In partial fulfillment of the requirements for the degree of

Doctor of Philosophy in Biology

In the

School of Biological Sciences

Maria Granada

Will defend her dissertation

PHYSIOLOGICAL AND GENOMIC ADAPTATION OF CANDIDA GLABRATA TO HOST-ASSOCIATED NICHES AND STANDARD LAB MEDIA

15, April, 2026

3:00 PM (EST) in EBB Krone, Conference Room: 4026

 Thesis Advisor:

Frank Rosenzweig, Ph.D., School of Biological Sciences, Georgia Institute of Technology

Committee Members:

Ingeborg Schmidt-Kray, Ph.D., School of Biological Sciences, Georgia Institute of Technology

Steve Diggle, Ph.D., School of Biological Sciences, Georgia Institute of Technology

Brian Hammer, Ph.D., School of Biological Sciences, Georgia Institute of Technology

Gavin Sherlock, Ph.D., Department of Genetics, Stanford University Medical School

ABSTRACT: 

Candida glabrata is an opportunistic fungal pathogen whose intrinsic drug resistance and ability to colonize different host niches pose major clinical challenges. Using RNA- and DNA-sequencing, we set out to understand how C. glabrata adapts to different host niches by formulating media to simulate different host environments. First, I measured the genome-wide transcriptional response of lab strain ATCC 2001 over a 48-hour time course in artificial saliva (AS), artificial urine (AU) and in two standard laboratory media, Synthetic Complete (SC) and Roswell Park Memorial Institute-1640 (RPMI). Expression profiles and growth parameters differed markedly across conditions. Expression profiles normalized to SC-cultured yeast showed that cells cultured in AS induce proteostasis pathways, while cells cultured in AU downregulate this function. AU- and RPMI-cultured cells upregulate genes in nitrogen metabolism and metabolite biosynthesis, while the latter which is down-regulated in AS. RNA-Seq also revealed condition-specific activation of genes related to drug resistance and virulence. Next, five-fold replicated evolution experiments were carried out in AS, AU and SC for 200 generations starting from a common ancestor, ATCC 2001. Whole-genome, whole population sequencing performed at 50 generation intervals showed that AS- and AU-evolved populations accumulated different sets of de novo mutations, especially in transcription factors and ubiquitin/proteasome pathways, whereas SC-evolved populations accumulated comparatively few mutations. Condition-specific evolutionary trajectories were correlated with condition-specific fitness gains, which were most pronounced in AU. Together, our findings demonstrate that the chemistry of simulated host niches influences C. glabrata’s physiology and evolutionary dynamics. They also suggest that niche-specific adaptation may influence antifungal susceptibility and disease severity in vivo. More broadly, this work highlights the importance of considering host-environment context when understanding how infections behave and predicting evolutionary outcomes in opportunistic pathogens.