The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged 4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute; The Rockefeller University; the St. Giles Foundation; the NIH (Grants R01AI088364 and R01AI163029); the National Center for Advancing Translational Sciences; NIH Clinical and Translational Science Awards program (Grant UL1 TR001866); a Fast Grant from Emergent Ventures; Mercatus Center at George Mason University; the Yale Center for Mendelian Genomics and the Genome Sequencing Program Coordinating Center funded by the National Human Genome Research Institute (Grants UM1HG006504 and U24HG008956); the Yale High Performance Computing Center (Grant S10OD018521); the Fisher Center for Alzheimer’s Research Foundation; the Meyer Foundation; the JPB Foundation; the French National Research Agency (ANR) under the “Investments for the Future” program (Grant ANR-10-IAHU-01); the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (Grant ANR-10-LABX-62-IBEID); the French Foundation for Medical Research (FRM) (Grant EQU201903007798); the French Agency for Research on AIDS and Viral hepatitis (ANRS) Nord-Sud (Grant ANRS-COV05); the ANR GENVIR (Grant ANR-20-CE93-003), AABIFNCOV (Grant ANR-20-CO11-0001), CNSVIRGEN (Grant ANR-19-CE15-0009-01), and GenMIS-C (Grant ANR-21-COVR-0039) projects; the Square Foundation; Grandir–Fonds de solidarité pour l’Enfance; the Fondation du Souffle; the SCOR Corporate Foundation for Science; The French Ministry of Higher Education, Research, and Innovation (Grant MESRI-COVID-19); Institut National de la Santé et de la Recherche Médicale (INSERM), REACTing-INSERM; and the University Paris Cité. P. Bastard was supported by the FRM (Award EA20170638020). P. Bastard., J.R., and T.L.V. were supported by the MD-PhD program of the Imagine Institute (with the support of Fondation Bettencourt Schueller). Work at the Neurometabolic Disease lab received funding from Centre for Biomedical Research on Rare Diseases (CIBERER) (Grant ACCI20-767) and the European Union's Horizon 2020 research and innovation program under grant agreement 824110 (EASI Genomics). Work in the Laboratory of Virology and Infectious Disease was supported by the NIH (Grants P01AI138398-S1, 2U19AI111825, and R01AI091707-10S1), a George Mason University Fast Grant, and the G. Harold and Leila Y. Mathers Charitable Foundation. The Infanta Leonor University Hospital supported the research of the Department of Internal Medicine and Allergology. The French COVID Cohort study group was sponsored by INSERM and supported by the REACTing consortium and by a grant from the French Ministry of Health (Grant PHRC 20-0424). The Cov-Contact Cohort was supported by the REACTing consortium, the French Ministry of Health, and the European Commission (Grant RECOVER WP 6). This work was also partly supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research, NIH (Grants ZIA AI001270 to L.D.N. and 1ZIAAI001265 to H.C.S.). This program is supported by the Agence Nationale de la Recherche (Grant ANR-10-LABX-69-01). K.K.’s group was supported by the Estonian Research Council, through Grants PRG117 and PRG377. R.H. was supported by an Al Jalila Foundation Seed Grant (Grant AJF202019), Dubai, United Arab Emirates, and a COVID-19 research grant (Grant CoV19-0307) from the University of Sharjah, United Arab Emirates. S.G.T. is supported by Investigator and Program Grants awarded by the National Health and Medical Research Council of Australia and a University of New South Wales COVID Rapid Response Initiative Grant. L.I. reports funding from Regione Lombardia, Italy (project “Risposta immune in pazienti con COVID-19 e co-morbidità”). This research was partially supported by the Instituto de Salud Carlos III (Grant COV20/0968). J.R.H. reports funding from Biomedical Advanced Research and Development Authority (Grant HHSO10201600031C). S.O. reports funding from Research