazole in vivo. mBio, 5(1), e00765-13. PMID: 24520056.

Wellington, M., Koselny, K., Sutterwala, F. S. & Krysan, D. J. (2014). Candida albicans triggers NLRP3-mediated pyroptosis in macrophages. Eukaryotic cell, 13(2), 329-40. PMID: 24376002.

Butts, A., DiDone, L., Koselny, K., Baxter, B. K., Chabrier-Rosello, Y., Wellington, M. & Krysan, D. J. (2013). A repurposing approach identifies off-patent drugs with fungicidal cryptococcal activity, a common structural chemotype, and pharmacological properties relevant to the treatment of cryptococcosis. Eukaryotic cell, 12(2), 278-87. PMID: 23243064.

Jacobs, A. C., Didone, L., Jobson, J., Sofia, M. K., Krysan, D. & Dunman, P. M. (2013). Adenylate kinase release as a high-throughput-screening-compatible reporter of bacterial lysis for identification of antibacterial agents. Antimicrobial agents and chemotherapy, 57(1), 26-36. PMID: 23027196.

Chabrier-Roselló, Y., Gerik, K. J., Koselny, K., DiDone, L., Lodge, J. K. & Krysan, D. J. (2013). Cryptococcus neoformans phosphoinositide-dependent kinase 1 (PDK1) ortholog is required for stress tolerance and survival in murine phagocytes. Eukaryotic cell, 12(1), 12-22. PMID: 23087368.

Wellington, M., Koselny, K. & Krysan, D. J. (2012). Candida albicans morphogenesis is not required for macrophage interleukin 1ß production. mBio, 4(1), e00433-12. PMID: 23269828.

DiDone, L., Oga, D. & Krysan, D. J. (2011). A novel assay of biofilm antifungal activity reveals that amphotericin B and caspofungin lyse Candida albicans cells in biofilms. Yeast (Chichester, England), 28(8), 561-8. PMID: 21674619.

Baxter, B. K., DiDone, L., Ogu, D., Schor, S. & Krysan, D. J. (2011). Identification, in vitro activity and mode of action of phosphoinositide-dependent-1 kinase inhibitors as antifungal molecules. ACS chemical biology, 6(5), 502-10. PMID: 21294551.

Bharucha, N., Chabrier-Rosello, Y., Xu, T., Johnson, C., Sobczynski, S., Song, Q., Dobry, C. J., Eckwahl, M. J., Anderson, C. P., Benjamin, A. J., Kumar, A. & Krysan, D. J. (2011). A large-scale complex haploinsufficiency-based genetic interaction screen in Candida albicans: analysis of the RAM network during morphogenesis. PLoS genetics, 7(4), e1002058. PMID: 22103005.

Miller, K. A., DiDone, L. & Krysan, D. J. (2010). Extracellular secretion of overexpressed glycosylphosphatidylinositol-linked cell wall protein Utr2/Crh2p as a novel protein quality control mechanism in Saccharomyces cerevisiae. Eukaryotic cell, 9(11), 1669-79. PMID: 20833895.

DiDone, L., Scrimale, T., Baxter, B. K. & Krysan, D. J. (2010). A high-throughput assay of yeast cell lysis for drug discovery and genetic analysis. Nature protocols, 5(6), 1107-14. PMID: 20539286.

Dolan, K., Montgomery, S., Buchheit, B., Didone, L., Wellington, M. & Krysan, D. J. (2009). Antifungal activity of tamoxifen: in vitro and in vivo activities and mechanistic characterization. Antimicrobial agents and chemotherapy, 53(8), 3337-46. PMID: 19487443.

Wellington, M., Dolan, K. & Krysan, D. J. (2009). Live Candida albicans suppresses production of reactive oxygen species in phagocytes. Infection and immunity, 77(1), 405-13. PMID: 18981256.

Scrimale, T., Didone, L., de Mesy Bentley, K. L. & Krysan, D. J. (2009). The unfolded protein response is induced by the cell wall integrity mitogen-activated protein kinase signaling cascade and is required for cell wall integrity in Saccharomyces cerevisiae. Molecular biology of the cell, 20(1), 164-75. PMID: 18971375.

Krysan, D. J., Didone, L. (2008). A high-throughput screening assay for small molecules that disrupt yeast cell integrity. Journal of biomolecular screening, 13(7), 657-64. PMID: 18626115.

Ma, J., Dobry, C. J., Krysan, D. J. & Kumar, A. (2008). Unconventional genomic architecture in the budding yeast saccharomyces cerevisiae masks the nested antisense gene NAG1. Eukaryotic cell, 7(8), 1289-98. PMID: 18310357.

Vadaie, N., Dionne, H., Akajagbor, D. S., Nickerson, S. R., Krysan, D. J. & Cullen, P. J. (2008). Cleavage of the signaling mucin Msb2 by the aspartyl protease Yps1 is required for MAPK activation in yeast. The Journal of cell biology, 181(7), 1073-81. PMID: 18591427.

Krysan, D. J., Ting, E. L., Abeijon, C., Kroos, L. & Fuller, R. S. (2005). Yapsins are a family of aspartyl proteases required for cell wall integrity in Saccharomyces cerevisiae. Eukaryotic cell, 4(8), 1364-74. PMID: 16087741.

Rozan, L., Krysan, D. J., Rockwell, N. C. & Fuller, R. S. (2004). Plasticity of extended subsites facilitates divergent substrate recognition by Kex2 and furin. The Journal of biological chemistry, 279(34), 35656-63. PMID: 15159396.

Krysan, D. J., Kemper, A. R. (2002). Claims of equivalence in randomized controlled trials of the treatment of bacterial meningitis in children. The Pediatric infectious disease journal, 21(8), 753-8. PMID: 12192164.

Krysan, D. J., Flynn, J. T. (2001). Renal transplantation after Streptococcus pneumoniae-associated hemolytic uremic syndrome. American journal of kidney diseases : the official journal of the National Kidney Foundation, 37(2), E15. PMID: 11157401.

Rockwell, N. C., Krysan, D. J. & Fuller, R. S. (2000). Synthesis of peptidyl methylcoumarin esters as substrates and active-site titrants for the prohormone processing proteases Kex2 and PC2. Analytical biochemistry, 280(2), 201-8. PMID: 10790301.

Krysan, D. J., Rockwell, N. C. & Fuller, R. S. (1999). Quantitative characterization of furin specificity. Energetics of substrate discrimination using an internally consistent set of hexapeptidyl methylcoumarinamides. The Journal of biological chemistry, 274(33), 23229-34. PMID: 10438496.