Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, USA.
Oral Immunity and Inflammation Section, National Institute of Dental and Craniofacial Research (NIDCR), Bethesda, MD, USA.
Science. 2021 Jan 15;371(6526). doi: 10.1126/science.aay5731.
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 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.
人类单基因疾病已经揭示了 17 型反应在黏膜真菌感染监测中的重要作用。我们出人意料地发现，在某些情况下，增强的 1 型免疫而不是有缺陷的 17 型反应可能会促进黏膜真菌感染的易感性。值得注意的是，在缺乏 的小鼠和人类中，这是一种自身免疫性疾病，其特征是对黏膜而不是系统性真菌感染具有选择性易感性，黏膜 17 型反应是完整的，而 1 型反应则加剧。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）依赖性上皮屏障缺陷以及黏膜真菌感染的易感性。一致地，IFN-γ或 Janus 激酶（JAK）-STAT 信号的遗传和药物抑制改善了黏膜真菌病。因此，我们确定了异常的 T 细胞依赖性、1 型黏膜炎症作为一种关键的组织特异性致病机制，促进了小鼠和人类黏膜真菌感染的易感性。
