To survive within the hostile environment of the infected host, pathogenic microorganisms must be able to sense and adapt to changing environmental conditions. This adaptation requires the coordinated regulation of multiple cellular factors. Like many infectious agents, the human fungal pathogen Cryptococcus neoformans uses the conserved signaling molecule cyclic AMP (cAMP) to regulate its response to external stresses. The central components of cAMP signal transduction pathways are highly conserved among microorganisms. However, the main hypothesis of this proposal is that the upstream activating signals and the downstream effectors of cAMP are functionally specialized in microbial pathogens. This specialization allows pathogenic organisms to use cAMP signaling to specifically control their virulence potential. Over the past several years, we have demonstrated that the C. neoformans cAMP pathway is required for adaptation to the host environment. This pathway regulates the induction of capsule and melanin, two cellular factors required for pathogenesis. This regulation occurs primarily at the level of transcription. Therefore, we designed the experiments of this proposal to identify trans- and cis-acting regulatory elements that control the transcription of capsule-associated genes.
Specific Aim 1 proposes bioinformatic and transcriptional profiling approaches to identify transcription factors that control C. neoformans capsule gene expression.
Specific Aim 2 outlines detailed testing of selected transcriptional regulators to define their role in capsule induction. Experiments in Specific Aim 3 will define the direct and indirect target genes of the transcription factors identified in the first two Aims. Upon completion, these experiments will offer new insight into the ways in which this specific pathogen senses and responds to its host. By defining new functions for conserved signaling pathways, these experiments will also explore broader issues in environmental sensing, cellular stress, and microbial virulence.

Public Health Relevance

In order to better treat infectious diseases, we must understand the ways in which infectious microorganisms survive within their host. The experiments in this proposal will study Cryptococcus neoformans, an important opportunistic fungal pathogen in AIDS patients, to define the cellular factors required for formation of a protective surface capsule. Capsule production will also be used as a model to better understand more fundamental issues of the interaction between microorganisms and the infected host.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-IDM-S (02))
Program Officer
Duncan, Rory A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Pianalto, Kaila M; Ost, Kyla S; Brown, Hannah E et al. (2018) Characterization of additional components of the environmental pH-sensing complex in the pathogenic fungus Cryptococcus neoformans. J Biol Chem 293:9995-10008
Brandão, Fabiana; Esher, Shannon K; Ost, Kyla S et al. (2018) HDAC genes play distinct and redundant roles in Cryptococcus neoformans virulence. Sci Rep 8:5209
Esher, Shannon K; Ost, Kyla S; Kohlbrenner, Maria A et al. (2018) Defects in intracellular trafficking of fungal cell wall synthases lead to aberrant host immune recognition. PLoS Pathog 14:e1007126
Esher, Shannon K; Zaragoza, Oscar; Alspaugh, James Andrew (2018) Cryptococcal pathogenic mechanisms: a dangerous trip from the environment to the brain. Mem Inst Oswaldo Cruz 113:e180057
Brown, Hannah E; Ost, Kyla S; Esher, Shannon K et al. (2018) Identifying a novel connection between the fungal plasma membrane and pH-sensing. Mol Microbiol 109:474-493
Gontijo, Fabiano de Assis; de Melo, Amanda Teixeira; Pascon, Renata C et al. (2017) The role of Aspartyl aminopeptidase (Ape4) in Cryptococcus neoformans virulence and authophagy. PLoS One 12:e0177461
Ost, Kyla S; Esher, Shannon K; Leopold Wager, Chrissy M et al. (2017) Rim Pathway-Mediated Alterations in the Fungal Cell Wall Influence Immune Recognition and Inflammation. MBio 8:
Alspaugh, J Andrew (2017) Targeting protein localization for anti-infective therapy. Virulence 8:1105-1107
Pianalto, Kaila M; Alspaugh, J Andrew (2016) New Horizons in Antifungal Therapy. J Fungi (Basel) 2:
Esher, Shannon K; Granek, Joshua A; Alspaugh, J Andrew (2015) Rapid mapping of insertional mutations to probe cell wall regulation in Cryptococcus neoformans. Fungal Genet Biol 82:9-21

Showing the most recent 10 out of 21 publications