Imperial College London

Dr Vanessa Sancho-Shimizu

Faculty of MedicineDepartment of Infectious Disease

Reader in Human Genetics of Infectious Diseases
 
 
 
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Contact

 

+44 (0)20 7594 3914v.sancho-shimizu

 
 
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Location

 

309Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
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71 results found

Philippot Q, Fekkar A, Gervais A, Le Voyer T, Boers LS, Conil C, Bizien L, de Brabander J, Duitman JW, Romano A, Rosain J, Blaize M, Migaud M, Jeljeli M, Hammadi B, Desmons A, Marchal A, ArtDECO consortium, COVID HGE consortium, Mayaux J, Zhang Q, Jouanguy E, Borie R, Crestani B, Luyt CE, Adle-Biassette H, Sene D, Megarbane B, Cobat A, Bastard P, Bos LDJ, Casanova J-L, Puel Aet al., 2023, Autoantibodies Neutralizing Type I IFNs in the Bronchoalveolar Lavage of at Least 10% of Patients During Life-Threatening COVID-19 Pneumonia., J Clin Immunol, Vol: 43, Pages: 1093-1103

Autoantibodies (auto-Abs) neutralizing type I interferons (IFNs) are found in the blood of at least 15% of unvaccinated patients with life-threatening COVID-19 pneumonia. We report here the presence of auto-Abs neutralizing type I IFNs in the bronchoalveolar lavage (BAL) of 54 of the 415 unvaccinated patients (13%) with life-threatening COVID-19 pneumonia tested. The 54 individuals with neutralizing auto-Abs in the BAL included 45 (11%) with auto-Abs against IFN-α2, 37 (9%) with auto-Abs against IFN-ω, 54 (13%) with auto-Abs against IFN-α2 and/or ω, and five (1%) with auto-Abs against IFN-β, including three (0.7%) with auto-Abs neutralizing IFN-α2, IFN-ω, and IFN-β, and two (0.5%) with auto-Abs neutralizing IFN-α2 and IFN-β. Auto-Abs against IFN-α2 also neutralize the other 12 subtypes of IFN-α. Paired plasma samples were available for 95 patients. All seven patients with paired samples who had detectable auto-Abs in BAL also had detectable auto-Abs in plasma, and one patient had auto-Abs detectable only in blood. Auto-Abs neutralizing type I IFNs are, therefore, present in the alveolar space of at least 10% of patients with life-threatening COVID-19 pneumonia. These findings suggest that these auto-Abs impair type I IFN immunity in the lower respiratory tract, thereby contributing to hypoxemic COVID-19 pneumonia.

Journal article

Lee D, Le Pen J, Yatim A, Dong B, Aquino Y, Ogishi M, Pescarmona R, Talouarn E, Rinchai D, Zhang P, Perret M, Liu Z, Jordan I, Elmas Bozdemir S, Bayhan GI, Beaufils C, Bizien L, Bisiaux A, Lei W, Hasan M, Chen J, Gaughan C, Asthana A, Libri V, Luna JM, Jaffré F, Hoffmann H-H, Michailidis E, Moreews M, Seeleuthner Y, Bilguvar K, Mane S, Flores C, Zhang Y, Arias AA, Bailey R, Schlüter A, Milisavljevic B, Bigio B, Le Voyer T, Materna M, Gervais A, Moncada-Velez M, Pala F, Lazarov T, Levy R, Neehus A-L, Rosain J, Peel J, Chan Y-H, Morin M-P, Pino-Ramirez RM, Belkaya S, Lorenzo L, Anton J, Delafontaine S, Toubiana J, Bajolle F, Fumadó V, DeDiego ML, Fidouh N, Rozenberg F, Pérez-Tur J, Chen S, Evans T, Geissmann F, Lebon P, Weiss SR, Bonnet D, Duval X, CoV-Contact Cohort, COVID Human Genetic Effort, Pan-Hammarström Q, Planas AM, Meyts I, Haerynck F, Pujol A, Sancho-Shimizu V, Dalgard CL, Bustamante J, Puel A, Boisson-Dupuis S, Boisson B, Maniatis T, Zhang Q, Bastard P, Notarangelo L, Béziat V, Perez de Diego R, Rodriguez-Gallego C, Su HC, Lifton RP, Jouanguy E, Cobat A, Alsina L, Keles S, Haddad E, Abel L, Belot A, Quintana-Murci L, Rice CM, Silverman RH, Zhang S-Y, Casanova J-Let al., 2023, Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children., Science, Vol: 379

Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.

Journal article

Wickenhagen A, Sugrue E, Lytras S, Kuchi S, Noerenberg M, Turnbull ML, Loney C, Herder V, Allan J, Jarmson I, Cameron-Ruiz N, Varjak M, Pinto RM, Lee JY, Iselin L, Palmalux N, Stewart DG, Swingler S, Greenwood EJD, Crozier TWM, Gu Q, Davies EL, Clohisey S, Wang B, Maranhao Costa FT, Santana MF, de Lima Ferreira LC, Murphy L, Fawkes A, Meynert A, Grimes G, Filho JLDS, Marti M, Hughes J, Stanton RJ, Wang ECY, Ho A, Davis I, Jarrett RF, Castello A, Robertson DL, Semple MG, Openshaw PJM, Palmarini M, Lehner PJ, Baillie JK, Rihn SJ, Wilson SJet al., 2021, A prenylated dsRNA sensor protects against severe COVID-19, Science, Vol: 374, Pages: 1-18, ISSN: 0036-8075

Journal article

Sabli IKD, Sancho-Shimizu V, 2021, Inborn errors of autophagy and infectious diseases, CURRENT OPINION IN IMMUNOLOGY, Vol: 72, Pages: 272-276, ISSN: 0952-7915

Journal article

Taft J, Markson M, Legarda D, Patel R, Chan M, Malle L, Richardson A, Gruber C, Martin-Fernandez M, Mancini GMS, van Laar JAM, van Pelt P, Buta S, Wokke BHA, Sabli IKD, Sancho-Shimizu V, Chavan PP, Schnappauf O, Khubchandani R, Cuceoglu MK, Ozen S, Kastner DL, Ting AT, Aksentijevich I, Hollink IHIM, Bogunovic Det al., 2021, Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death, CELL, Vol: 184, Pages: 4447-+, ISSN: 0092-8674

Journal article

Drake TM, Riad AM, Fairfield CJ, Egan C, Knight SR, Pius R, Hardwick HE, Norman L, Shaw CA, McLean KA, Thompson AAR, Ho A, Swann OV, Sullivan M, Soares F, Holden KA, Merson L, Plotkin D, Sigfrid L, de Silva TI, Girvan M, Jackson C, Russell CD, Dunning J, Solomon T, Carson G, Olliaro P, Nguyen-Van-Tam JS, Turtle L, Docherty AB, Openshaw PJ, Baillie JK, Harrison EM, Semple MG, ISARIC4C investigatorset al., 2021, Characterisation of in-hospital complications associated with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol UK: a prospective, multicentre cohort study, The Lancet, Vol: 398, Pages: 223-237, ISSN: 0140-6736

