Structure-function relationships of Toll-like receptors, key mediators of antiviral innate immunity, in Human Papillomavirus 16 infection and cervical cancer

Toll 样受体（抗病毒先天免疫的关键介质）在人乳头瘤病毒 16 感染和宫颈癌中的结构-功能关系

• 批准号: 23262953
• 负责人: Professor Dr. Alexander Weber, Ph.D.
• 金额: --
• 依托单位: Abteilung Immunologie
• 依托单位国家: 德国
• 项目类别: Independent Junior Research Groups
• 财政年份: 2006
• 资助国家: 德国
• 起止时间: 2005-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/23262953?language=en
• 关键词: Structure; function; relationships; Toll; like

Toll-like receptors (TLRs) are a family of cell surface receptors required for innate activation and subsequent adaptive immunity in response to invasion by bacteria, viruses, and other microbes. TLRs detect a multitude of conserved molecular structures such as bacterial lipopolysaccharide (TLR4), lipoproteins (TLR2); bacterial DNA (TLR9); viral RNA (TLR3 and 7), viral proteins (TLRs 2 and 4) but the molecular principles of ligand recognition, receptor activation and intracellular signalling remain largely unknown. Human Papillomavirus (HPV) 16 is the primary etiological agent for cervical cancer and the second biggest cause of female cancer mortality worldwide. There is evidence that components of the innate immune response are crucial in controlling viral infection. TLRs are among the primary candidates for HPV immune recognition. Consequently, TLRs have an enormous potential in the fight against HPV16-infection and the prevention of cervical cancer. This project attempts to address key aspects of TLR biology from a structure-function perspective. Using available (from protein crystal structures) and deducible (by comparative modelling) structural information, a functional assay based on mutagenesis is employed to identify amino acids of importance for signalling. Subsequently, the effects of mutagenesis will be investigated in more detail using biochemical and biophysical methods. Additionally, the role of TLRs in HPV16 immunity will be investigated. Correlations between TLR single nucleotide polymorphisms (SNPs) and persistent HPV16 infection/cervical cancer will be analyzed by introducing SNP information into the established mutagenesis-based functional screen. Furthermore, TLR expression and the influence of receptor stimulation on the progression of viral infection will be studied in an HPV model of infection.

Toll样受体（TLR）是响应细菌、病毒和其他微生物入侵的先天激活和随后的适应性免疫所需的细胞表面受体家族。TLR检测许多保守的分子结构，例如细菌脂多糖（TLR 4）、脂蛋白（TLR 2）;细菌DNA（TLR 9）;病毒RNA（TLR 3和7）、病毒蛋白（TLR 2和4），但是配体识别、受体活化和细胞内信号传导的分子原理仍然在很大程度上未知。人乳头瘤病毒（HPV）16是宫颈癌的主要病原体，也是全球女性癌症死亡的第二大原因。有证据表明，先天免疫反应的组成部分在控制病毒感染方面至关重要。TLR是HPV免疫识别的主要候选者之一。因此，TLR在对抗HPV 16感染和预防宫颈癌方面具有巨大的潜力。该项目试图从结构-功能的角度解决TLR生物学的关键方面。使用可用的（从蛋白质晶体结构）和可推断的（通过比较建模）结构信息，基于诱变的功能测定被用来鉴定对信号传导重要的氨基酸。随后，将使用生物化学和生物物理方法更详细地研究诱变的影响。此外，还将研究TLR在HPV 16免疫中的作用。TLR单核苷酸多态性（SNP）与持续性HPV 16感染/宫颈癌之间的相关性将通过将SNP信息引入已建立的基于诱变的功能筛选来分析。此外，TLR表达和受体刺激对病毒感染进展的影响将在HPV感染模型中进行研究。