Determining age dependent factors driving COVID-19 disease severity using experimental human paediatric and adult models of SARS-CoV-2 infection

使用 SARS-CoV-2 感染的实验性人类儿童和成人模型确定导致 COVID-19 疾病严重程度的年龄依赖因素

• 批准号: BB/V006738/1
• 负责人: Claire Smith
• 金额: $ 48.83万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV006738%2F1
• 关键词: Determining; age; dependent; factors; driving

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic of COVID-19. Our lack of understanding about the pathogenesis of SARS-CoV-2 in the human airways is an important barrier to developing effective treatment strategies for COVID-19. So far, we know that COVID-19 disease severity increases with age, with very few severe cases among children. In China, the case fatality ratio was 60-year olds, rising to 15% in those >80. This project will focus on two aspects of the host response of infection, studying how the cells that line the airway respond to the virus, and whether the recruited immune cells (focussing on the behaviour of neutrophils that are the first to respond to infection) the help reduce viral load or contribute to airway damage and the build-up of debris in the airways. We will use an experimental SARS-CoV-2 infection model of the airway epithelium from young children, adults and the elderly. Our objectives are to determine: 1) if the primary site of infection - the nasal epithelium - of the elderly exhibit increased viral replication and increased inflammatory response to SARS-CoV-2 infection compared to children.2) the molecular mechanisms that govern age-determinants of COVID-19 disease severity using single-cell genomic analysis of cultured cells and comparing outputs to the same data from age-matched COVID-19 patients using scRNAseq.3) whether the innate immune response to SARS-CoV2 infected airway epithelium exacerbates inflammation and contributes to the severity of illness in the elderly by measuring a) the intensity of immune cell (neutrophil) recruitment to the airway b) epithelial damage and c) neutrophil phenotype and function.It is important that we understand the reasons for these fundamental differences in responses in order to help determine what the most appropriate therapy is for COVID-19 disease in these age groups. There is much debate about the utility of novel and exsiting anti-virals as well as immune modulator therapies including NSAIDs and Tocilizumab. This project will rapidly deliver new understanding about the viral pathogenesis and the cause of these age-related disparties in disease outcomes. Not only will this help support the development of effective therapeutics in the short-term, underlining the relevance of this model for the preclinical evaluation of antiviral candidates, but it may also highlight important risk factors or protective mechanisms that could be used to develop early interventional or prophylaxtic therapies in the long-term.

严重急性呼吸道综合征冠状病毒2（SARS-CoV-2）已导致COVID-19全球大流行。我们对SARS-CoV-2在人类气道中的发病机制缺乏了解，这是开发COVID-19有效治疗策略的一个重要障碍。到目前为止，我们知道COVID-19疾病的严重程度随着年龄的增长而增加，儿童中的重症病例很少。在中国，病死率为60奥尔兹，而在80岁以上的人群中，病死率上升至15%。该项目将重点关注感染的宿主反应的两个方面，研究气道细胞如何对病毒作出反应，以及招募的免疫细胞（重点关注首先对感染作出反应的中性粒细胞的行为）是否有助于减少病毒载量或有助于气道损伤和气道碎片的积聚。我们将使用来自幼儿、成人和老年人的气道上皮的SARS-CoV-2感染实验模型。我们的目标是确定：1）与儿童相比，老年人的主要感染部位-鼻上皮-是否表现出增加的病毒复制和增加的对SARS-CoV-2感染的炎症反应。2）使用培养细胞的单细胞基因组分析并将输出与年龄匹配的COVID-19疾病严重程度的相同数据进行比较，3）对SARS-CoV 2感染的气道上皮的先天免疫应答是否加剧炎症并有助于老年人疾病的严重性，通过测量a）免疫细胞的强度，（嗜中性粒细胞）募集到气道B）上皮损伤和c）重要的是，我们要了解这些反应的根本差异的原因，以帮助确定什么是中性粒细胞表型和功能。最合适的治疗方法是针对这些年龄组的COVID-19疾病。关于新的和现有的抗病毒药物以及免疫调节剂疗法（包括NSAID和托珠单抗）的效用存在很多争论。该项目将迅速提供有关病毒发病机制和疾病结局中这些年龄相关疾病的原因的新认识。这不仅有助于支持在短期内开发有效的治疗方法，强调该模型与抗病毒候选药物临床前评价的相关性，而且还可能突出重要的风险因素或保护机制，可用于开发早期干预或长期治疗。

项目成果

The cellular immune response to COVID-19 deciphered by single cell multi-omics across three UK centres