BACKGROUND: COVID-19 is a multisystem disease and patients who survive might have in-hospital complications. These complications are likely to have important short-term and long-term consequences for patients, health-care utilisation, health-care system preparedness, and society amidst the ongoing COVID-19 pandemic. Our aim was to characterise the extent and effect of COVID-19 complications, particularly in those who survive, using the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK. METHODS: We did a prospective, multicentre cohort study in 302 UK health-care facilities. Adult patients aged 19 years or older, with confirmed or highly suspected SARS-CoV-2 infection leading to COVID-19 were included in the study. The primary outcome of this study was the incidence of in-hospital complications, defined as organ-specific diagnoses occurring alone or in addition to any hallmarks of COVID-19 illness. We used multilevel logistic regression and survival models to explore associations between these outcomes and in-hospital complications, age, and pre-existing comorbidities. FINDINGS: Between Jan 17 and Aug 4, 2020, 80 388 patients were included in the study. Of the patients admitted to hospital for management of COVID-19, 49·7% (36 367 of 73 197) had at least one complication. The mean age of our cohort was 71·1 years (SD 18·7), with 56·0% (41 025 of 73 197) being male and 81·0% (59 289 of 73 197) having at least one comorbidity. Males and those aged older than 60 years were most likely to have a complication (aged ≥60 years: 54·5% [16 579 of 30 416] in males and 48·2% [11 707 of 24 288] in females; aged <60 years: 48·8% [5179 of 10 609] in males and 36·6% [2814 of 7689] in females). Renal (24·3%, 17 752 of 73 197), complex respiratory (18·4%, 13 486 of 73 197), and systemic (16·3%, 11 895 of 73 197) complications were

Journal article

COVID-19 Host Genetics Initiative, 2021, Mapping the human genetic architecture of COVID-19, Nature, Vol: 600, Pages: 472-477, ISSN: 0028-0836

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3-7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

Journal article

ISARIC Clinical Characterisation Group, 2021, COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study, Infection: journal of infectious disease, Vol: 49, Pages: 899-905, ISSN: 0300-8126

BACKGROUND: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. METHODS: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. RESULTS: 'Typical' symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. INTERPRETATION: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men.

Journal article

Sancho-Shimizu V, Brodin P, Cobat A, Biggs CM, Toubiana J, Lucas CL, Henrickson SE, Belot A, Haddad E, Beland K, Pujol A, Schlüter A, Planas-Serra L, Aguilera-Albesa S, Valencia-Ramos J, Rodríguez-Palmero A, Gut M, Rivière JG, Colobran R, Soler-Palacin P, Rodriguez-Gallego C, Perez De Diego R, Flores C, Alsina L, Blazquez-Gamero D, Jordan I, Keles S, Emiroglu M, Akcan OM, Alkan G, Aytekin SE, Gul Y, Tüter Öz ŞK, Bozdemir SE, Bayhan GI, Yüksek SK, Parlakay AÖ, Gülhan B, Yahşi A, Kilic AO, Karbuz A, Erdeniz EH, Özkan EA, Orbak Z, Aydemir Ş, Celik JB, Kandemir B, Aytekin G, Kapakli H, Yarar V, Yosunkaya A, Vatansev H, Aytekin C, Torun SH, Nepesov S, Coskuner T, Sözeri B, Demirkol YK, Kasapcopur O, Yıldız M, Sevketoglu E, Hatipoğlu N, Özçelik T, Yesilbas O, Gayretli Aydin ZG, Sediva A, Klocperk A, Bloomfield M, Meyts I, Delafontaine S, Haerynck F, Hoste L, Shahrooei M, Marque L, Neves JF, Novelli G, Novelli A, Aiuti A, Casari G, Bousfiha AA, Almuhsen SZ, Sobh A, Gagro A, Bajolle F, Bonnet D, Lebon P, Lei W, Lee D, Seeleuthner Y, Zhang P, Maglorius M, Philippot Q, Pelham S, Bastard P, Zhang Q, Jouanguy E, Puel A, Herberg J, Kuijpers TW, Bellos E, Kaforou M, Menikou S, Pan-Hammarström Q, Hammarström L, Abolhassani H, Bryceson Y, Condino-Neto A, Prando C, Bando SY, Cavalcanti A, Fellay J, Blanchard-Hohner G, Mansouri D, Mahmoudi S, Boyarchuk O, Volokha A, Bondarenko A, Stepanovskiy Y, Mogensen T, van de Beek D, Andreakos E, Papadaki M, Abou Tayoun A, Halwani R, Al-Mulla F, Franco JL, Lau Y-L, Kwan M, Imai K, Okada S, Bolze A, Butte MJ, Hsieh E, Drolet BA, Arkin L, Itan Y, Maniatis T, Arditi M, Cooper M, Schmitt E, Chakravorty S, Anderson MS, Su HC, Notarangelo LD, Tangye SG, Milner JD, Levin M, Abel L, Bogunovic D, Casanova J-L, Zhang S-Yet al., 2021, SARS-CoV-2–related MIS-C: A key to the viral and genetic causes of Kawasaki disease?, Journal of Experimental Medicine, Vol: 218, Pages: 1-16, ISSN: 0022-1007

Multisystem inflammatory syndrome in children (MIS-C) emerged in April 2020 in communities with high COVID-19 rates. This new condition is heterogenous but resembles Kawasaki disease (KD), a well-known but poorly understood and clinically heterogenous pediatric inflammatory condition for which weak associations have been found with a myriad of viral illnesses. Epidemiological data clearly indicate that SARS-CoV-2 is the trigger for MIS-C, which typically occurs about 1 mo after infection. These findings support the hypothesis of viral triggers for the various forms of classic KD. We further suggest that rare inborn errors of immunity (IEIs) altering the immune response to SARS-CoV-2 may underlie the pathogenesis of MIS-C in some children. The discovery of monogenic IEIs underlying MIS-C would shed light on its pathogenesis, paving the way for a new genetic approach to classic KD, revisited as a heterogeneous collection of IEIs to viruses.

