Alpha1-antitrypsin impacts innate host-pathogen interactions with Candida albicans by stimulating fungal filamentation.

Our immune system possesses sophisticatedmechanisms to cope with invading microorganisms, while pathogensevolve strategies to deal with threats imposed by host immunity. Thehuman plasma protein α1-antitrypsin (AAT) exhibits pleiotropicimmune-modulating properties by both preventing immunopathology andimproving antimicrobial host defence. Genetic associations suggesteda role for AAT in candidemia, the most frequent fungal bloodstreaminfection in the ICU, yet little is known about how AAT influencesinteractions between Candidaalbicans and the immunesystem.Here we show that AAT differentiallyimpacts fungal killing by innate phagocytes. We observed that AATinduces fungal transcriptional reprogramming, associated with cellwall remodelling and downregulation of filamentation repressors. Atlow concentrations, the cell-wall remodelling induced by AAT increasedimmunogenic β-glucan exposure and consequently improved fungal clearance by monocytes.Contrastingly, higher AAT concentrations led to excessive C. albicans filamentation and thus promoted fungal immune escape from monocytesand macrophages.This underscores that fungal adaptationsto the host protein AAT can differentially define the outcome ofencounters with innate immune cells, eithercontributing to improved immune recognition or fungal immune escape.