Molecular characterisation of Toll-like receptor 4 biased signalling through the TIR-domain-containing adapter-inducing interferon-beta

通过含有 TIR 结构域的接头诱导干扰素-β 的 Toll 样受体 4 偏向信号传导的分子表征

• 批准号: BB/V000276/1
• 负责人: Clare Bryant
• 金额: $ 144.14万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV000276%2F1
• 关键词: Molecular; characterisation; Toll; like; receptor

Development of successful vaccination strategies in humans of all ages is important not only for healthy ageing across the lifecourse, but also to reduce antimicrobial resistance. Vaccination of animals both to prevent animal diseases and to reduce the burden of zoonotic pathogens is critical to improve animal health and welfare as well as increasing food security. Adjuvants are molecules used to to improve the efficiency of vaccines in man and animals. Many adjuvants target a class of receptors that recognise pathogenic micro-organisms called Pattern Recognition Receptors (PRRs). One PRR, Toll-like Receptor 4 (TLR4), is important for recognising Gram negative bacteria and protecting the host against infections with these bacterial species. Over activity of this receptor, however, leads to severe inflammation and it is thought that increased activation of TLR4 as we age underpins many of the conditions commonly seen in an ageing population. TLR4 activates separate, but linked arms of the immune response. One arm, through a protein called Toll-Interleukin 1 Receptor (TIR)-domain-containing adapter-inducing interferon-beta (Trif), is very efficient at facilitating the development of protective vaccine responses. The other, through a protein called Myeloid Differentiation Primary Response 88 (MyD88), protects animals against Gram negative bacterial infections. An adjuvant molecule monophosphoryl lipid A (MPLA) selectively activates Trif in humans, but the mechanisms by which this occurs are not understood. In this grant we will determine how MPLA activates TLR4-Trif by changing the structure of TLR4 and determining whether this alters activation of Trif and/or MyD88. We will also determine the protein complexes formed by Trif after MPLA activation of immune cells. Finally we will try and identify molecules that will selectively target TLR4 and Trif driven immune responses to generate new compounds for vaccine adjuvants and other therapeutic applications.

在所有年龄段的人类中，制定成功的疫苗接种策略不仅对整个生命过程的健康衰老都很重要，而且对于降低抗菌素耐药性也很重要。动物的疫苗接种以预防动物疾病和减轻人畜共患病原体的负担对于改善动物健康和福利以及提高粮食安全至关重要。佐剂是用于提高人和动物疫苗效率的分子。许多佐剂靶向一类识别称为模式识别受体（PRR）的致病微生物的受体。一个PRR Toll样受体4（TLR4）对于识别革兰氏阴性细菌并保护宿主免受这些细菌物种的感染至关重要。然而，这种受体的活性导致严重的炎症，人们认为随着年龄的增长为基础，TLR4的激活增加了许多在老龄化人群中常见的疾病。 TLR4激活免疫反应的分开但连接的臂。通过称为Toll-Interleukin 1受体（TIR） - 富含域的辅助转络诱导干扰素β（TRIF）的蛋白质的一只臂非常有效地促进保护性疫苗反应的发展。另一个通过一种称为髓样分化的蛋白质原发性反应88（MYD88）保护动物免受革兰氏阴性细菌感染的影响。辅助分子单磷酸脂质A（MPLA）选择性地激活了人类中的TRIF，但尚不清楚发生这种情况的机制。在这笔赠款中，我们将通过更改TLR4的结构并确定这种激活TRIF和/或MYD88来确定MPLA如何激活TLR4-TRIF。我们还将确定免疫细胞MPLA激活后TRIF形成的蛋白质复合物。最后，我们将尝试确定将有选择地靶向TLR4和TRIF驱动免疫反应的分子，以生成用于疫苗佐剂和其他治疗应用的新化合物。

项目成果

The delayed kinetics of Myddosome formation explains why Aß aggregates trigger TLR4 less efficiently than LPS

Myddosome 形成的延迟动力学解释了为什么 A 聚集体触发 TLR4 的效率低于 LPS

• DOI: 10.7554/elife.92350.1
• 发表时间: 2024
• 作者: Suresh P

Toll-like receptor 4 and macrophage scavenger receptor 1 crosstalk regulates phagocytosis of a fungal pathogen.

• DOI: 10.1038/s41467-023-40635-w
• 发表时间: 2023-08-14
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Onyishi, Chinaemerem U.;Desanti, Guillaume E.;Wilkinson, Alex L.;Lara-Reyna, Samuel;Frickel, Eva-Maria;Fejer, Gyorgy;Christophe, Olivier D.;Bryant, Clare E.;Mukhopadhyay, Subhankar;Gordon, Siamon;May, Robin C.
• 通讯作者: May, Robin C.

The IRAK4 scaffold integrates TLR4-driven TRIF and MYD88 signaling pathways.

• DOI: 10.1016/j.celrep.2022.111225
• 发表时间: 2022-08-16
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Pereira, Milton;Durso, Danielle F.;Bryant, Clare E.;Kurt-Jones, Evelyn A.;Silverman, Neal;Golenbock, Douglas T.;Gazzinelli, Ricardo T.
• 通讯作者: Gazzinelli, Ricardo T.