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I began my doctoral training in the Molecular Genetics and Microbiology program at Duke University in the fall of 2016 in Dr. Andrew Alspaugh’s laboratory and graduated in 2022. I am interested in understanding how pathogenic fungi sense and adapt to the human host environment in order to cause disease. Specifically, I use genetic tools to explore the human fungal pathogen Cryptococcus neoformans, with the ultimate goal of identifying fungal genes that can be targeted by future antifungal approaches. I am currently pursuing two distinct projects to identify and characterize C. neoformans genes that contribute to virulence in the human host.
Cell cycle progression
Cell cycle progression
The cell cycle controls the fundamental ability of cells to grow and proliferate. Cell cycle regulation is essential for pathogens when they encounter the stressful environment of the human host. Arrestins, a structurally specialized and functionally diverse group of proteins, are central regulators of cell cycle progression in many eukaryotes, but have largely remained unexplored in pathogenic fungi.
We have identified four arrestin proteins - Ali1, Ali2, Ali3, and Ali4 - in the opportunistic human fungal pathogen Cryptococcus neoformans. We have observed that the arrestin loss-of-function mutants exhibit varying defects in cell cycle progression. Structural evidence and preliminary proteomic studies indicate that the C. neoformans arrestins interact strongly with ubiquitin ligases. Based on these observations, we hypothesize that the C. neoformans arrestins function as non-redundant regulators of fungal cell cycle progression by serving as adaptors to direct ubiquitin ligase activity to specific target proteins.
We recently defined and published a specific adaptor function for Ali1 in the regulation of cytokinesis. Ali1 acts as an adaptor for the ubiquitin ligase Rsp5, to facilitate the ubiquitination of the fatty acid synthases, Fas1 and Fas2. Ali1-mediated ubiquitination directs the localization of Fas1 and Fas2 to the septum and poles to synthesize the cell membrane during cytokinesis.
Current projects are focused on defining the mechanisms by which Ali2, Ali3, and Ali4 contribute to cell cycle progression and virulence. Thus far, we have found that the arrestin family, collectively, is required for virulence in murine models of cryptococcosis, indicating that the arrestins may serve as a promising antifungal drug target.
We have identified four arrestin proteins - Ali1, Ali2, Ali3, and Ali4 - in the opportunistic human fungal pathogen Cryptococcus neoformans. We have observed that the arrestin loss-of-function mutants exhibit varying defects in cell cycle progression. Structural evidence and preliminary proteomic studies indicate that the C. neoformans arrestins interact strongly with ubiquitin ligases. Based on these observations, we hypothesize that the C. neoformans arrestins function as non-redundant regulators of fungal cell cycle progression by serving as adaptors to direct ubiquitin ligase activity to specific target proteins.
We recently defined and published a specific adaptor function for Ali1 in the regulation of cytokinesis. Ali1 acts as an adaptor for the ubiquitin ligase Rsp5, to facilitate the ubiquitination of the fatty acid synthases, Fas1 and Fas2. Ali1-mediated ubiquitination directs the localization of Fas1 and Fas2 to the septum and poles to synthesize the cell membrane during cytokinesis.
Current projects are focused on defining the mechanisms by which Ali2, Ali3, and Ali4 contribute to cell cycle progression and virulence. Thus far, we have found that the arrestin family, collectively, is required for virulence in murine models of cryptococcosis, indicating that the arrestins may serve as a promising antifungal drug target.
Cell surface remodeling
Cell surface remodeling
The fungal cell surface serves as a dynamic shield that protects fungal pathogens when they enter the human host environment. The opportunistic human pathogen Cryptococcus neoformans dramatically alters its cell surface, specifically its cell wall and capsule, upon infection. Through a genetic screen for loss-of-function mutants with cell surface defects, we identified a novel protein, Mar1. Detailed phenotypic characterization of the mar1Δ mutant has determined that Mar1 is required for cell surface remodeling, and as a result, virulence.