Program on Emerging and Re-emerging Infectious Diseases from Japan Agency for Medical Research and Development (Grant JP20fk0108531). G.G. was supported by the ANR Flash COVID-19 program and SARS-CoV-2 Program of the Faculty of Medicine from Sorbonne University iCOVID programs. The 3C Study was conducted under a partnership agreement between INSERM, Victor Segalen Bordeaux 2 University, and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also supported by the Caisse Nationale d’Assurance Maladie des Travailleurs Salariés, Direction générale de la Santé, Mutuelle Générale de l’Education Nationale, Institut de la Longévité, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research–INSERM Program “Cohortes et collections de données biologiques.” S. Debette was supported by the University of Bordeaux Initiative of Excellence. P.K.G. reports funding from the National Cancer Institute, NIH, under Contract 75N91019D00024, Task Order 75N91021F00001. J.W. is supported by a Research Foundation - Flanders (FWO) Fundamental Clinical Mandate (Grant 1833317N). Sample processing at IrsiCaixa was possible thanks to the crowdfunding initiative YoMeCorono. Work at Vall d’Hebron was also partly supported by research funding from Instituto de Salud Carlos III Grant PI17/00660 cofinanced by the European Regional Development Fund (ERDF/FEDER). C.R.-G. and colleagues from the Canarian Health System Sequencing Hub were supported by the Instituto de Salud Carlos III (Grants COV20_01333 and COV20_01334), the Spanish Ministry for Science and Innovation (RTC-2017-6471-1; AEI/FEDER, European Union), Fundación DISA (Grants OA18/017 and OA20/024), and Cabildo Insular de Tenerife (Grants CGIEU0000219140 and “Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19”). T.H.M. was supported by grants from the Novo Nordisk Foundation (Grants NNF20OC0064890 and NNF21OC0067157). C.M.B. is supported by a Michael Smith Foundation for Health Research Health Professional-Investigator Award. P.Q.H. and L. Hammarström were funded by the European Union’s Horizon 2020 research and innovation program (Antibody Therapy Against Coronavirus consortium, Grant 101003650). Work at Y.-L.L.’s laboratory in the University of Hong Kong (HKU) was supported by the Society for the Relief of Disabled Children. MBBS/PhD study of D.L. in HKU was supported by the Croucher Foundation. J.L.F. was supported in part by the Evaluation-Orientation de la Coopération Scientifique (ECOS) Nord - Coopération Scientifique France-Colombie (ECOS-Nord/Columbian Administrative department of Science, Technology and Innovation [COLCIENCIAS]/Colombian Ministry of National Education [MEN]/Colombian Institute of Educational Credit and Technical Studies Abroad [ICETEX, Grant 806-2018] and Colciencias Contract 713-2016 [Code 111574455633]). A. Klocperk was, in part, supported by Grants NU20-05-00282 and NV18-05-00162 issued by the Czech Health Research Council and Ministry of Health, Czech Republic. L.P. was funded by Program Project COVID-19 OSR-UniSR and Ministero della Salute (Grant COVID-2020-12371617). I.M. is a Senior Clinical Investigator at the Research Foundation–Flanders and is supported by the CSL Behring Chair of Primary Immunodeficiencies (PID); by the Katholieke Universiteit Leuven C1 Grant C16/18/007; by a Flanders Institute for Biotechnology-Grand Challenges - PID grant; by the FWO Grants G0C8517N, G0B5120N, and G0E8420N; and by the Jeffrey Modell Foundation. I.M. has received funding under the European Union’s Horizon 2020 research and innovation program (Grant Agreement 948959). E.A. received funding from the Hellenic Foundation for Research and Innovation (Grant INTERFLU 1574). M. Vidigal received funding from the São Paulo Research Foundation (Grant 2020/09702-1) and JBS SA (Grant 69004). The NH-COVAIR study group consortium was supported by a grant from the Meath Foundation.Peer reviewe