Journal article

Gupta RK, Harrison EM, Ho A, Docherty AB, Knight SR, van Smeden M, Abubakar I, Lipman M, Quartagno M, Pius R, Buchan I, Carson G, Drake TM, Dunning J, Fairfield CJ, Gamble C, Green CA, Halpin S, Hardwick HE, Holden KA, Horby PW, Jackson C, Mclean KA, Merson L, Nguyen-Van-Tam JS, Norman L, Olliaro PL, Pritchard MG, Russell CD, Scott-Brown J, Shaw CA, Sheikh A, Solomon T, Sudlow C, Swann OV, Turtle L, Openshaw PJM, Baillie JK, Semple MG, Noursadeghi M, Baillie JK, Semple MG, Openshaw PJM, Carson G, Alex B, Bach B, Barclay WS, Bogaert D, Chand M, Cooke GS, Docherty AB, Dunning J, Filipe ADS, Fletcher T, Green CA, Harrison EM, Hiscox JA, Ho AYW, Horby PW, Ijaz S, Khoo S, Klenerman P, Law A, Lim WS, Mentzer AJ, Merson L, Meynert AM, Noursadeghi M, Moore SC, Palmarini M, Paxton WA, Pollakis G, Price N, Rambaut A, Robertson DL, Russell CD, Sancho-Shimizu V, Scott JT, de Silva T, Sigfrid L, Solomon T, Sriskandan S, Stuart D, Summers C, Tedder RS, Thomson EC, Thompson AAR, Thwaites RS, Turtle LCW, Zambon M, Hardwick H, Donohue C, Lyons R, Griffiths F, Oosthuyzen W, Norman L, Pius R, Drake TM, Fairfield CJ, Knight S, Mclean KA, Murphy D, Shaw CA, Dalton J, Lee J, Plotkin D, Girvan M, Mullaney S, Petersen C, Saviciute E, Roberts S, Harrison J, Marsh L, Connor M, Halpin S, Jackson C, Gamble C, Leeming G, Law A, Wham M, Clohisey S, Hendry R, Scott-Brown J, Greenhalf W, Shaw V, McDonald S, Keating S, Ahmed KA, Armstrong JA, Ashworth M, Asiimwe IG, Bakshi S, Barlow SL, Booth L, Brennan B, Bullock K, Catterall BWA, Clark JJ, Clarke EA, Cole S, Cooper L, Cox H, Davis C, Dincarslan O, Dunn C, Dyer P, Elliott A, Evans A, Finch L, Fisher LWS, Foster T, Garcia-Dorival I, Greenhalf W, Gunning P, Hartley C, Ho A, Jensen RL, Jones CB, Jones TR, Khandaker S, King K, Kiy RT, Koukorava C, Lake A, Lant S, Latawiec D, Lavelle-Langham L, Lefteri D, Lett L, Livoti LA, Mancini M, McDonald S, McEvoy L, McLauchlan J, Metelmann S, Miah NS, Middleton J, Mitchell J, Moore SC, Murphy EG, Penrice-Randalet al., 2021, Development and validation of the ISARIC 4C Deterioration model for adults hospitalised with COVID-19: a prospective cohort study, The Lancet Respiratory Medicine, Vol: 9, Pages: 349-359, ISSN: 2213-2600

BackgroundPrognostic models to predict the risk of clinical deterioration in acute COVID-19 cases are urgently required to inform clinical management decisions.MethodsWe developed and validated a multivariable logistic regression model for in-hospital clinical deterioration (defined as any requirement of ventilatory support or critical care, or death) among consecutively hospitalised adults with highly suspected or confirmed COVID-19 who were prospectively recruited to the International Severe Acute Respiratory and Emerging Infections Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) study across 260 hospitals in England, Scotland, and Wales. Candidate predictors that were specified a priori were considered for inclusion in the model on the basis of previous prognostic scores and emerging literature describing routinely measured biomarkers associated with COVID-19 prognosis. We used internal–external cross-validation to evaluate discrimination, calibration, and clinical utility across eight National Health Service (NHS) regions in the development cohort. We further validated the final model in held-out data from an additional NHS region (London).Findings74 944 participants (recruited between Feb 6 and Aug 26, 2020) were included, of whom 31 924 (43·2%) of 73 948 with available outcomes met the composite clinical deterioration outcome. In internal–external cross-validation in the development cohort of 66 705 participants, the selected model (comprising 11 predictors routinely measured at the point of hospital admission) showed consistent discrimination, calibration, and clinical utility across all eight NHS regions. In held-out data from London (n=8239), the model showed a similarly consistent performance (C-statistic 0·77 [95% CI 0·76 to 0·78]; calibration-in-the-large 0·00 [–0·05 to 0·05]); calibration slope 0·96 [0·91 to 1·01]), and greater net benefit than

Journal article

Yates T, Zaccardi F, Islam N, Razieh C, Gillies CL, Lawson CA, Chudasama Y, Rowlands A, Davies MJ, Docherty AB, Openshaw PJ, Baillie JK, Semple MG, ISARIC4C investigators, Khunti Ket al., 2021, Obesity, ethnicity and risk of critical care, mechanical ventilation and mortality in patients admitted to hospital with COVID-19: Analysis of the ISARIC CCP-UK cohort., Obesity (Silver Spring, Md.), Vol: 29, Pages: 1223-1230, ISSN: 1071-7323

OBJECTIVE: To investigate the association of obesity with in-hospital COVID-19 outcomes in different ethnic groups. METHODS: Patients admitted to hospital with COVID-19 in the United Kingdom through the Clinical Characterisation Protocol UK (CCP-UK) developed by the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) were included from 6th February to 12th October 2020. Ethnicity was classified as: white, South Asian, black and other minority ethnic groups. Outcomes were admission to critical care, mechanical ventilation and in-hospital mortality, adjusted for age, sex and chronic diseases. RESULTS: 54,254 (age = 76 years; 45.0% women) white, 3,728 (57 years; 41.1%) South Asian, 2,523 (58 years; 44.9%) black and 5,427 (61 years; 40.8%) other ethnicities were included. Obesity was associated with all outcomes in all ethnic groups, with associations strongest for black ethnicities. When stratified by ethnicity and obesity status, the OR for admission to critical care, mechanical ventilation and mortality in black ethnicities with obesity were 3.91 (3.13, 4.88), 5.03 (3.94, 6.63), 1.93 (1.49, 2.51) respectively, compared to white ethnicities without obesity. CONCLUSIONS: Obesity was associated with an elevated risk of in-hospital COVID-19 outcomes in all ethnic groups, with associations strongest in black ethnicities.

