Computational Analysis Reveals a Key Regulator of Cryptococcal Virulence and Determinant of Host Response

Gish, Stacey R.; Maier, Ezekiel J.; Haynes, Brian C.; Santiago-Tirado, Felipe H.; Srikanta, Deepa L.; Ma, Cynthia Z.; Li, Lucy X.; Williams, Matthew; Crouch, Erika C.; Khader, Shabaana A.; Brent, Michael R.; Doering, Tamara L.

doi:10.1128/mBio.00313-16

Computational Analysis Reveals a Key Regulator of Cryptococcal Virulence and Determinant of Host Response

Journal Article · Tue Apr 19 00:00:00 EDT 2016 · mBio (Online)

DOI:https://doi.org/10.1128/mBio.00313-16· OSTI ID:1630030

Gish, Stacey R. ^[1]; Maier, Ezekiel J. ^[2]; Haynes, Brian C. ^[2]; Santiago-Tirado, Felipe H. ^[3]; Srikanta, Deepa L. ^[3]; Ma, Cynthia Z. ^[2]; Li, Lucy X. ^[3]; Williams, Matthew ^[3]; Crouch, Erika C. ^[4]; Khader, Shabaana A. ^[3]; Brent, Michael R. ^[5]; Doering, Tamara L. ^[3]

Washington Univ., St. Louis, MO (United States). Center for Genome Sciences and Systems Biology. Dept. of Molecular Microbiology; DOE/OSTI
Washington Univ., St. Louis, MO (United States). School of Medicine; Washington Univ., St. Louis, MO (United States). Dept. of Computer Science and Engineering
Washington Univ., St. Louis, MO (United States). Center for Genome Sciences and Systems Biology. Dept. of Molecular Microbiology
Washington Univ., St. Louis, MO (United States). Dept. of Pathology and Immunology
Washington Univ., St. Louis, MO (United States). School of Medicine; Washington Univ., St. Louis, MO (United States). Dept. of Computer Science and Engineering; Washington Univ., St. Louis, MO (United States). Dept. of Genetics

Cryptococcus neoformans is a ubiquitous, opportunistic fungal pathogen that kills over 600,000 people annually. Here, we report integrated computational and experimental investigations of the role and mechanisms of transcriptional regulation in cryptococcal infection. Major cryptococcal virulence traits include melanin production and the development of a large polysaccharide capsule upon host entry; shed capsule polysaccharides also impair host defenses. We found that both transcription and translation are required for capsule growth and that Usv101 is a master regulator of pathogenesis, regulating melanin production, capsule growth, and capsule shedding. It does this by directly regulating genes encoding glycoactive enzymes and genes encoding three other transcription factors that are essential for capsule growth: GAT201, RIM101, and SP1. Murine infection with cryptococci lacking Usv101 significantly alters the kinetics and pathogenesis of disease, with extended survival and, unexpectedly, death by pneumonia rather than meningitis. Our approaches and findings will inform studies of other pathogenic microbes.

View Accepted Manuscript (DOE)

Research Organization:: Washington Univ., St. Louis, MO (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

Grant/Contract Number:: FG02-93ER20097

OSTI ID:: 1630030

Journal Information:: mBio (Online), Journal Name: mBio (Online) Journal Issue: 2 Vol. 7; ISSN 2150-7511

Publisher:: American Society for Microbiology (ASM)Copyright Statement

Country of Publication:: United States

Language:: English

References (40)

