美国国家过敏和传染病研究所（NIAID）DiseaMichail S. Lionakis研究组取得最新进展。他们提出1型异常免疫增强了对粘膜真菌感染的易感性。相关论文于2021年1月15日发表于国际顶尖学术期刊《科学》。

他们意外地发现，在某些情况下，增强的1型免疫力而不是缺陷的17型应答可以促进粘膜真菌感染的易感性。值得注意的是，在具有AIRE缺乏症（一种自身免疫性疾病）的小鼠和人类中，其特征是对粘膜具有选择性易感性，但对全身性真菌感染无敏感性，粘膜17型应答完整的，而1型应答却加剧。这些反应促进了异常的干扰素-γ（IFN-γ）和信号转导和转录激活因子1（STAT1）依赖的上皮屏障缺陷以及粘膜真菌感染的易感性。

相应地，对IFN-γ或Janus激酶（JAK）–STAT信号的遗传和药理抑制可改善粘膜真菌病。因此，他们确定异常依赖T细胞的1型粘膜炎症是一种关键的组织特异性致病机制，可促进小鼠和人类的粘膜真菌感染易感性。

研究人员表示，人类单基因疾病已揭示了17型应答在黏膜真菌监测中的关键作用。

附：英文原文

Title: Aberrant type 1 immunity drives susceptibility to mucosal fungal infections

Author: Timothy J. Break, Vasileios Oikonomou, Nicolas Dutzan, Jigar V. Desai, Marc Swidergall, Tilo Freiwald, Daniel Chauss, Oliver J. Harrison, Julie Alejo, Drake W. Williams, Stefania Pittaluga, Chyi-Chia R. Lee, Nicolas Bouladoux, Muthulekha Swamydas, Kevin W. Hoffman, Teresa Greenwell-Wild, Vincent M. Bruno, Lindsey B. Rosen, Wint Lwin, Andy Renteria, Sergio M. Pontejo, John P. Shannon, Ian A. Myles, Peter Olbrich, Elise M. N. Ferré, Monica Schmitt, Daniel Martin, Genomics and Computational Biology Core, Daniel L. Barber, Norma V. Solis, Luigi D. Notarangelo, David V. Serreze, Mitsuru Matsumoto, Heather D. Hickman, Philip M. Murphy, Mark S. Anderson, Jean K. Lim, Steven M. Holland, Scott G. Filler, Behdad Afzali, Yasmine Belkaid, Niki M. Moutsopoulos, Michail S. Lionakis

Issue&Volume: 2021/01/15

Abstract: 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.

DOI: 10.1126/science.aay5731

Source: https://science.sciencemag.org/content/371/6526/eaay5731