Journal article

Pairo-Castineira E, Clohisey S, Klaric L, Bretherick AD, Rawlik K, Pasko D, Walker S, Parkinson N, Fourman MH, Russell CD, Furniss J, Richmond A, Gountouna E, Wrobel N, Harrison D, Wang B, Wu Y, Meynert A, Griffiths F, Oosthuyzen W, Kousathanas A, Moutsianas L, Yang Z, Zhai R, Zheng C, Grimes G, Beale R, Millar J, Shih B, Keating S, Zechner M, Haley C, Porteous DJ, Hayward C, Yang J, Knight J, Summers C, Shankar-Hari M, Klenerman P, Turtle L, Ho A, Moore SC, Hinds C, Horby P, Nichol A, Maslove D, Ling L, McAuley D, Montgomery H, Walsh T, Pereira A, Renieri A, GenOMICC Investigators, ISARICC Investigators, COVID-19 Human Genetics Initiative, 23andMe Investigators, BRACOVID Investigators, Gen-COVID Investigators, Shen X, Ponting CP, Fawkes A, Tenesa A, Caulfield M, Scott R, Rowan K, Murphy L, Openshaw PJM, Semple MG, Law A, Vitart V, Wilson JF, Baillie JKet al., 2021, Genetic mechanisms of critical illness in Covid-19, Nature, Vol: 591, Pages: 92-98, ISSN: 0028-0836

Host-mediated lung inflammation is present,1 and drives mortality,2 in critical illness caused by Covid-19. Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development.3 Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study(GWAS) in 2244 critically ill Covid-19 patients from 208 UK intensive care units (ICUs). We identify and replicate novel genome-wide significant associations, on chr12q24.13 (rs10735079, p=1.65 [Formula: see text] 10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), on chr19p13.2 (rs2109069, p=2.3 [Formula: see text] 10-12) near the gene encoding tyrosine kinase 2 (TYK2), on chr19p13.3 (rs2109069, p=3.98 [Formula: see text] 10-12) within the gene encoding dipeptidyl peptidase 9 (DPP9), and on chr21q22.1 (rs2236757, p=4.99 [Formula: see text] 10-8) in the interferon receptor gene IFNAR2. We identify potential targets for repurposing of licensed medications: using Mendelian randomisation we found evidence in support of a causal link from low expression of IFNAR2, and high expression of TYK2, to life-threatening disease; transcriptome-wide association in lung tissue revealed that high expression of the monocyte/macrophage chemotactic receptor CCR2 is associated with severe Covid-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms, and mediators of inflammatory organ damage in Covid-19. Both mechanisms may be amenable to targeted treatment with existing drugs. Large-scale randomised clinical trials will be essential before any change to clinical practice.

Journal article

Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, Abdellatif M, Abdoli A, Abel S, Abeliovich H, Abildgaard MH, Abudu YP, Acevedo-Arozena A, Adamopoulos IE, Adeli K, Adolph TE, Adornetto A, Aflaki E, Agam G, Agarwal A, Aggarwal BB, Agnello M, Agostinis P, Agrewala JN, Agrotis A, Aguilar P, Ahmad ST, Ahmed ZM, Ahumada-Castro U, Aits S, Aizawa S, Akkoc Y, Akoumianaki T, Akpinar HA, Al-Abd AM, Al-Akra L, Al-Gharaibeh A, Alaoui-Jamali MA, Alberti S, Alcocer-Gomez E, Alessandri C, Ali M, Al-Bari MAA, Aliwaini S, Alizadeh J, Almacellas E, Almasan A, Alonso A, Alonso GD, Altan-Bonnet N, Altieri DC, Alves S, da Costa CA, Alzaharna MM, Amadio M, Amantini C, Amaral C, Ambrosio S, Amer AO, Ammanathan V, An Z, Andersen SU, Andrabi SA, Andrade-Silva M, Andres AM, Angelini S, Ann D, Anozie UC, Ansari MY, Antas P, Antebi A, Anton Z, Anwar T, Apetoh L, Apostolova N, Araki T, Araki Y, Arasaki K, Araujo WL, Araya J, Arden C, Arevalo M-A, Arguelles S, Arias E, Arikkath J, Arimoto H, Ariosa AR, Armstrong-James D, Arnaune-Pelloquin L, Aroca A, Arroyo DS, Arsov I, Artero R, Asaro DML, Aschner M, Ashrafizadeh M, Ashur-Fabian O, Atanasov AG, Au AK, Auberger P, Auner HW, Aurelian L, Autelli R, Avagliano L, Avalos Y, Aveic S, Aveleira CA, AvinWittenberg T, Aydin Y, Ayton S, Ayyadevara S, Azzopardi M, Baba M, Backer JM, Backues SK, Bae D-H, Bae O-N, Bae SH, Baehrecke EH, Baek A, Baek S-H, Baek SH, Bagetta G, Bagniewska-Zadworna A, Bai H, Bai J, Bai X, Bai Y, Bairagi N, Baksi S, Balbi T, Baldari CT, Balduini W, Ballabio A, Ballester M, Balazadeh S, Balzan R, Bandopadhyay R, Banerjee S, Banerjee S, Bao Y, Baptista MS, Baracca A, Barbati C, Bargiela A, Barila D, Barlow PG, Barmada SJ, Barreiro E, Barreto GE, Bartek J, Bartel B, Bartolome A, Barve GR, Basagoudanavar SH, Bassham DC, Jr RCB, Basu A, Batoko H, Batten I, Baulieu EE, Baumgarner BL, Bayry J, Beale R, Beau I, Beaumatin F, Bechara LRG, Beck GR, Beers MF, Begun J, Behrends C, Behrens GMN, Bei R, Bejarano E, Bel S, Behl C, Belaid A, Belgareh-Touzeet al., 2021, Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition), Autophagy, Vol: 17, Pages: 1-382, ISSN: 1554-8627

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Journal article

Gao D, Ciancanelli MJ, Zhang P, Harschnitz O, Bondet V, Hasek M, Chen J, Mu X, Itan Y, Cobat A, Sancho-Shimizu V, Bigio B, Lorenzo L, Ciceri G, McAlpine J, Anguiano E, Jouanguy E, Chaussabel D, Meyts I, Diamond MS, Abel L, Hur S, Smith GA, Notarangelo L, Duffy D, Studer L, Casanova J-L, Zhang S-Yet al., 2021, TLR3 controls constitutive IFN-beta antiviral immunity in human fibroblasts and cortical neurons, JOURNAL OF CLINICAL INVESTIGATION, Vol: 131, ISSN: 0021-9738

Journal article

Staller E, Sheppard CM, Baillon L, Frise R, Peacock TP, Sancho-Shimizu V, Barclay WSet al., 2021, A natural variant in ANP32B impairs influenza virus replication in human cells, JOURNAL OF GENERAL VIROLOGY, Vol: 102, ISSN: 0022-1317