Construction of Saccharomyces cerevisiae strains with enhanced ethanol tolerance by mutagenesis of the TATA-binding protein gene and identification of novel genes associated with ethanol tolerance Yang, Jungwoo; Bae, Ju Yun; Lee, Young Mi Biotechnology and Bioengineering, Vol. 108, Issue 8 https://doi.org/10.1002/bit.23141	journal	April 2011
Cryptococcus neoformans : historical curiosity to modern pathogen: Cryptococcus neoformans Srikanta, Deepa; Santiago-Tirado, Felipe H.; Doering, Tamara L. Yeast, Vol. 31, Issue 2 https://doi.org/10.1002/yea.2997	journal	January 2014
Mutations of the TATA-binding protein confer enhanced tolerance to hyperosmotic stress in Saccharomyces cerevisiae Kim, Na-Rae; Yang, Jungwoo; Kwon, Hyeji Applied Microbiology and Biotechnology, Vol. 97, Issue 18 https://doi.org/10.1007/s00253-013-4985-8	journal	May 2013
Preventing Cryptococcosis—Shifting the Paradigm in the Era of Highly Active Antiretroviral Therapy Meya, David; Rajasingham, Radha; Nalintya, Elizabeth Current Tropical Medicine Reports, Vol. 2, Issue 2 https://doi.org/10.1007/s40475-015-0045-z	journal	April 2015
Distinct sets of SEC genes govern transport vesicle formation and fusion early in the secretory pathway Kaiser, Chris A.; Schekman, Randy Cell, Vol. 61, Issue 4 https://doi.org/10.1016/0092-8674(90)90483-U	journal	May 1990
Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions Haddow, Lewis J.; Colebunders, Robert; Meintjes, Graeme The Lancet Infectious Diseases, Vol. 10, Issue 11 https://doi.org/10.1016/S1473-3099(10)70170-5	journal	November 2010
Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease Turner, Mark D.; Nedjai, Belinda; Hurst, Tara Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Vol. 1843, Issue 11 https://doi.org/10.1016/j.bbamcr.2014.05.014	journal	November 2014
Systematic Genetic Analysis of Virulence in the Human Fungal Pathogen Cryptococcus neoformans Liu, Oliver W.; Chun, Cheryl D.; Chow, Eric D. Cell, Vol. 135, Issue 1 https://doi.org/10.1016/j.cell.2008.07.046	journal	October 2008
A Major Role for Capsule-Independent Phagocytosis-Inhibitory Mechanisms in Mammalian Infection by Cryptococcus neoformans Chun, Cheryl D.; Brown, Jessica C. S.; Madhani, Hiten D. Cell Host & Microbe, Vol. 9, Issue 3 https://doi.org/10.1016/j.chom.2011.02.003	journal	March 2011
Cryptococcus neoformans Copper Detoxification Machinery Is Critical for Fungal Virulence Ding, Chen; Festa, Richard A.; Chen, Ying-Lien Cell Host & Microbe, Vol. 13, Issue 3 https://doi.org/10.1016/j.chom.2013.02.002	journal	March 2013
Immortalized human cerebral microvascular endothelial cells maintain the properties of primary cells in an in vitro model of immune migration across the blood brain barrier Daniels, Brian P.; Cruz-Orengo, Lillian; Pasieka, Tracy Jo Journal of Neuroscience Methods, Vol. 212, Issue 1 https://doi.org/10.1016/j.jneumeth.2012.10.001	journal	January 2013
Cryptococcus neoformans, a fungus under stress Brown, Sarah M.; Campbell, Leona T.; Lodge, Jennifer K. Current Opinion in Microbiology, Vol. 10, Issue 4 https://doi.org/10.1016/j.mib.2007.05.014	journal	August 2007
A Library of Yeast Transcription Factor Motifs Reveals a Widespread Function for Rsc3 in Targeting Nucleosome Exclusion at Promoters Badis, Gwenael; Chan, Esther T.; van Bakel, Harm Molecular Cell, Vol. 32, Issue 6 https://doi.org/10.1016/j.molcel.2008.11.020	journal	December 2008
Emerging themes in cryptococcal capsule synthesis Kumar, Pardeep; Yang, Meng; Haynes, Brian C. Current Opinion in Structural Biology, Vol. 21, Issue 5 https://doi.org/10.1016/j.sbi.2011.08.006	journal	October 2011
Systematic functional profiling of transcription factor networks in Cryptococcus neoformans Jung, Kwang-Woo; Yang, Dong-Hoon; Maeng, Shinae Nature Communications, Vol. 6, Issue 1 https://doi.org/10.1038/ncomms7757	journal	April 2015
Isolation and characterization of capsule structure mutant strains of Cryptococcus neoformans: C. neoformans capsule structure mutants Moyrand, Frédérique; Klaproth, Birgit; Himmelreich, Uwe Molecular Microbiology, Vol. 45, Issue 3 https://doi.org/10.1046/j.1365-2958.2002.03059.x	journal	July 2002
Functional cloning and characterization of a UDP- glucuronic acid decarboxylase: The pathogenic fungus Cryptococcus neoformans elucidates UDP-xylose synthesis Bar-Peled, M.; Griffith, C. L.; Doering, T. L. Proceedings of the National Academy of Sciences, Vol. 98, Issue 21 https://doi.org/10.1073/pnas.211229198	journal	October 2001
A Novel Specificity Protein 1 (SP1)-like Gene Regulating Protein Kinase C-1 (Pkc1)-dependent Cell Wall Integrity and Virulence Factors in Cryptococcus neoformans Adler, Amos; Park, Yoon-Dong; Larsen, Peter Journal of Biological Chemistry, Vol. 286, Issue 23 https://doi.org/10.1074/jbc.M111.230268	journal	June 2011
UDP-glucose Dehydrogenase Plays Multiple Roles in the Biology of the Pathogenic Fungus Cryptococcus neoformans Griffith, Cara L.; Klutts, J. Stacey; Zhang, Lijuan Journal of Biological Chemistry, Vol. 279, Issue 49 https://doi.org/10.1074/jbc.M408889200	journal	September 2004