Mycobacterium simiae Infection in Two Unrelated Patients with Different Forms of Inherited IFN-γR2 Deficiency

International audienceInterferon-γ receptor 2 (IFN-γR2) deficiency is a rare primary immunodeficiency characterized by predisposition to infections with weakly virulent mycobacteria, such as environmental mycobacteria and BCG vaccines. We describe here two children with IFN-γR2 deficiency, from unrelated, consanguineous kindreds of Arab and Israeli descent. The first patient was a boy who died at the age of 4.5 years, from recurrent, disseminated disease caused by Mycobacterium simiae. His IFN-γR2 defect was autosomal recessive and complete. The second patient was a girl with multiple disseminated mycobacterial infections, including infection with M. simiae. She died at the age of 5 years, a short time after the transplantation of umbilical cord blood cells from an unrelated donor. Her IFN-γR2 defect was autosomal recessive and partial. Autosomal recessive IFN-γR2 deficiency is life-threatening, even in its partial form, and genetic diagnosis and familial counseling are therefore particularly important for this condition. These two cases are the first of IFN-γR2 deficiency associated with M. simiae infection to be described

Haploinsufficiency at the human IFNGR2 locus contributes to mycobacterial disease

Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare syndrome, the known genetic etiologies of which impair the production of, or the response to interferon-gamma (IFN-γ). We report here a patient (P1) with MSMD whose cells display mildly impaired responses to IFN-γ, at levels, however, similar to those from MSMD patients with autosomal recessive (AR) partial IFN-γR2 or STAT1 deficiency. Whole-exome sequencing (WES) and Sanger sequencing revealed only one candidate variation for both MSMD-causing and IFN-γ-related genes. P1 carried a heterozygous frame-shift IFNGR2 mutation inherited from her father. We show that the mutant allele is intrinsically loss-of-function and not dominant-negative, suggesting haploinsufficiency at the IFNGR2 locus. We also show that Epstein-Barr virus transformed B lymphocyte cells from 10 heterozygous relatives of patients with AR complete IFN-γR2 deficiency respond poorly to IFN-γ, in some cases as poorly as the cells of P1. Naive CD4(+) T cells and memory IL-4-producing T cells from these individuals also responded poorly to IFN-γ, whereas monocytes and monocyte-derived macrophages (MDMs) did not. This is consistent with the lower levels of expression of IFN-γR2 in lymphoid than in myeloid cells. Overall, MSMD in this patient is probably due to autosomal dominant (AD) IFN-γR2 deficiency, resulting from haploinsufficiency, at least in lymphoid cells. The clinical penetrance of AD IFN-γR2 deficiency is incomplete, possibly due, at least partly, to the variability of cellular responses to IFN-γ in these individuals

Partial IFN-gamma R2 deficiency is due to protein misfolding and can be rescued by inhibitors of glycosylation

WOS: 000326078200022PubMed ID: 23963039We report a molecular study of the two known patients with autosomal recessive, partial interferon-gamma receptor (IFN-gamma R)2 deficiency (homozygous for mutations R114C and G227R), and three novel, unrelated children, homozygous for S124F (P1) and G141R (P2 and P3). IFN-gamma R2 levels on the surface of the three latter patients' cells are slightly lower than those on control cells. The patients' cells also display impaired, but not abolished, response to IFN-gamma. Moreover, the R114C, S124F, G141R and G227R IFNGR2 hypomorphic alleles all encode misfolded proteins with abnormal N-glycosylation. The mutants are largely retained in the endoplasmic reticulum, although a small proportion reach and function at the cell surface. Strikingly, the IFN-gamma response of the patients' cells is enhanced by chemical modifiers of N-glycosylation, as previously shown for patients with gain-of-glysosylation T168N and misfolding 382-387dup null mutations. All four in-frame IFNGR2 hypomorphic mutant alleles encoding surface-expressed receptors are thus deleterious by a mechanism involving abnormal N-glycosylation and misfolding of the IFN-gamma R2 protein. The diagnosis of partial IFN-gamma R2 deficiency is clinically useful, as affected patients should be treated with IFN-, unlike patients with complete IFN-gamma R2 deficiency. Moreover, inhibitors of glycosylation might be beneficial in patients with complete or partial IFN-gamma R2 deficiency due to misfolding or gain-of-glycosylation receptors.European Research CouncilEuropean Research Council (ERC) [ERC-2010-AdG-268777]; Institut National de la Sante et de la Recherche Medicale, University Paris Descartes, French National Agency for Research (ANR)French National Research Agency (ANR); EUEuropean Union (EU) [HEALTH-F3-2008-200732]; Bill and Melinda Gates FoundationGates Foundation; St. Giles Foundation; Jeffrey Modell Foundation; Talecris Biotherapeutics; Rockefeller University Center for Clinical and Translational Science from the National Center for Research Resources and the National Center for Advancing Sciences (NCATS) [8UL1TR000043]; Rockefeller University; National Institute of Allergy and Infectious DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [1R01AI089970]; EMBO Long Term Fellowship program; Stony Wold-Herbert Fund; Choh-Hao Li Memorial Fund Scholar award; Shanghai Educational Development Foundation; AXA Research Fund; Fondation Medicale Medische Stichting Mathilde E. Horlait-DapsensThis work was supported by grants from the European Research Council (ERC-2010-AdG-268777), Institut National de la Sante et de la Recherche Medicale, University Paris Descartes, French National Agency for Research (ANR), the EU-grant HOMITB (grant HEALTH-F3-2008-200732), the Bill and Melinda Gates Foundation, the St. Giles Foundation, the Jeffrey Modell Foundation, and Talecris Biotherapeutics, Rockefeller University Center for Clinical and Translational Science grant 8UL1TR000043 from the National Center for Research Resources and the National Center for Advancing Sciences (NCATS), the Rockefeller University, and the National Institute of Allergy and Infectious Diseases (grant 1R01AI089970). R.M.-B. is supported by the EMBO Long Term Fellowship program. X.-F.K. is supported by the Stony Wold-Herbert Fund, Choh-Hao Li Memorial Fund Scholar award, and the Shanghai Educational Development Foundation, Y.I. was supported by the AXA Research Fund. V.L.B. was supported by the Stony Wold-Herbert Fund, and A.Y.K. was supported by the Fondation Medicale Medische Stichting Mathilde E. Horlait-Dapsens

