Zinc Cluster Transcription Factors Alter Virulence in Candida albicans

Virtually all humans are colonized with Candida albicans . However, in immunocompromised individuals this benign commensal organism becomes a serious, life-threatening pathogen. Here, we describe and analyze the regulatory networks that modulate innate responses in the host niches. We identified Zcf15 and Zcf29, two Z inc C luster transcription F actors (ZCF) that are required for C. albicans virulence. Previous sequence analysis of clinical C. albicans isolates from immunocompromised patients indicates that both ZCF genes diverged during clonal evolution. Using in vivo animal models, ex vivo cell culture methods, and in vitro sensitivity assays, we demonstrate that knockout mutants of both ZCF15 and ZCF29 are hypersensitive to reactive oxygen species (ROS), suggesting they help neutralize the host derived ROS produced by phagocytes, as well as establish a sustained infection in vivo . Transcriptomic analysis of mutants under resting conditions where cells were not experiencing oxidative stress revealed a large network that control macro and micronutrient homeostasis, which likely contributes to overall pathogen fitness in host niches. Under oxidative stress both transcription factors regulate a separate set of genes involved detoxification of ROS and down regulate ribosome biogenesis. These results are further confirmed by whole genome location analysis, which reveals vastly different binding partners for each TF before and after oxidative stress. Furthermore the absence of a dominant binding motif likely facilitates their mobility and supports the notion they represent a recent expansion of the ZCF family in the pathogenic Candida species. Our analyses provide a framework for understanding new aspects of the interface between C. albicans and host defense response, and extends our understanding of how complex cell behaviors are linked to the evolution of transcription factors.