A Eukaryotic Capsular Polysaccharide Is Synthesized Intracellularly and Secreted via Exocytosis Yoneda, Aki; Doering, Tamara L. Molecular Biology of the Cell, Vol. 17, Issue 12 https://doi.org/10.1091/mbc.E06-08-0701	journal	December 2006
The yeast putative transcriptional repressor RGM1 is a proline-rich zinc finger protein Estruch, Francisco Nucleic Acids Research, Vol. 19, Issue 18 https://doi.org/10.1093/nar/19.18.4873	journal	January 1991
Saccharomyces Genome Database: the genomics resource of budding yeast Cherry, J. M.; Hong, E. L.; Amundsen, C. Nucleic Acids Research, Vol. 40, Issue D1 https://doi.org/10.1093/nar/gkr1029	journal	November 2011
Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS Park, Benjamin J.; Wannemuehler, Kathleen A.; Marston, Barbara J. AIDS, Vol. 23, Issue 4 https://doi.org/10.1097/QAD.0b013e328322ffac	journal	January 2009
Nsf1/Ypl230w participates in transcriptional activation during non-fermentative growth and in response to salt stress in Saccharomyces cerevisiae Hlynialuk, Chris; Schierholtz, Ryan; Vernooy, Amanda Microbiology, Vol. 154, Issue 8 https://doi.org/10.1099/mic.0.2008/019976-0	journal	August 2008
Cryptococcus neoformans and Cryptococcus gattii, the Etiologic Agents of Cryptococcosis Kwon-Chung, K. J.; Fraser, J. A.; Doering, T. L. Cold Spring Harbor Perspectives in Medicine, Vol. 4, Issue 7 https://doi.org/10.1101/cshperspect.a019760	journal	July 2014
Mapping functional transcription factor networks from gene expression data Haynes, B. C.; Maier, E. J.; Kramer, M. H. Genome Research, Vol. 23, Issue 8 https://doi.org/10.1101/gr.150904.112	journal	May 2013
Model-driven mapping of transcriptional networks reveals the circuitry and dynamics of virulence regulation Maier, Ezekiel J.; Haynes, Brian C.; Gish, Stacey R. Genome Research, Vol. 25, Issue 5 https://doi.org/10.1101/gr.184101.114	journal	February 2015
The ethanol stress response and ethanol tolerance of Saccharomyces cerevisiae Stanley, D.; Bandara, A.; Fraser, S. Journal of Applied Microbiology https://doi.org/10.1111/j.1365-2672.2009.04657.x	journal	January 2010
Comprehensive phenotypic analysis for identification of genes affecting growth under ethanol stress in Saccharomyces cerevisiae Yoshikawa, Katsunori; Tanaka, Tadamasa; Furusawa, Chikara FEMS Yeast Research, Vol. 9, Issue 1 https://doi.org/10.1111/j.1567-1364.2008.00456.x	journal	February 2009
The Cryptococcus neoformans Capsule: a Sword and a Shield O'Meara, T. R.; Alspaugh, J. A. Clinical Microbiology Reviews, Vol. 25, Issue 3 https://doi.org/10.1128/CMR.00001-12	journal	July 2012
Posttranslational, Translational, and Transcriptional Responses to Nitric Oxide Stress in Cryptococcus neoformans : Implications for Virulence Missall, Tricia A.; Pusateri, Mary Ellen; Donlin, Maureen J. Eukaryotic Cell, Vol. 5, Issue 3 https://doi.org/10.1128/EC.5.3.518-529.2006	journal	March 2006
Sexual Cycle of Cryptococcus neoformans var. grubii and Virulence of Congenic a and α Isolates Nielsen, Kirsten; Cox, Gary M.; Wang, Ping Infection and Immunity, Vol. 71, Issue 9 https://doi.org/10.1128/IAI.71.9.4831-4841.2003	journal	September 2003
The Cryptococcus neoformans Rim101 Transcription Factor Directly Regulates Genes Required for Adaptation to the Host O'Meara, T. R.; Xu, W.; Selvig, K. M. Molecular and Cellular Biology, Vol. 34, Issue 4 https://doi.org/10.1128/MCB.01359-13	journal	December 2013
Ctr2 Links Copper Homeostasis to Polysaccharide Capsule Formation and Phagocytosis Inhibition in the Human Fungal Pathogen Cryptococcus neoformans Chun, Cheryl D.; Madhani, Hiten D. PLoS ONE, Vol. 5, Issue 9 https://doi.org/10.1371/journal.pone.0012503	journal	September 2010
A Sensitive High-Throughput Assay for Evaluating Host-Pathogen Interactions in Cryptococcus neoformans Infection Srikanta, Deepa; Yang, Meng; Williams, Matthew PLoS ONE, Vol. 6, Issue 7 https://doi.org/10.1371/journal.pone.0022773	journal	July 2011
Functional Analyses of NSF1 in Wine Yeast Using Interconnected Correlation Clustering and Molecular Analyses Bessonov, Kyrylo; Walkey, Christopher J.; Shelp, Barry J. PLoS ONE, Vol. 8, Issue 10 https://doi.org/10.1371/journal.pone.0077192	journal	October 2013
Interaction of Cryptococcus neoformans Rim101 and Protein Kinase A Regulates Capsule O'Meara, Teresa R.; Norton, Diana; Price, Michael S. PLoS Pathogens, Vol. 6, Issue 2 https://doi.org/10.1371/journal.ppat.1000776	journal	February 2010
Toward an Integrated Model of Capsule Regulation in Cryptococcus neoformans Haynes, Brian C.; Skowyra, Michael L.; Spencer, Sarah J. PLoS Pathogens, Vol. 7, Issue 12 https://doi.org/10.1371/journal.ppat.1002411	journal	December 2011
Elucidating the immunological function of the Cryptococcus neoformans capsule Vecchiarelli, Anna; Pericolini, Eva; Gabrielli, Elena Future Microbiology, Vol. 8, Issue 9 https://doi.org/10.2217/fmb.13.84	journal	September 2013
IL-1α and IL-1β Recruit Different Myeloid Cells and Promote Different Stages of Sterile Inflammation Rider, Peleg; Carmi, Yaron; Guttman, Ofer The Journal of Immunology, Vol. 187, Issue 9 https://doi.org/10.4049/jimmunol.1102048	journal	September 2011