Biotecnología y sus aplicaciones en el sector salud

Este libro es el resultado de la ejecución del proyecto “Desarrollo de Capacidades Científicas y Tecnológicas Aplicadas a los Sectores de la Salud y la Agroindustria en el Departamento de Risaralda (2014-2019)” financiado por el Sistema General de Regalías. Contiene tres capítulos que abarcan desde la información básica asociada a los ácidos nucleicos, el estudio de las células madre, las proteínas y enzimas, para continuar con el uso de la biotecnología en procesos como la inmovilización de enzimas y la producción de proteínas recombinantes. Finalmente, el lector encontrará información relacionada a los múltiples usos de la biotecnología roja, con especial énfasis en aplicaciones clínicas de las células madre, los biomateriales, la metagenómica, la metabolómica, la producción de vacunas y finalmente, la importancia de las plantas medicinales como fuente de moléculas con actividad biológica (bioprospección). Los autores han tratado de presentar la información compleja de una manera sencilla y comprensible para el público en general y, por lo tanto, se considera que el libro podrá ser de utilidad para lectores de diversas disciplinas científicas, así como para estudiantes de pre y posgrado. Adicionalmente, el lenguaje empleado. permite convertir al libro en una guía para los docentes de la básica y la media, como texto para orientar los conceptos básicos y aplicaciones de la Biotecnología en sus estudiantes. Es importante mencionar que los autores realizaron un gran trabajo al elaborar sus propias figuras, excepto en los casos donde se indica la fuente a partir de la cual se realizó la modificación correspondiente.Resúmen del Contrato o Licitación Objeto Asesoría para definir e implementar un protocolo de identificación y colecta de micorrizadas en plantas del orden de las Zingiberales marco del programa Desarrollo de Capacidades Científicas y tecnológicas en biotecnología aplicada a los sectores de la salud y la agroindustria en el Departamento de Risaralda. Código BPIN 2012000100050 financiado con cargo a recursos del Sistema General de Regalías. Cuantia $2,500,000 Vigencia Proceso asignado o cerrado. No se aceptan nuevos aplicantes. Entidad RISARALDA - UNIVERSIDAD TECNOLÓGICA DE PEREIRAResúmenBuscar Estado CelebradoResúmenBuscar Tipo Régimen EspecialResúmenBuscar Tipo de Fecha Fecha de Celebración del Primer ContratoResúmenBuscar Fecha de Detección 2019-07-17 19:18:52 Cód. Secop 1 19-4-9710142 Número del Proceso ORDEN DE SERVICIOS 2061Sistema General de Regalías de ColombiaCONTENIDO INTRODUCCIÓN.................................................................................................8 CAPÍTULO 1.......................................................................................................10 GENERALIDADES O FUNDAMENTOS BÁSICOS..........................................11 La Biotecnología..................................................................................................11 Fermentaciones microbianas..............................................................................15 Enzimas: generalidades, aislamiento y purificación ..........................................27 El ácido desoxirribonucleico (ADN) ..................................................................53 Células madre: generalidades .............................................................................67 CAPÍTULO 2.......................................................................................................93 HERRAMIENTAS CLAVE EN LA BIOTECNOLOGÍA ....................................94 Inmovilización enzimática y sus aplicaciones....................................................94 Producción de proteínas recombinantes de interés farmacológico.................112 Bacteriocinas: péptidos bioactivos con propiedad antimicrobial ...................141 CAPÍTULO 3. ...................................................................................................175 APLICACIONES EN LA BIOTECNOLOGÍA MÉDICA .................................176 La biotecnología como herramienta para la generación de vacunas de uso humano y animal...............................................................................................176 Aplicaciones clínicas de las células madre y de productos de células madre...216 Biomateriales y su aplicación en el campo de la Salud.....................................282 Metagenómica y Metabolómica: Generalidades y Potencial en Salud Humana .............................................................................................................316 Plantas Medicinales...........................................................................................343 Actividad Biológica de Plantas de la Familia Bignoniaceae ............................35

