Tamara L. Doering, M.D., Ph.D.
Molecular Microbiology and Microbial Pathogenesis Program
Molecular Cell Biology Program
Plant and Microbial Biosciences Program
10230 McDonnell Pediatric Research Building
gene regulation, host-pathogen interactions, biochemistry, microbial pathogenesis, pathogenic fungi, yeast, glycobiology, biosynthetic pathways, blood-brain barrier, host response
Investigations of capsule synthesis and host interactions of the pathogenic fungus Cryptococcus neoformans
We are interested in the fundamental biology and host interactions of the pathogenic fungus Cryptococcus neoformans. This yeast causes serious infections in immunocompromised individuals worldwide, killing over 600,000 people each year, mainly in developing countries. Our goal is to elucidate unique aspects of cryptococcal biology that are of biological interest and may suggest targets for badly needed antifungal chemotherapy.
The main virulence factor of C. neoformans is its extensive polysaccharide capsule, a unique protective structure that is required for virulence and changes dramatically in response to environmental cues. The chemical structure of the cryptococcal capsule is known, but many questions remain about its synthesis, assembly, and regulation. The pathways of capsule biosynthesis, and how we might inhibit them, are one major interest in the lab. We are also combining new technologies and approaches in computational biology with molecular experimentation to examine capsule regulation. The goal of this work is to reconstruct the transcriptional regulatory network of capsule, defining how Cryptococcus modulates this key structure in response to its environment.
Another area of focus in the Doering group is how this fungal pathogen interacts with host cells during infection, with the aim of understanding and potentially influencing these critical events. We have recently begun applying high throughput image-based screening to explore this area, which has opened exciting directions for our research. This work has led us to projects ranging from studies of host kinases, fungal mitochondria, and lipid modification of proteins. We are also interested in the fascinating question of how this pathogen breaches the blood-brain barrier to cause lethal meningitis (see research image).
Overall, we are elucidating the molecular mechanisms by which an important pathogen deploys and regulates its major virulence factor and interacts with its host. These studies increase our basic science knowledge, deepen our understanding of fungal pathogenesis, and enhance the potential for development of new therapeutic agents.
Lucy X. Li LX, Ashikov A, Liu H, Griffith CL, Bakker H, and Doering TL. (2016) Cryptococcus neoformans UGT1 encodes a UDP-Galactose/UDP-GalNAc transporter. Glycobiology, in press.
Gish SR, Maier EJ, Haynes BC, Santiago-Tirado FH, Srikanta DL, Williams M, Crouch EC, Khader S, Brent MR, and Doering TL. (2016) Usv101 is a key regulator of cryptococcal virulence and determinant of host response. mBio, 7, 313-316, PMID: 27094327.
Santiago-Tirado FH and Doering TL. (2016). All about that fat: Lipid modification of proteins in Cryptococcus neoformans. Journal of Microbiology, 54, 212-222, PMID: 26920881.
Santiago-Tirado FH, Peng T, Yang M, Hang HC, and Doering TL. (2015) A single protein S-acyltransferase is a major determinant of cryptococcal pathogenesis. PLoS Pathogens, 11(5):e1004908. doi: 10.1371/journal.ppat.1004908. PMID: 25970403.
Maier EJ, Haynes BC, Gish SR, Wang ZA, Skowyra ML, Marulli AL, Doering TL, and Brent MR. (2015) Model-driven mapping of transcriptional networks reveals the circuitry and dynamics of virulence regulation. Genome Research, 25, 690-700, PMID: 25644834.
Srikanta D, Santiago-Tirado FH, and Doering TL. (2014) Cryptococcus neoformans: Historical curiosity to modern pathogen. Yeast, 31, 47-60. PMID: 24375706.
Wang Z, Griffith C, Skowyra ML, Salinas N, Williams M, Maier EJ, Gish SR, and Doering TL. (2014) The dual GDP-mannose transporters of Cryptococcus neoformans and their role in biology and virulence. Eukaryotic Cell, 13, 832-42. PMID: 24747214.
Skowyra ML and Doering TL. (2012) RNA interference in Cryptococcus neoformans. Methods Mol Biol, 845:165-186. PMID: 22328374.
Haynes BC, Skowyra ML, Spencer SJ, Gish SR, Williams M, Brent MR, and Doering TL. (2011) Toward an integrated model of capsule replication in Cryptococcus neoformans. PLoS Pathogens, 7(12):e1002411. PMID: 22174677.
Kumar P, Yang M, Haynes BC, Skowyra ML, and Doering TL. (2011) Emerging themes in cryptococcal capsule synthesis. Current Opinions in Structural Biology, 5: 597-602. PMID: 21889889.
Srikanta D, Yang M, Williams M, and Doering TL. (2011) A sensitive high throughput assay for evaluation of host-pathogen interactions in Cryptococcus neoformans infection. PLoS ONE (6/7): e22773. Doi:10.1371/journal.pone.0022773. PMID: 21829509.
Last Updated: 9/14/2016 8:54:28 AM