Journal article

Hait AS, Olagnier D, Sancho-Shimizu V, Skipper KA, Helleberg M, Larsen SM, Bodda C, Moldovan LI, Ren F, Andersen N-SB, Thomsen MM, Freytag MR, Darmalinggam S, Parkes I, Kadekar DD, Rahbek SH, van der Horst D, Kristensen LS, Eriksson K, Kjems J, Mostowy S, Christiansen M, Mikkelsen JG, Brandt CT, Paludan SR, Mogensen THet al., 2020, Defects in LC3B2 and ATG4A underlie HSV2 meningitis and reveal a critical role for autophagy in antiviral defense in humans, SCIENCE IMMUNOLOGY, Vol: 5, ISSN: 2470-9468

Journal article

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, EUCLIDS consortium and the Swiss Paediatric Sepsis Studyet al., 2020, Whole-exome sequencing for the identification of rare variants in primary immunodeficiency genes in children with sepsis - a prospective population-based cohort study., Clinical Infectious Diseases, Vol: 71, Pages: e614-e623, ISSN: 1058-4838

BACKGROUND: The role of primary immunodeficiencies (PID) in susceptibility to sepsis remains unknown. It is unclear whether children with sepsis benefit from genetic investigations. We hypothesized that sepsis may represent the first manifestation of underlying PID. We applied whole-exome sequencing (WES) to a national cohort of children with sepsis to identify rare, predicted pathogenic variants in PID genes. METHODS: Multicenter population-based prospective study including previously healthy children ≥28 days and <17 years admitted with blood culture-proven sepsis. Using a stringent variant filtering procedure, analysis of WES data was restricted to rare, predicted pathogenic variants in 240 PID genes for which increased susceptibility to bacterial infection has been reported. RESULTS: 176 children presenting with 185 sepsis episodes underwent WES (median age 52 months, IQR 15.4-126.4). 41 unique predicted pathogenic PID variants (1 homozygous, 5 hemizygous, and 35 heterozygous) were found in 35/176 (20%) patients, including 3/176 (2%) patients carrying variants which were previously reported to lead to PID. The variants occurred in PID genes across all 8 PID categories as defined by the International Union of Immunological Societies. We did not observe a significant correlation between clinical or laboratory characteristics of patients and the presence or absence of PID variants. CONCLUSIONS: Applying WES to a population-based cohort of previously healthy children with bacterial sepsis detected Variants of Uncertain Significance in PID genes in one out of five children. Future studies need to investigate the functional relevance of these variants to determine whether variants in PID genes contribute to pediatric sepsis susceptibility.

Journal article

Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J, Ogishi M, Sabli IKD, Hodeib S, Korol C, Rosain J, Bilguvar K, Ye J, Bolze A, Bigio B, Yang R, Arias AA, Zhou Q, Zhang Y, Onodi F, Korniotis S, Karpf L, Philippot Q, Chbihi M, Bonnet-Madin L, Dorgham K, Smith N, Schneider WM, Razooky BS, Hoffmann H-H, Michailidis E, Moens L, Han JE, Lorenzo L, Bizien L, Meade P, Neehus A-L, Ugurbil AC, Corneau A, Kerner G, Zhang P, Rapaport F, Seeleuthner Y, Manry J, Masson C, Schmitt Y, Schlüter A, Le Voyer T, Khan T, Li J, Fellay J, Roussel L, Shahrooei M, Alosaimi MF, Mansouri D, Al-Saud H, Al-Mulla F, Almourfi F, Al-Muhsen SZ, Alsohime F, Al Turki S, Hasanato R, van de Beek D, Biondi A, Bettini LR, D'Angio M, Bonfanti P, Imberti L, Sottini A, Paghera S, Quiros-Roldan E, Rossi C, Oler AJ, Tompkins MF, Alba C, Vandernoot I, Goffard J-C, Smits G, Migeotte I, Haerynck F, Soler-Palacin P, Martin-Nalda A, Colobran R, Morange P-E, Keles S, Çölkesen F, Ozcelik T, Yasar KK, Senoglu S, Karabela ŞN, Gallego CR, Novelli G, Hraiech S, Tandjaoui-Lambiotte Y, Duval X, Laouénan C, COVID-STORM Clinicians, COVID Clinicians, Imagine COVID Group, French COVID Cohort Study Group, CoV-Contact Cohort, Amsterdam UMC Covid-19, Biobank, COVID Human Genetic Effort, NIAID-USUHS, TAGC COVID Immunity Group, Snow AL, Dalgard CL, Milner J, Vinh DC, Mogensen TH, Marr N, Spaan AN, Boisson B, Boisson-Dupuis S, Bustamante J, Puel A, Ciancanelli M, Meyts I, Maniatis T, Soumelis V, Amara A, Nussenzweig M, García-Sastre A, Krammer F, Pujol A, Duffy D, Lifton R, Zhang S-Y, Gorochov G, Béziat V, Jouanguy E, Sancho-Shimizu V, Rice CM, Abel L, Notarangelo LD, Cobat A, Su HC, Casanova J-Let al., 2020, Inborn errors of type I IFN immunity in patients with life-threatening COVID-19, Science, Vol: 370, Pages: 1-16, ISSN: 0036-8075

Clinical outcome upon infection with SARS-CoV-2 ranges from silent infection to lethal COVID-19. We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern TLR3- and IRF7-dependent type I interferon (IFN) immunity to influenza virus, in 659 patients with life-threatening COVID-19 pneumonia, relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally define LOF variants in 23 patients (3.5%), aged 17 to 77 years, underlying autosomal recessive or dominant deficiencies. We show that human fibroblasts with mutations affecting this pathway are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.

Journal article

Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann H-H, Zhang Y, Dorgham K, Philippot Q, Rosain J, Béziat V, Manry J, Shaw E, Haljasmägi L, Peterson P, Lorenzo L, Bizien L, Trouillet-Assant S, Dobbs K, de Jesus AA, Belot A, Kallaste A, Catherinot E, Tandjaoui-Lambiotte Y, Le Pen J, Kerner G, Bigio B, Seeleuthner Y, Yang R, Bolze A, Spaan AN, Delmonte OM, Abers MS, Aiuti A, Casari G, Lampasona V, Piemonti L, Ciceri F, Bilguvar K, Lifton RP, Vasse M, Smadja DM, Migaud M, Hadjadj J, Terrier B, Duffy D, Quintana-Murci L, van de Beek D, Roussel L, Vinh DC, Tangye SG, Haerynck F, Dalmau D, Martinez-Picado J, Brodin P, Nussenzweig MC, Boisson-Dupuis S, Rodríguez-Gallego C, Vogt G, Mogensen TH, Oler AJ, Gu J, Burbelo PD, Cohen JI, Biondi A, Bettini LR, D'Angio M, Bonfanti P, Rossignol P, Mayaux J, Rieux-Laucat F, Husebye ES, Fusco F, Ursini MV, Imberti L, Sottini A, Paghera S, Quiros-Roldan E, Rossi C, Castagnoli R, Montagna D, Licari A, Marseglia GL, Duval X, Ghosn J, HGID Lab, NIAID-USUHS Immune Response to COVID Group, COVID Clinicians, COVID-STORM Clinicians, Imagine COVID Group, French COVID Cohort Study Group, Milieu Intérieur Consortium, CoV-Contact Cohort, Amsterdam UMC Covid-19 Biobank, COVID Human Genetic Effort, Tsang JS, Goldbach-Mansky R, Kisand K, Lionakis MS, Puel A, Zhang S-Y, Holland SM, Gorochov G, Jouanguy E, Rice CM, Cobat A, Notarangelo LD, Abel L, Su HC, Casanova J-Let al., 2020, Autoantibodies against type I IFNs in patients with life-threatening COVID-19, Science, Vol: 370, ISSN: 1095-9203

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.

