The genetic basis of invasive meningococcal disease

侵袭性脑膜炎球菌病的遗传基础

• 批准号: MR/S032304/1
• 负责人: Vanessa Sancho Shimizu
• 金额: $ 156.05万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS032304%2F1
• 关键词: genetic; basis; invasive; meningococcal; disease

Invasive meningococcal disease (IMD) is a rare disease affecting children and young adults due to bacterial infection by Neisseria meningitidis. Life-threatening infection of the blood, and/or brain lead to IMD. Although most people carry this bacteria in their nose, the majority do not develop IMD. We know that genetic mutations of specific immune pathways make individuals more susceptible to IMD. Patients with these mutations are unable to produce factors that help kill the bacteria. These mutations however are only present in a small number of IMD patients. We thus put forward the idea that other genetic mutations may exist in IMD patients. To identify new genes in IMD, we sequenced DNA from ~700 children with life-threatening bacterial infections, including 250 IMD patients. The sequences from these patients revealed mutations in other protective immune signalling pathways known to be involved in sensing invading bacteria. Here, we propose to test whether these new mutations affect the way a cell responds to the bacteria in an experimental infection. We will use cells from the lining of the airway, and blood cells. We chose to carry out these experiments in these cell types as airway cells are important for the entry of bacteria into the nose, and the blood cells will model the 'invasive' stage of disease when the bacteria replicates in the blood leading to life-threatening infection. Finally we will test some of these mutations in a zebrafish model of bacterial infection where we may visualize how the body responds to infection in real-time. Understanding the role of these genes will improve our understanding of why certain individuals develop life-threatening infections and may lead to better treatment and prevention of childhood infections.

侵袭性脑膜炎球菌病（IMD）是一种罕见的疾病，影响儿童和年轻人由于细菌感染脑膜炎奈瑟菌。危及生命的血液和/或大脑感染导致IMD。虽然大多数人的鼻子里都有这种细菌，但大多数人不会患上IMD。我们知道，特定免疫途径的基因突变使个体更容易患IMD。具有这些突变的患者无法产生有助于杀死细菌的因子。然而，这些突变仅存在于少数IMD患者中。因此，我们提出了IMD患者中可能存在其他基因突变的想法。为了确定IMD中的新基因，我们对约700名患有危及生命的细菌感染的儿童进行了DNA测序，其中包括250名IMD患者。来自这些患者的序列揭示了已知参与感知入侵细菌的其他保护性免疫信号通路的突变。在这里，我们建议测试这些新的突变是否会影响细胞在实验感染中对细菌的反应方式。我们将使用来自气道内层的细胞和血细胞。我们选择在这些细胞类型中进行这些实验，因为气道细胞对于细菌进入鼻子很重要，而血细胞将模拟疾病的“侵入性”阶段，当细菌在血液中复制导致危及生命的感染时。最后，我们将在细菌感染的斑马鱼模型中测试其中的一些突变，在那里我们可以实时观察身体对感染的反应。了解这些基因的作用将有助于我们了解为什么某些人会发生危及生命的感染，并可能导致更好的治疗和预防儿童感染。

项目成果

Risk of adverse outcomes in patients with underlying respiratory conditions admitted to hospital with COVID-19: a national, multicentre prospective cohort study using the ISARIC WHO Clinical Characterisation Protocol UK.

• DOI: 10.1016/s2213-2600(21)00013-8
• 发表时间: 2021-07
• 期刊: The Lancet. Respiratory medicine
• 作者: Bloom CI;Drake TM;Docherty AB;Lipworth BJ;Johnston SL;Nguyen-Van-Tam JS;Carson G;Dunning J;Harrison EM;Baillie JK;Semple MG;Cullinan P;Openshaw PJM;ISARIC investigators
• 通讯作者: ISARIC investigators

Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths.

