Highlights d TF loss frequently occurs during murine infections and drives host adaptation d Hemizygosity of the EFG1 TF licenses a phenotypic transition in C. albicans cells d Numerous clinical isolates are EFG1 hemizygous and thus can undergo this transition d This ''phenotypic switch'' corresponds to mutational loss of EFG1 function

Candida albicans is a commensal in heathy people but has the potential to become an opportunistic pathogen and is responsible for half of all clinical infections in immunocompromised patients. Central to understanding C. albicans behavior is the whiteopaque phenotypic switch, in which cells can undergo an epigenetic transition between the white state and the opaque state. The phenotypic switch regulates multiple properties, including biofilm formation, virulence, mating, and fungus-host interactions. Switching between the white and opaque states is associated with many external stimuli, such as oxidative stress, pH, and N-acetylglucosamine, and is directly regulated by the Wor1 transcriptional circuit. The Hog1 stress-activated protein kinase (SAPK) pathway is recognized as the main pathway for adapting to environmental stress in C. albicans. In this work, we first show that loss of the HOG1 gene in a/a and ␣/␣ cells, but not a/␣ cells, results in 100% white-to-opaque switching when cells are grown on synthetic medium, indicating that switching is repressed by the a1/␣2 heterodimer that represses WOR1 gene expression. Indeed, switching in the hog1⌬ strain was dependent on the presence of WOR1, as a hog1⌬ wor1⌬ strain did not show switching to the opaque state. Deletion of PBS2 and SSK2 also resulted in C. albicans cells switching from white to opaque with 100% efficiency, indicating that the entire Hog1 SAPK pathway is involved in regulating this unique phenotypic transition. Interestingly, all Hog1 pathway mutants also caused defects in shmoo formation and mating efficiencies. Overall, this work reveals a novel role for the Hog1 SAPK pathway in regulating white-opaque switching and sexual behavior in C. albicans.

Understanding how fungi colonize the GI tract is increasingly recognized as highly relevant to human health. The animal models used to study Candida albicans commensalism commonly rely on altering the host microbiome (via antibiotic treatment or defined diets) to establish successful GI colonization by the C. albicans reference isolate SC5314.