Journal article

Thompson CP, Grayson NE, Paton RS, Bolton JS, Lourenço J, Penman BS, Lee LN, Odon V, Mongkolsapaya J, Chinnakannan S, Dejnirattisai W, Edmans M, Fyfe A, Imlach C, Kooblall K, Lim N, Liu C, López-Camacho C, McInally C, McNaughton AL, Ramamurthy N, Ratcliff J, Supasa P, Sampson O, Wang B, Mentzer AJ, Turner M, Semple MG, Baillie K, ISARIC4C Investigators, Harvala H, Screaton GR, Temperton N, Klenerman P, Jarvis LM, Gupta S, Simmonds Pet al., 2020, Detection of neutralising antibodies to SARS-CoV-2 to determine population exposure in Scottish blood donors between March and May 2020., Euro Surveillance, Vol: 25, Pages: 1-9

BackgroundThe progression and geographical distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the United Kingdom (UK) and elsewhere is unknown because typically only symptomatic individuals are diagnosed. We performed a serological study of blood donors in Scotland in the spring of 2020 to detect neutralising antibodies to SARS-CoV-2 as a marker of past infection and epidemic progression.AimOur objective was to determine if sera from blood bank donors can be used to track the emergence and progression of the SARS-CoV-2 epidemic.MethodsA pseudotyped SARS-CoV-2 virus microneutralisation assay was used to detect neutralising antibodies to SARS-CoV-2. The study comprised samples from 3,500 blood donors collected in Scotland between 17 March and 18 May 2020. Controls were collected from 100 donors in Scotland during 2019.ResultsAll samples collected on 17 March 2020 (n = 500) were negative in the pseudotyped SARS-CoV-2 virus microneutralisation assay. Neutralising antibodies were detected in six of 500 donors from 23 to 26 March. The number of samples containing neutralising antibodies did not significantly rise after 5-6 April until the end of the study on 18 May. We found that infections were concentrated in certain postcodes, indicating that outbreaks of infection were extremely localised. In contrast, other areas remained comparatively untouched by the epidemic.ConclusionAlthough blood donors are not representative of the overall population, we demonstrated that serosurveys of blood banks can serve as a useful tool for tracking the emergence and progression of an epidemic such as the SARS-CoV-2 outbreak.

Journal article

Nishimura S, Kobayashi Y, Ohnishi H, Moriya K, Tsumura M, Sakata S, Mizoguchi Y, Takada H, Kato Z, Sancho-Shimizu V, Picard C, Irani SR, Ohara O, Casanova J-L, Puel A, Ishikawa N, Okada S, Kobayashi Met al., 2020, IRAK4 deficiency presenting with anti-NMDAR encephalitis and HHV6 reactivation, Journal of Clinical Immunology, Vol: 41, Pages: 125-135, ISSN: 0271-9142

IRAK4 deficiency is an inborn error of immunity predisposing patients to invasive pyogenic infections. Currently, there is no established simple assay that enables precise characterization of IRAK4 mutant alleles in isolation. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune condition that is characterized by psychiatric symptoms, involuntary movement, seizures, autonomic dysfunction, and central hypoventilation. It typically occurs in adult females associated with tumors. Only a few infantile cases with anti-NMDAR encephalitis have been so far reported. We identified a 10-month-old boy with IRAK4 deficiency presenting with anti-NMDAR encephalitis and human herpes virus 6 (HHV6) reactivation. The diagnosis of IRAK4 deficiency was confirmed by the identification of compound heterozygous mutations c.29_30delAT (p.Y10Cfs*9) and c.35G>C (p.R12P) in the IRAK4 gene, low levels of IRAK4 protein expression in peripheral blood, and defective fibroblastic cell responses to TLR and IL-1 (TIR) agonist. We established a novel NF-κB reporter assay using IRAK4-null HEK293T, which enabled the precise evaluation of IRAK4 mutations. Using this system, we confirmed that both novel mutations identified in the patient are deleterious. Our study provides a new simple and reliable method to analyze IRAK4 mutant alleles. It also suggests the possible link between inborn errors of immunity and early onset anti-NMDAR encephalitis.

Journal article

Drake TM, Docherty AB, Harrison EM, Quint JK, Adamali H, Agnew S, Babu S, Barber CM, Barratt S, Bendstrup E, Bianchi S, Castillo Villegas D, Chaudhuri N, Chua F, Coker R, Chang W, Crawshaw A, Crowley LE, Dosanjh D, Fiddler CA, Forrest IA, George PM, Gibbons MA, Groom K, Haney S, Hart SP, Heiden E, Henry M, Ho L-P, Hoyles RK, Hutchinson J, Hurley K, Jones MG, Jones S, Kokosi M, Kreuter M, Mackay LS, Mahendran S, Margaritopoulos G, Molina-Molina M, Molyneaux PL, O'Brien A, O'Reilly K, Packham A, Parfrey H, Poletti V, Porter JC, Renzoni E, Rivera-Ortega P, Russell A-M, Saini G, Spencer LG, Stella GM, Stone H, Sturney S, Thickett D, Thillai M, Wallis T, Ward K, Wells AU, West A, Wickremasinghe M, Woodhead F, Hearson G, Howard L, Baillie JK, Openshaw PJM, Semple MG, Stewart I, Jenkins RG, ISARIC4C Investigatorset al., 2020, Outcome of hospitalization for COVID-19 in patients with interstitial lung disease: an international multicenter study., American Journal of Respiratory and Critical Care Medicine, Vol: 202, Pages: 1656-1665, ISSN: 1073-449X

