N6-methyladenosine (m6A) RNA modification restrains antifungal immunity and is a therapeutic target in oral candidiasis

Fungal infections represent a major global threat, yet to date there is a paucity of effective antifungal drugs and no licensed vaccines to any pathogenic fungi. The commensal pathobiont Candida albicans can cause severe oropharyngeal and mucocutaneous infections in immunocompromised individuals. The initial point of interaction of C. albicans in the oral mucosa is with superficial oral epithelial cells (OECs). Upon fungal encounter, OECs upregulate a program of anti-fungal defense genes, a process that has been extensively studied at the level of proximal signaling pathways, transcriptional induction, and epigenetic control. However, inflammatory genes are also subject to extensive regulation at the mRNA level, yet little is known about mechanisms that control C. albicans-induced genes post-transcriptionally. The importance of epitranscriptomic gene regulation by mRNA methylation is becoming increasingly appreciated, yet its contribution to host responses during fungal infection remains poorly understood. N6-methyladenosine (m6A) is the most abundant RNA modification and influences numerous transcript fates including mRNA stabilization. Here, we demonstrate that C. albicans-induced genes in human and mouse OECs are widely subject to m6A modification following infection. Silencing of a specific subclass of m6A binding proteins, the YTHDF1/2/3 readers, reprogrammed the OEC response to C. albicans by up- and down-regulating antifungal transcripts. The net effect of blocking the m6A pathway using a first-in-class METTL3 inhibitor was to amplify mRNA expression of antimicrobial peptides that reduce fungal burden. These studies establish a role for the m6A pathway as a modulator of immunity to mucosal candidiasis and suggest a new therapeutic avenue to treating this condition.