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.

为所有年龄段的人类制定成功的疫苗接种策略不仅对于整个生命周期的健康老龄化很重要，而且对于减少抗菌素耐药性也很重要。为动物接种疫苗以预防动物疾病并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。佐剂是用于提高人类和动物疫苗效率的分子。许多佐剂针对一类识别病原微生物的受体，称为模式识别受体（PRR）。一种 PRR，即 Toll 样受体 4 (TLR4)，对于识别革兰氏阴性细菌和保护宿主免受这些细菌种类的感染非常重要。然而，这种受体的过度活性会导致严重的炎症，并且人们认为，随着年龄的增长，TLR4 的激活增加是老龄化人群中常见的许多疾病的基础。 TLR4 激活独立但相互关联的免疫反应分支。一只臂通过一种名为 Toll-白细胞介素 1 受体 (TIR) 结构域的蛋白质（包含接头诱导干扰素 β (Trif)），非常有效地促进保护性疫苗反应的发展。另一种是通过一种名为骨髓分化初级反应 88 (MyD88) 的蛋白质，保护动物免受革兰氏阴性细菌感染。佐剂分子单磷酰脂质 A (MPLA) 选择性激活人体中的 Trif，但其发生机制尚不清楚。在这笔资助中，我们将通过改变 TLR4 的结构来确定 MPLA 如何激活 TLR4-Trif，并确定这是否会改变 Trif 和/或 MyD88 的激活。我们还将测定 MPLA 激活免疫细胞后 Trif 形成的蛋白质复合物。最后，我们将尝试识别选择性靶向 TLR4 和 Trif 驱动的免疫反应的分子，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.