Current work is focused on understanding the mechanism by which Mar1 regulates fungal cell surface remodeling. An unbiased protein interactome screen demonstrated that Mar1 interacts strongly with protein trafficking machinery, such as the Arf-GAP Glo3. Comparative mutant phenotypic studies between the mar1Δ and glo3Δ mutants suggest that unlike Glo3, Mar1 is likely not a protein trafficking component. Instead, based on the Mar1 protein structure and Mar1-dependent transcriptome data, we hypothesize that Mar1 serves as an intracellular stress sensor. We posit that Mar1-dependent stress sensing regulates protein trafficking, and subsequently cell surface structure, in the host environment.
Additional studies are exploring how Mar1 impacts host-fungi interactions. We have observed that Mar1 mediates the host granulomatous response by regulating fungal immunogenicity and growth rate. Elucidating mechanisms by which the fungal cell surface contributes to the host immune response to can inform future antifungal drug development.
Current work is focused on understanding the mechanism by which Mar1 regulates fungal cell surface remodeling. An unbiased protein interactome screen demonstrated that Mar1 interacts strongly with protein trafficking machinery, such as the Arf-GAP Glo3. Comparative mutant phenotypic studies between the mar1Δ and glo3Δ mutants suggest that unlike Glo3, Mar1 is likely not a protein trafficking component. Instead, based on the Mar1 protein structure and Mar1-dependent transcriptome data, we hypothesize that Mar1 serves as an intracellular stress sensor. We posit that Mar1-dependent stress sensing regulates protein trafficking, and subsequently cell surface structure, in the host environment.
Additional studies are exploring how Mar1 impacts host-fungi interactions. We have observed that Mar1 mediates the host granulomatous response by regulating fungal immunogenicity and growth rate. Elucidating mechanisms by which the fungal cell surface contributes to the host immune response to can inform future antifungal drug development.
Publications
Publications
Telzrow CL, Esher Righi S, Cathey JM, Granek JA, Alspaugh JA. 2023. Cryptococcus neoformans Mar1 Function Links Mitochondrial Metabolism, Oxidative Stress, and Antifungal Tolerance. Front Physiol. doi: 10.3389/fphys.2023.1150272.
Telzrow CL, Esher Righi S, Castro-Lopez N, Campuzano A, Brooks JT, Carney JM, Wormley FL, Alspaugh JA. 2022. An Immunogenic and Slow-Growing Cryptococcal Strain Induces a Chronic Granulomatous Infection in Murine Lungs. Infect Immun. doi: 10.1128/iai.00580-21.
Telzrow CL, Zwack PJ, Esher Righi S, Dietrich FS, Chan C, Owzar K, Alspaugh JA, Granek JA. 2021. Comparative Analysis of RNA Enrichment Methods for Preparation of Cryptococcus neoformans RNA Sequencing Libraries. G3. doi: 10.1093/g3journal/jkab301.
Brown HE, Telzrow CL, Saelens JW, Fernandes L, Alspaugh JA. 2020. Sterol-Response Pathways Mediate Alkaline Survival in Diverse Fungi. mBio. doi: 10.1128/mBio.00719-20.
Telzrow CL, Nichols CB, Castro-Lopez N, Wormley FL, Alspaugh JA. 2019. A Fungal Arrestin Protein Contributes to Cell Cycle Progression and Pathogenesis. mBio. doi: 10.1128/mBio.02682-19.
Pianalto KM, Billmyre RB, Telzrow CL, Alspaugh JA. 2019. Roles for Stress Response and Cell Wall Biosynthesis Pathways in Caspofungin Tolerance in Cryptococcus neoformans. Genetics. doi: 10.1534/genetics.119.302290.
Esher SK, Ost KS, Kohlbrenner MA, Pianalto KM, Telzrow CL, Campuzano A, Munro C, Wormley FL, Alspaugh JA. 2018. Defects in Intracellular Trafficking of Fungal Cell Wall Synthases lead to Aberrant Host Immune Recognition. PLoS Pathog. doi: 10.1371/journal.ppat.1007126.
Hayes G, Wright N, Gardner SL, Telzrow CL, Wommack AJ, Vigueira PA. 2018. Manuka Honey and Methylglyoxal Increase the Sensitivity of Staphylococcus aureus to Linezolid. Lett Appl Microbiol. doi: 10.1111/lam.12880.
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