Mycobacterial Disease And Impaired Ifn-Gamma Immunity In Humans With Inherited Isg15 Deficiency

ISG15 is an interferon (IFN)-alpha/beta-inducible, ubiquitin-like intracellular protein. Its conjugation to various proteins (ISGylation) contributes to antiviral immunity in mice. Here, we describe human patients with inherited ISG15 deficiency and mycobacterial, but not viral, diseases. The lack of intracellular ISG15 production and protein ISGylation was not associated with cellular susceptibility to any viruses that we tested, consistent with the lack of viral diseases in these patients. By contrast, the lack of mycobacterium-induced ISG15 secretion by leukocytes-granulocyte, in particular-reduced the production of IFN-gamma by lymphocytes, including natural killer cells, probably accounting for the enhanced susceptibility to mycobacterial disease. This experiment of nature shows that human ISGylation is largely redundant for antiviral immunity, but that ISG15 plays an essential role as an IFN-gamma-inducing secreted molecule for optimal antimycobacterial immunity.Wo

Respiratory viral infections in otherwise healthy humans with inherited IRF7 deficiency.

Autosomal recessive IRF7 deficiency was previously reported in three patients with single critical influenza or COVID-19 pneumonia episodes. The patients' fibroblasts and plasmacytoid dendritic cells produced no detectable type I and III IFNs, except IFN-β. Having discovered four new patients, we describe the genetic, immunological, and clinical features of seven IRF7-deficient patients from six families and five ancestries. Five were homozygous and two were compound heterozygous for IRF7 variants. Patients typically had one episode of pulmonary viral disease. Age at onset was surprisingly broad, from 6 mo to 50 yr (mean age 29 yr). The respiratory viruses implicated included SARS-CoV-2, influenza virus, respiratory syncytial virus, and adenovirus. Serological analyses indicated previous infections with many common viruses. Cellular analyses revealed strong antiviral immunity and expanded populations of influenza- and SARS-CoV-2-specific memory CD4+ and CD8+ T cells. IRF7-deficient individuals are prone to viral infections of the respiratory tract but are otherwise healthy, potentially due to residual IFN-β and compensatory adaptive immunity

Mycobacterium simiae Infection in Two Unrelated Patients with Different Forms of Inherited IFN-γR2 Deficiency

Interferon-γ receptor 2 (IFN-γR2) deficiency is a rare primary immunodeficiency characterized by predisposition to infections with weakly virulent mycobacteria, such as environmental mycobacteria and BCG vaccines. We describe here two children with IFN-γR2 deficiency, from unrelated, consanguineous kindreds of Arab and Israeli descent. The first patient was a boy who died at the age of 4.5 years, from recurrent, disseminated disease caused by Mycobacterium simiae. His IFN-γR2 defect was autosomal recessive and complete. The second patient was a girl with multiple disseminated mycobacterial infections, including infection with M. simiae. She died at the age of five years, a short time after the transplantation of umbilical cord blood cells from an unrelated donor. Her IFN-γR2 defect was autosomal recessive and partial. Autosomal recessive IFN-γR2 deficiency is life-threatening, even in its partial form, and genetic diagnosis and familial counseling are therefore particularly important for this condition. These two cases are the first of IFN-γR2 deficiency associated with M simiae infection to be described

X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19

Publisher Copyright: Copyright © 2021Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean, 36.7 years) from a cohort of 1202 male patients aged 0.5 to 99 years (mean, 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean, 38.7 years) tested carry such TLR7 variants (P = 3.5 × 10−5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n = 2) or moderate (n = 1), severe (n = 1), or critical (n = 1) pneumonia. Two patients from a cohort of 262 male patients with severe COVID-19 pneumonia (mean, 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is <6.5 × 10−4. We show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7. The patients’ blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.Peer reviewe