• DOI: 10.1101/2021.01.13.21249725
• 发表时间: 2021-01
• 作者: Emily Stephenson;Gary Reynolds;R. Botting;F. Calero-Nieto;Michael Morgan;Z. Tuong;Karsten Bach;W. Sungnak;Kaylee B. Worlock;M. Yoshida;Natsuhiko Kumasaka;Katarzyna Kania;J. Engelbert;B. Olabi;J. Spegarova;Nicola K Wilson;N. Mende;Laura Jardine;Louis C. S. Gardner;Issac Goh;Dave Horsfall;J. McGrath;S. Webb;M. Mather;Rik G. H. Lindeboom;Emma Dann;N. Huang;K. Polański;E. Prigmore;F. Gothe;Jonathan Scott;R. Payne;K. Baker;Aidan T. Hanrath;Ina Schim van der Loeff;Andrew S Barr;A. Sánchez-González;L. Bergamaschi;F. Mescia;Josephine L. Barnes;E. Kilich;A. de Wilton;Anita Saigal;Aarash Saleh;Sam M. Janes;Claire M. Smith;N. Gopee;Caroline Wilson;P. Coupland;J.M Coxhead;Vladimir Y Kiselev;Stijn van Dongen;Jaume Bacardit;Hamish W. King;A. Rostron;A. J. Simpson;S. Hambleton;E. Laurenti;Paul A. Lyons;Kerstin B. Meyer;Marko Z Nikolić;Christopher J A Duncan;Kenneth G. C. Smith;Sarah A. Teichmann;M. Clatworthy;J. Marioni;Berthold Gottgens;M. Haniffa

COVID-19: Extensive epithelial damage and ciliary dyskinesia in hospitalised patients.

COVID-19：住院患者出现广泛的上皮损伤和纤毛运动障碍。

• DOI: 10.4193/rhin21.233
• 发表时间: 2022
• 期刊: Rhinology
• 影响因子: 7.2
• 作者: Lee DDH

Cell-intrinsic differences between human airway epithelial cells from children and adults.

• DOI: 10.1016/j.isci.2022.105409
• 发表时间: 2022-11-18
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Maughan, Elizabeth F.;Hynds, Robert E.;Pennycuick, Adam;Nigro, Ersilia;Gowers, Kate H. C.;Denais, Celine;Gomez-Lopez, Sandra;Lazarus, Kyren A.;Orr, Jessica C.;Pearce, David R.;Clarke, Sarah E.;Lee, Dani Do Hyang;Woodall, Maximillian N. J.;Masonou, Tereza;Case, Katie-Marie;Teixeira, Vitor H.;Hartley, Benjamin E.;Hewitt, Richard J.;Al Yaghchi, Chadwan;Sandhu, Gurpreet S.;Birchall, Martin A.;O'Callaghan, Christopher;Smith, Claire M.;De Coppi, Paolo;Butler, Colin R.;Janes, Sam M.
• 通讯作者: Janes, Sam M.

Lung viral infection modelling in a bioengineered whole-organ.

• DOI: 10.1016/j.biomaterials.2023.122203
• 发表时间: 2023-10
• 期刊: Biomaterials
• 影响因子: 14

Single-cell multi-omics analysis of the immune response in COVID-19.

• DOI: 10.1038/s41591-021-01329-2
• 发表时间: 2021-05
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Stephenson E;Reynolds G;Botting RA;Calero-Nieto FJ;Morgan MD;Tuong ZK;Bach K;Sungnak W;Worlock KB;Yoshida M;Kumasaka N;Kania K;Engelbert J;Olabi B;Spegarova JS;Wilson NK;Mende N;Jardine L;Gardner LCS;Goh I;Horsfall D;McGrath J;Webb S;Mather MW;Lindeboom RGH;Dann E;Huang N;Polanski K;Prigmore E;Gothe F;Scott J;Payne RP;Baker KF;Hanrath AT;Schim van der Loeff ICD;Barr AS;Sanchez-Gonzalez A;Bergamaschi L;Mescia F;Barnes JL;Kilich E;de Wilton A;Saigal A;Saleh A;Janes SM;Smith CM;Gopee N;Wilson C;Coupland P;Coxhead JM;Kiselev VY;van Dongen S;Bacardit J;King HW;Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID-19 BioResource Collaboration;Rostron AJ;Simpson AJ;Hambleton S;Laurenti E;Lyons PA;Meyer KB;Nikolić MZ;Duncan CJA;Smith KGC;Teichmann SA;Clatworthy MR;Marioni JC;Göttgens B;Haniffa M
• 通讯作者: Haniffa M