Toll样蛋白受体13的天然免疫识别

Toll样蛋白受体（Toll-like receptors，TLRs）是机体识别病原菌相关分子模式的天然免疫识别受体。不同于其他TLRs，TLR13是TLR家族被忽视的受体。近年研究发现TLR13受体特异性识别细菌23S核糖体RNA，然而其同配体RNA的天然免疫特异性分子识别的机理和动态过程这一基础科学问题不完全清楚。本项目应用分子动力学模拟阐明胞内体/溶酶体生理条件下(pH = 5.0) TLR13同其配体识别的分子机理。同静态的晶体结构比较，分子动力学模拟能提供丰富的分子识别动态过程。为了更好地验证TLR13的天然免疫识别机理，除了计算模拟外，本项目将应用超分辨成像原位研究TLR13受体在膜域的动态平衡分布及其配体RNA诱导TLR13受体存在形式的转换和其动力学。综上，本项目将阐明TLR13特异性识别配体RNA的分子机理，加深了解天然免疫系统识别病原菌的分子机制，因而具有重要意义。

Innate immunity is a conserved mechanism for protecting host from pathogenic bacteria infection. Toll-like receptors (TLRs) detect pathogen-associated molecular patterns (PAMPs). Unlike other TLRs, TLR13 has long been neglected. Recently TLR13 has been discovered to recognize 23S ribosomal RNA. However, how TLR13 recognizes RNA ligand is NOT fully understood. Herein, molecular dynamics (MD) simulations will be used to dissect the molecular mechanism of the innate immune recognition of TLR13 with RNA ligand at the physiology condition (pH = 5.0) of endosome/lysozyme. Compared to static X-ray crystallography, MD simulations can provide information of the dynamic process of how TLR13 detects RNA ligand. Meanwhile, super-resolution microscopy imaging will be used to see how the dynamic equilibrium of TLR13 is distributed at the membrane of endosome/lysozyme and how RNA ligand binding shifts the distribution of different forms of TLR13, which will experimentally testify the possible binding mechanisms proposed by MD simulations. By combining in-silico computation and cell based in-situ super-resolution microscopy imaging, this project will dissect molecular mechanism and dynamic process of the innate immune recognition of RNA ligand by TLR13, which will further our understanding of how innate immunity detects pathogenic bacteria.