Forward genetic screen in zebrafish identifies new fungal regulators that limit host-protective <i>Candida</i> -innate immune interaction

<i>Candida albicans</i> is part of the human microbial community and is a dangerous opportunistic pathogen, able to prevent its elimination by the host immune system. Although <i>Candida</i> avoids immune attack through several strategies, we still understand little about how it regulates when immune phagocytes get recruited to the infection site and when they engulf fungal cells. We tested over 130 selected <i>Candida</i> mutants for their ability to cause lethal infection and found several hypovirulent mutants, which provoked altered innate immune responses, resulting in lower overall inflammation and greater host survival. Of particular interest is <i>NMD5</i>, which acts to limit fungal phagocytosis and is predicted to regulate the activity of stress-associated transcription factors. Our high-content screening was enabled by modeling <i>Candida</i> infection in transparent vertebrate zebrafish larva. Our findings help us understand how <i>Candida</i> survives immune attack during commensal and pathogenic growth, and may eventually inform new strategies for controlling disease.