RATIONALE: The impact of COVID-19 on patients with Interstitial Lung Disease (ILD) has not been established. OBJECTIVES: To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age, sex and comorbidity matched population. METHODS: An international multicenter audit of patients with a prior diagnosis of ILD admitted to hospital with COVID-19 between 1 March and 1 May 2020 was undertaken and compared with patients, without ILD obtained from the ISARIC 4C cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished IPF from non-IPF ILD and used lung function to determine the greatest risks of death. MEASUREMENTS AND MAIN RESULTS: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity-score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching ILD patients with COVID-19 had higher mortality (HR 1.60, Confidence Intervals 1.17-2.18 p=0.003) compared with age, sex and co-morbidity matched controls without ILD. Patients with a Forced Vital Capacity (FVC) of <80% had an increased risk of death versus patients with FVC ≥80% (HR 1.72, 1.05-2.83). Furthermore, obese patients with ILD had an elevated risk of death (HR 2.27, 1.39-3.71). CONCLUSIONS: Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Journal article

Casanova J-L, Su HC, COVID Human Genetic Effort, 2020, A global effort to define the human genetics of protective immunity to SARS-CoV-2 infection., Cell, Vol: 181, Pages: 1194-1199, ISSN: 0092-8674

SARS-CoV-2 infection displays immense inter-individual clinical variability, ranging from silent infection to lethal disease. The role of human genetics in determining clinical response to the virus remains unclear. Studies of outliers-individuals remaining uninfected despite viral exposure and healthy young patients with life-threatening disease-present a unique opportunity to reveal human genetic determinants of infection and disease.

Journal article

Hodeib S, Herberg JA, Levin M, Sancho-Shimizu Vet al., 2020, Human genetics of meningococcal infections, Human Genetics, Vol: 139, Pages: 961-980, ISSN: 0340-6717

Neisseria meningitidis is a leading cause of bacterial septicaemia and meningitis worldwide. Meningococcal disease is rare but can be life threatening with a tendency to affect children. Many studies have investigated the role of human genetics in predisposition to N. meningitidis infection. These have identified both rare single-gene mutations as well as more common polymorphisms associated with meningococcal disease susceptibility and severity. These findings provide clues to the pathogenesis of N. meningitidis, the basis of host susceptibility to infection and to the aetiology of severe disease. From the multiple discoveries of monogenic complement deficiencies to the associations of complement factor H and complement factor H-related three polymorphisms to meningococcal disease, the complement pathway is highlighted as being central to the genetic control of meningococcal disease. This review aims to summarise the current understanding of the host genetic basis of meningococcal disease with respect to the different stages of meningococcal infection.

Journal article

Mashbat B, Bellos E, Hodeib S, Bidmos F, Thwaites RS, Lu Y, Wright VJ, Herberg JA, Klobassa DS, Zenz W, Hansel TT, Nadel S, Langford PR, Schlapbach LJ, Li M-S, Redinbo MR, Di YP, Levin M, Sancho-Shimizu Vet al., 2020, A rare mutation in SPLUNC1 underlies meningococcal disease affecting bacterial adherence and invasion, Clinical Infectious Diseases, Vol: 70, Pages: 2045-2053, ISSN: 1058-4838

BackgroundNeisseriameningitidis (Nm) is a nasopharyngeal commensal carried by healthy individuals. However, invasive infections occurs in a minority of individuals, with devastating consequences. There is evidence that common polymorphisms are associated with invasive meningococcal disease (IMD) but the contribution of rare variants other than complement has not been determined.MethodsWe identified familial cases of IMD in the UK meningococcal disease study and the European Union Life-threatening Infectious Disease Study. Candidate genetic variants were identified by whole exome sequencing of two patients with familial IMD. Candidate variants were further validated by in vitro assays.ResultsExomes of two siblings with IMD identified a novel heterozygous missense mutation in BPIFA1/SPLUNC1. Sequencing of 186 other non-familial cases identified another unrelated IMD patient with the same mutation. SPLUNC1 is an innate immune defence protein expressed in the nasopharyngeal epithelia, however, its role in invasive infections is unknown. In vitro assays demonstrated that recombinant SPLUNC1 inhibits biofilm formation by Nm, and impedes Nm adhesion and invasion of human airway cells. The dominant negative mutant rSPLUNC1 (p.G22E) showed reduced anti-biofilm activity, increased meningococcal adhesion and invasion of cells compared with wild type SPLUNC1.ConclusionsA mutation in SPLUNC1 affecting mucosal attachment, biofilm formation and invasion of mucosal epithelial cells is a new genetic cause of meningococcal disease.

Journal article

Staller E, Baillon L, Frise R, Peacock T, Sheppard C, Sancho-Shimizu V, Barclay Wet al., 2020, A rare variant in ANP32B impairs influenza virus replication in human cells, biorxiv

Viruses require host factors to support their replication, and genetic variation in such factors can affect susceptibility to infectious disease. Influenza virus replication in human cells relies on ANP32 proteins, which are involved in assembly of replication-competent dimeric influenza virus polymerase (FluPol) complexes. Here, we investigate naturally occurring single nucleotide variants (SNV) in the human Anp32A and Anp32B genes. We note that variant rs182096718 in Anp32B is found at a higher frequency than other variants in either gene. This SNV results in a D130A substitution in ANP32B, which is less able to support FluPol activity than wildtype ANP32B and binds FluPol with lower affinity. Interestingly, ANP32B-D130A exerts a dominant negative effect over wildtype ANP32B and interferes with the functionally redundant paralogue ANP32A. FluPol activity and virus replication are attenuated in CRISPR-edited cells expressing wildtype ANP32A and mutant ANP32B-D130A. We propose a model in which the D130A mutation impairs FluPol dimer formation, thus resulting in compromised replication. We suggest that both homozygous and heterozygous carriers of rs182096718 may have some genetic protection against influenza viruses.

Journal article

Torraca V, Kaforou M, Watson J, Duggan GM, Guerrero-Gutierrez H, Krokowski S, Hollinshead M, Clarke TB, Mostowy RJ, Tomlinson GS, Sancho-Shimizu V, Clements A, Mostowy Set al., 2019, Shigella sonnei infection of zebrafish reveals that O-antigen mediates neutrophil tolerance and dysentery incidence, PLoS Pathogens, Vol: 15, Pages: 1-26, ISSN: 1553-7366

Shigella flexneri is historically regarded as the primary agent of bacillary dysentery, yet the closely-related Shigella sonnei is replacing S. flexneri, especially in developing countries. The underlying reasons for this dramatic shift are mostly unknown. Using a zebrafish (Danio rerio) model of Shigella infection, we discover that S. sonnei is more virulent than S. flexneri in vivo. Whole animal dual-RNAseq and testing of bacterial mutants suggest that S. sonnei virulence depends on its O-antigen oligosaccharide (which is unique among Shigella species). We show in vivo using zebrafish and ex vivo using human neutrophils that S. sonnei O-antigen can mediate neutrophil tolerance. Consistent with this, we demonstrate that O-antigen enables S. sonnei to resist phagolysosome acidification and promotes neutrophil cell death. Chemical inhibition or promotion of phagolysosome maturation respectively decreases and increases neutrophil control of S. sonnei and zebrafish survival. Strikingly, larvae primed with a sublethal dose of S. sonnei are protected against a secondary lethal dose of S. sonnei in an O-antigen-dependent manner, indicating that exposure to O-antigen can train the innate immune system against S. sonnei. Collectively, these findings reveal O-antigen as an important therapeutic target against bacillary dysentery, and may explain the rapidly increasing S. sonnei burden in developing countries.

