炎性小体是先天免疫防御的重要前哨，可响应多种刺激（包括病原体相关分子模式，PAMP）。炎性小体的活化为曲霉病提供了宿主防御能力，这是免疫受损患者的主要健康问题。响应细菌和病毒感染而激活炎性体的特定PAMPs是已知的，但真菌PAMP的身份仍不清楚。以往的研究表明，烟曲霉的分生孢子不能激活炎性体，而其菌丝却能激活炎性体。所以，研究人员猜测激活炎症小体的成分仅存在于烟曲霉菌丝中。真菌的细胞壁表面主要由多糖组成，这种组成在真菌的整个生命周期中都会发生变化。半乳糖氨基半乳聚糖（GAG）存在于菌丝上，但在分生孢子上却完全不存在，被认为是主要的毒力因子。来自其他微生物病原体的多糖能够触发炎性小体的激活。因此，研究人员假设GAG可能是烟曲霉诱导炎性小体激活的关键。

研究人员发现，烟曲霉的GAG是激活NLRP3炎性小体的PAMP。GAG与核糖体蛋白的结合会抑制细胞翻译机器，从而激活NLRP3炎性小体。半乳糖胺部分与核糖体蛋白结合并阻止细胞翻译，从而触发了NLRP3炎性体的激活。在小鼠中，GAG缺陷型曲霉突变体（Δgt4c）不会引起炎性小体的保护性活化，并且该菌株表现出增强的毒力。此外，GAG的给药以炎症小体依赖性方式保护小鼠免受硫酸葡聚糖钠诱导的结肠炎。因此，核糖体将这种真菌PAMP的感应与先天免疫应答的激活联系起来。

附：英文原文

Title: Galactosaminogalactan activates the inflammasome to provide host protection

Author: Benoit Briard, Thierry Fontaine, Parimal Samir, David E. Place, Laetitia Muszkieta, R. K. Subbarao Malireddi, Rajendra Karki, Shelbi Christgen, Perrine Bomme, Peter Vogel, Rmi Beau, Emilia Mellado, Oumaima Ibrahim-Granet, Bernard Henrissat, Ravi C. Kalathur, Cam Robinson, Jean-Paul Latg, Thirumala-Devi Kanneganti

Issue&Volume: 2020-12-02

Abstract: Inflammasomes are important sentinels of innate immune defence that are activated in response to diverse stimuli, including pathogen-associated molecular patterns (PAMPs)1. Activation of the inflammasome provides host defence against aspergillosis2,3, which is a major health concern for patients who are immunocompromised. However, the Aspergillus fumigatus PAMPs that are responsible for inflammasome activation are not known. Here we show that the polysaccharide galactosaminogalactan (GAG) of A. fumigatus is a PAMP that activates the NLRP3 inflammasome. The binding of GAG to ribosomal proteins inhibited cellular translation machinery, and thus activated the NLRP3 inflammasome. The galactosamine moiety bound to ribosomal proteins and blocked cellular translation, which triggered activation of the NLRP3 inflammasome. In mice, a GAG-deficient Aspergillus mutant (Δgt4c) did not elicit protective activation of the inflammasome, and this strain exhibited enhanced virulence. Moreover, administration of GAG protected mice from colitis induced by dextran sulfate sodium in an inflammasome-dependent manner. Thus, ribosomes connect the sensing of this fungal PAMP to the activation of an innate immune response.

DOI: 10.1038/s41586-020-2996-z

Source: https://www.nature.com/articles/s41586-020-2996-z