Immune responses to SARS-CoV2 cause activation of platelets, resulting in thrombosis, which can be ameliorated by re-purposed drugs

对 SARS-CoV2 的免疫反应会导致血小板活化，导致血栓形成，可以通过重新利用药物来改善血栓形成

• 批准号: MR/W015293/1
• 负责人: Jonathan Gibbins
• 金额: $ 47.26万
• 依托单位: University of Reading
• 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: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW015293%2F1
• 关键词: Immune; responses; SARS; CoV2; cause

Severe COVID-19 infection is associated with the formation of blood clots in the lungs and other organs which dangerously compromise their functions and contribute to mortality of this disease. Platelets are blood cells that trigger blood clotting following an injury, and while abnormal platelet function is associated with thrombosis, the role of these cells in triggering COVID-19-associated clotting is uncertain. In this study we will determine whether changes in platelet function accompanies disease progression and recovery. The serious symptoms suffered by COVID-19 patients are associated with an exaggerated inflammatory response. We hypothesise that this leads to activation of clotting within the blood vessels of the lungs. Importantly the control of clotting and inflammation involves similar processes and proteins within platelets and immune cells involving molecules that may be controlled using drugs that have been designed to control immune responses. Our preliminary experiments have revealed a mechanism which may explain why some patients appear to be particularly predisposed to serious effects of COVID-19 infection while others are relatively unaffected. Antibodies again the virus formed in seriously ill patients appear to be abnormal (pathological antibodies). These stimulate enhanced immune cell function, which may initiate inflammation of blood vessels. Importantly, we have found that these antibodies also stimulate enhanced platelet clotting. This study will be incorporated with an ongoing clinical trial to test the benefits of repurposing drugs that are designed to target the over-active inflammatory response to virus seen in severe infection through inhibiting enzyme proteins that are also important for the regulation of platelet function. Importantly, we have shown that one drug in our trial, fostamatinib, targets the effects of pathological antibodies on platelets, and prevents them from enhancing platelet clotting. We will therefore assess whether drugs that target the effects of these antibodies reduce platelet function in patients, in comparison with patients receiving standard treatments, and examine whether potential benefits of these new treatments are associated with diminished platelet function. The outcomes from this study will establish whether abnormal platelet function lies behind life-threatening COVID pathology, and whether use of drugs that target both the platelet and immune responses to the virus offer promising therapeutic options. If successful, drug repurposing would offer the potential for rapid impact on patient outcomes.

严重的COVID-19感染与肺部和其他器官中血栓的形成有关，这会危险地损害其功能并导致这种疾病的死亡率。血小板是在受伤后触发血液凝固的血细胞，虽然血小板功能异常与血栓形成有关，但这些细胞在触发COVID-19相关凝血中的作用尚不确定。在这项研究中，我们将确定血小板功能的变化是否伴随着疾病的进展和恢复。COVID-19患者的严重症状与夸张的炎症反应有关。我们假设这导致肺血管内凝血的激活。重要的是，凝血和炎症的控制涉及血小板和免疫细胞内的类似过程和蛋白质，涉及可以使用设计用于控制免疫反应的药物控制的分子。我们的初步实验揭示了一种机制，可以解释为什么有些患者似乎特别容易受到COVID-19感染的严重影响，而其他人则相对不受影响。抗体再次病毒形成的重病患者似乎是不正常的（病理性抗体）.这些刺激增强的免疫细胞功能，这可能会引发血管炎症。重要的是，我们发现这些抗体还刺激增强的血小板凝血。这项研究将与一项正在进行的临床试验相结合，以测试重新利用药物的益处，这些药物旨在通过抑制对血小板功能调节也很重要的酶蛋白来靶向严重感染中对病毒过度活跃的炎症反应。重要的是，我们已经证明，在我们的试验中，一种药物，fostamatinib，靶向病理抗体对血小板的影响，并防止它们增强血小板凝血。因此，我们将评估与接受标准治疗的患者相比，靶向这些抗体作用的药物是否会降低患者的血小板功能，并检查这些新治疗的潜在益处是否与血小板功能降低相关。这项研究的结果将确定血小板功能异常是否是威胁生命的COVID病理学的原因，以及使用靶向血小板和对病毒的免疫反应的药物是否提供了有希望的治疗选择。如果成功，药物再利用将提供对患者结果产生快速影响的潜力。

项目成果

An agent-based approach for modelling and simulation of glycoprotein VI receptor diffusion, localisation and dimerisation in platelet lipid rafts.

• DOI: 10.1038/s41598-023-30884-6
• 发表时间: 2023-03-08
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Tantiwong, Chukiat;Dunster, Joanne L.;Cavill, Rachel;Tomlinson, Michael G.;Wierling, Christoph;Heemskerk, Johan W. M.;Gibbins, Jonathan M.
• 通讯作者: Gibbins, Jonathan M.

Identification of new drugs to counteract anti-spike IgG-induced hyperinflammation in severe COVID-19.

• DOI: 10.26508/lsa.202302106
• 发表时间: 2023-11
• 期刊: LIFE SCIENCE ALLIANCE
• 影响因子: 4.4
• 作者: Geyer, Chiara E.;Chen, Hung-Jen;Bye, Alexander P.;Manz, Xue;Guerra, Denise;Caniels, Tom G.;Bijl, Tom P. L.;Griffith, Guillermo R.;Hoepel, Willianne;de Taeye, Steven W.;Veth, Jennifer;Vlaar, Alexander P. J.;Vidarsson, Gestur;Bogaard, Harm Jan;Aman, Jurjan;Gibbins, Jonathan M.;van Gils, Marit J.;de Winther, Menno P. J.;den Dunnen, Jeroen
• 通讯作者: den Dunnen, Jeroen

Aberrant glycosylation of anti-SARS-CoV-2 spike IgG is a prothrombotic stimulus for platelets.

• DOI: 10.1182/blood.2021011871
• 发表时间: 2021-10-21
• 期刊: Blood
• 影响因子: 20.3
• 作者: Bye AP;Hoepel W;Mitchell JL;Jégouic S;Loureiro S;Sage T;Vidarsson G;Nouta J;Wuhrer M;de Taeye S;van Gils M;Kriek N;Cooper N;Jones I;den Dunnen J;Gibbins JM
• 通讯作者: Gibbins JM

A System-Wide Investigation and Stratification of the Hemostatic Proteome in Premature Myocardial Infarction.

• DOI: 10.3389/fcvm.2022.919394
• 发表时间: 2022
• 期刊: FRONTIERS IN CARDIOVASCULAR MEDICINE
• 影响因子: 3.6
• 作者: Dunster, Joanne L.;Wright, Joy R.;Samani, Nilesh J.;Goodall, Alison H.
• 通讯作者: Goodall, Alison H.

Platelet-driven routes to chaos in a model of hepatitis

肝炎模型中血小板驱动的混乱途径

• DOI: 10.1016/j.chaos.2023.113338
• 发表时间: 2023
• 期刊: Chaos, Solitons & Fractals
• 作者: Nelson M