Aberrant type 1 immunity drives susceptibility to mucosal fungal infections.
Science 2021 Jan 15; 371(6526):eaay5731
Human monogenic disorders have revealed the critical contribution of type 17 responses in mucosal fungal surveillance. We unexpectedly found that in certain settings, enhanced type 1 immunity rather than defective type 17 responses can promote mucosal fungal infection susceptibility. Notably, in mice and humans with AIRE deficiency, an autoimmune disease characterized by selective susceptibility to mucosal but not systemic fungal infection, mucosal type 17 responses are intact while type 1 responses are exacerbated. These responses promote aberrant interferon-γ (IFN-γ)- and signal transducer and activator of transcription 1 (STAT1)-dependent epithelial barrier defects as well as mucosal fungal infection susceptibility. Concordantly, genetic and pharmacologic inhibition of IFN-γ or Janus kinase (JAK)-STAT signaling ameliorates mucosal fungal disease. Thus, we identify aberrant T cell-dependent, type 1 mucosal inflammation as a critical tissue-specific pathogenic mechanism that promotes mucosal fungal infection susceptibility in mice and humans.
Break, Timothy J; Oikonomou, Vasileios; Dutzan, Nicolas; Desai, Jigar V; Swidergall, Marc; Freiwald, Tilo; Chauss, Daniel; Harrison, Oliver J; Alejo, Julie; Williams, Drake W; Pittaluga, Stefania; Lee, Chyi-Chia R; Bouladoux, Nicolas; Swamydas, Muthulekha; Hoffman, Kevin W; Greenwell-Wild, Teresa; Bruno, Vincent M; Rosen, Lindsey B; Lwin, Wint; Renteria, Andy; Pontejo, Sergio M; Shannon, John P; Myles, Ian A; Olbrich, Peter; Ferré, Elise M N; Schmitt, Monica; Martin, Daniel; Barber, Daniel L; Solis, Norma V; Notarangelo, Luigi D; Serreze, David V.; Matsumoto, Mitsuru; Hickman, Heather D; Murphy, Philip M; Anderson, Mark S; Lim, Jean K; Holland, Steven M; Filler, Scott G; Afzali, Behdad; Belkaid, Yasmine; Moutsopoulos, Niki M; and Lionakis, Michail S, "Aberrant type 1 immunity drives susceptibility to mucosal fungal infections." (2021). Faculty Research 2021. 28.