Journal article

Wang X, Nijman R, Camuzeaux S, Sands C, Jackson H, Kaforou M, Emonts M, Herberg J, Maconochie I, Carrol E, Paulus S, Zenz W, Coin L, Flier MVD, Groot RD, Martinon-Torres F, Schlapbach LJ, Pollard A, Fink C, Kuijpers TT, Anderson S, Lewis M, Levin M, McClure M, EUCLIDS consortiumet al., 2019, Plasma lipid profiles discriminate bacterial from viral infection in febrile children, Scientific Reports, Vol: 9, ISSN: 2045-2322

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The ‘omics’ approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n=20) and confirmed viral infection (n=20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group..A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics.

Journal article

Torraca V, Kaforou M, Watson J, Duggan GM, Guerrero-Gutierrez H, Krokowski S, Hollinshead M, Clarke TB, Mostowy RJ, Tomlinson GS, Sancho-Shimizu V, Clements A, Mostowy Set al., 2019, <i>Shigella sonnei</i>infection of zebrafish reveals that O-antigen mediates neutrophil tolerance and dysentery incidence

<jats:title>Abstract</jats:title><jats:p><jats:italic>Shigella flexneri</jats:italic>is historically regarded as the primary agent of bacillary dysentery, yet the closely-related<jats:italic>Shigella sonnei</jats:italic>is replacing<jats:italic>S. flexneri</jats:italic>, especially in developing countries. The underlying reasons for this dramatic shift are mostly unknown. Using a zebrafish (<jats:italic>Danio rerio</jats:italic>) model of<jats:italic>Shigella</jats:italic>infection, we discover that<jats:italic>S. sonnei</jats:italic>is more virulent than<jats:italic>S. flexneri in vivo</jats:italic>. Whole animal dual-RNAseq and testing of bacterial mutants suggest that<jats:italic>S. sonnei</jats:italic>virulence depends on its O-antigen oligosaccharide (which is unique among<jats:italic>Shigella</jats:italic>species). We show<jats:italic>in vivo</jats:italic>using zebrafish and<jats:italic>ex vivo</jats:italic>using human neutrophils that<jats:italic>S. sonnei</jats:italic>O-antigen can mediate neutrophil tolerance. Consistent with this, we demonstrate that O-antigen enables<jats:italic>S. sonnei</jats:italic>to resist phagolysosome acidification and promotes neutrophil cell death. Chemical inhibition or promotion of phagolysosome maturation respectively decreases and increases neutrophil control of<jats:italic>S. sonnei</jats:italic>and zebrafish survival. Strikingly, larvae primed with a sublethal dose of<jats:italic>S. sonnei</jats:italic>are protected against a secondary lethal dose of<jats:italic>S. sonnei</jats:italic>in an O-antigen-dependent manner, indicating that exposure to O-antigen can train the innate immune system against<jats:italic>S. sonnei</jats:italic>. Collectively, these findings reveal O-antigen as an important therapeutic

Working paper

Borghini L, Png E, Binder A, Wright VJ, Pinnock E, de Groot R, Hazelzet J, Emonts M, Van der Flier M, Schlapbach LJ, Anderson S, Secka F, Salas A, Fink C, Carrol ED, Pollard AJ, Coin LJ, Kuijpers TW, Martinon-Torres F, Zenz W, Levin M, Hibberd ML, Davila S, Gormley S, Hamilton S, Herberg J, Hourmat B, Hoggart C, Kaforou M, Sancho-Shimizu V, Abdulla A, Agapow P, Bartlett M, Bellos E, Eleftherohorinou H, Galassini R, Inwald D, Mashbat M, Menikou S, Mustafa S, Nadel S, Rahman R, Thakker C, Bokhandi S, Power S, Barham H, Pathan N, Ridout J, White D, Thurston S, Faust S, Patel S, McCorkell J, Davies P, Cratev L, Navarra H, Carter S, Ramaiah R, Patel R, Tuffrey C, Gribbin A, McCready S, Peters M, Hardy K, Standing F, O'Neill L, Abelake E, Deep A, Nsirim E, Willis L, Young Z, Royad C, White S, Fortune PM, Hudnott P, Alvez Gonzalez F, Barral-Arca R, Cebey-Lopez M, Jose Curras-Tuala M, Garcia N, Garcia Vicente L, Gomez-Carballa A, Gomez Rial J, Grela Beiroa A, Justicia Grande A, Leborans Iglesias P, Martinez Santos AE, Martinon-Torres N, Martinon Sanchez JM, Mosquera Perez B, Obando Pacheco P, Pardo-Seco J, Pischedda S, Rivero Calle I, Rodriguez-Tenreiro C, Redondo-Collazo L, Seren Fernandez S, Porto Silva MDS, Vega A, Beatriz Reyes S, Leon Leon MC, Navarro Mingorance A, Gabaldo Barrios X, Onate Vergara E, Concha Torre A, Vivanco A, Fernandez R, Gimenez Sanchez F, Sanchez Forte M, Rojo P, Ruiz Contreras J, Palacios A, Navarro M, Alvarez Alvarez C, Jose Lozano M, Carreras E, Brio Sanagustin S, Neth O, Martinez Padilla MDC, Prieto Tato LM, Guillen S, Fernandez Silveira L, Moreno D, van Furth AMT, van der Flier M, Boeddha NP, Driessen GJA, Pajkrt D, Sanders EAM, van de Beek D, van der Ende A, Philipsen HLA, Adeel AOA, Breukels MA, Brinkman DMC, de Korte CCMM, de Vries E, de Waal WJ, Dekkers R, Dings-Lammertink A, Doedens RA, Donker AE, Dousma M, Faber TE, Gerrits GPJM, Gerver JAM, Heidema J, Homan-van der Veen J, Jacobs MAM, Jansen NJG, Kawczynski P, Klucovska K, Kneyber MCJ Ket al., 2019, Identification of regulatory variants associated with genetic susceptibility to meningococcal disease, Scientific Reports, Vol: 9, ISSN: 2045-2322

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA – a NF-kB subunit, master regulator of the response to infection – under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes.

Journal article

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