• DOI: 10.1126/sciimmunol.abl4340
• 发表时间: 2021-08-19
• 期刊: Science immunology
• 影响因子: 24.8
• 作者: Bastard P;Gervais A;Le Voyer T;Rosain J;Philippot Q;Manry J;Michailidis E;Hoffmann HH;Eto S;Garcia-Prat M;Bizien L;Parra-Martínez A;Yang R;Haljasmägi L;Migaud M;Särekannu K;Maslovskaja J;de Prost N;Tandjaoui-Lambiotte Y;Luyt CE;Amador-Borrero B;Gaudet A;Poissy J;Morel P;Richard P;Cognasse F;Troya J;Trouillet-Assant S;Belot A;Saker K;Garçon P;Rivière JG;Lagier JC;Gentile S;Rosen LB;Shaw E;Morio T;Tanaka J;Dalmau D;Tharaux PL;Sene D;Stepanian A;Megarbane B;Triantafyllia V;Fekkar A;Heath JR;Franco JL;Anaya JM;Solé-Violán J;Imberti L;Biondi A;Bonfanti P;Castagnoli R;Delmonte OM;Zhang Y;Snow AL;Holland SM;Biggs C;Moncada-Vélez M;Arias AA;Lorenzo L;Boucherit S;Coulibaly B;Anglicheau D;Planas AM;Haerynck F;Duvlis S;Nussbaum RL;Ozcelik T;Keles S;Bousfiha AA;El Bakkouri J;Ramirez-Santana C;Paul S;Pan-Hammarström Q;Hammarström L;Dupont A;Kurolap A;Metz CN;Aiuti A;Casari G;Lampasona V;Ciceri F;Barreiros LA;Dominguez-Garrido E;Vidigal M;Zatz M;van de Beek D;Sahanic S;Tancevski I;Stepanovskyy Y;Boyarchuk O;Nukui Y;Tsumura M;Vidaur L;Tangye SG;Burrel S;Duffy D;Quintana-Murci L;Klocperk A;Kann NY;Shcherbina A;Lau YL;Leung D;Coulongeat M;Marlet J;Koning R;Reyes LF;Chauvineau-Grenier A;Venet F;Monneret G;Nussenzweig MC;Arrestier R;Boudhabhay I;Baris-Feldman H;Hagin D;Wauters J;Meyts I;Dyer AH;Kennelly SP;Bourke NM;Halwani R;Sharif-Askari NS;Dorgham K;Sallette J;Sedkaoui SM;AlKhater S;Rigo-Bonnin R;Morandeira F;Roussel L;Vinh DC;Ostrowski SR;Condino-Neto A;Prando C;Bonradenko A;Spaan AN;Gilardin L;Fellay J;Lyonnet S;Bilguvar K;Lifton RP;Mane S;HGID Lab;COVID Clinicians;COVID-STORM Clinicians;NIAID Immune Response to COVID Group;NH-COVAIR Study Group;Danish CHGE;Danish Blood Donor Study;St. James's Hospital;SARS CoV2 Interest group;French COVID Cohort Study Group;Imagine COVID-Group;Milieu Intérieur Consortium;CoV-Contact Cohort;Amsterdam UMC Covid-19;Biobank Investigators;COVID Human Genetic Effort;CONSTANCES cohort;3C-Dijon Study;Cerba Health-Care;Etablissement du Sang study group;Anderson MS;Boisson B;Béziat V;Zhang SY;Vandreakos E;Hermine O;Pujol A;Peterson P;Mogensen TH;Rowen L;Mond J;Debette S;de Lamballerie X;Duval X;Mentré F;Zins M;Soler-Palacin P;Colobran R;Gorochov G;Solanich X;Susen S;Martinez-Picado J;Raoult D;Vasse M;Gregersen PK;Piemonti L;Rodríguez-Gallego C;Notarangelo LD;Su HC;Kisand K;Okada S;Puel A;Jouanguy E;Rice CM;Tiberghien P;Zhang Q;Cobat A;Abel L;Casanova JL
• 通讯作者: Casanova JL

Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children.

• DOI: 10.1084/jem.20231353
• 发表时间: 2024-02-05
• 期刊: The Journal of experimental medicine

Group A streptococcal disease in paediatric inpatients: a European perspective.

• DOI: 10.1007/s00431-022-04718-y
• 发表时间: 2023-02
• 期刊: European journal of pediatrics
• 影响因子: 3.6
• 作者: Boeddha NP;Atkins L;de Groot R;Driessen G;Hazelzet J;Zenz W;Carrol ED;Anderson ST;Martinon-Torres F;Agyeman PKA;Galassini R;Herberg J;Levin M;Schlapbach LJ;Emonts M;EUCLIDS consortium
• 通讯作者: EUCLIDS consortium

Whole-exome Sequencing for the Identification of Rare Variants in Primary Immunodeficiency Genes in Children With Sepsis: A Prospective, Population-based Cohort Study.

脓毒症儿童原发性免疫缺陷基因中稀有变异的稀有变异的全外观测序：一项前瞻性，基于人群的队列研究。

• DOI: 10.1093/cid/ciaa290
• 发表时间: 2020-12-17
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
• 作者: Borghesi A;Trück J;Asgari S;Sancho-Shimizu V;Agyeman PKA;Bellos E;Giannoni E;Stocker M;Posfay-Barbe KM;Heininger U;Bernhard-Stirnemann S;Niederer-Loher A;Kahlert CR;Natalucci G;Relly C;Riedel T;Kuehni CE;Thorball CW;Chaturvedi N;Martinon-Torres F;Kuijpers TW;Coin L;Wright V;Herberg J;Levin M;Aebi C;Berger C;Fellay J;Schlapbach LJ
• 通讯作者: Schlapbach LJ