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Mon1 Is Essential for Fungal Virulence and Stress Survival in Cryptococcus neoformans Son, Ye-Eun; Jung, Won-Hee; Oh, Sang-Hun Mycobiology, Vol. 46, Issue 2 https://doi.org/10.1080/12298093.2018.1468053	journal	April 2018
Unraveling synthesis of the cryptococcal cell wall and capsule Wang, Zhuo A.; Li, Lucy X.; Doering, Tamara L. Glycobiology, Vol. 28, Issue 10 https://doi.org/10.1093/glycob/cwy030	journal	April 2018
Unraveling Melanin Biosynthesis and Signaling Networks in Cryptococcus neoformans Lee, Dongpil; Jang, Eun-Ha; Lee, Minjae mBio, Vol. 10, Issue 5 https://doi.org/10.1128/mbio.02267-19	journal	October 2019
Cdk8 and Ssn801 Regulate Oxidative Stress Resistance and Virulence in Cryptococcus neoformans Chang, Andrew L.; Kang, Yiming; Doering, Tamara L. mBio, Vol. 10, Issue 1 https://doi.org/10.1128/mbio.02818-18	journal	February 2019
Unintended Side Effects of Transformation Are Very Rare in Cryptococcus neoformans Friedman, Ryan Z.; Gish, Stacey R.; Brown, Holly G3: Genes\|Genomes\|Genetics, Vol. 8, Issue 3 https://doi.org/10.1534/g3.117.300357	journal	January 2018
Comparative Ecology of Capsular Exophiala Species Causing Disseminated Infection in Humans Song, Yinggai; Laureijssen-van de Sande, Wendy W. J.; Moreno, Leandro F. Frontiers in Microbiology, Vol. 8 https://doi.org/10.3389/fmicb.2017.02514	journal	December 2017
Cryptococcal Traits Mediating Adherence to Biotic and Abiotic Surfaces Camacho, Emma; Casadevall, Arturo Journal of Fungi, Vol. 4, Issue 3 https://doi.org/10.3390/jof4030088	journal	July 2018

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