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Principal Investigator: Raphaela Goldbach-Mansky
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2023
Award: $10,739
Funding agency: National Institute of Allergy and Infectious Diseases
In collaboration with the NIAID COVID consortium we have analyzed longitudinally collected whole blood samples collected for RNA isolation from 84 adult patients hospitalized with severe COVID.
We also assessed serum samples from a larger panel of adult patients hospitalized with severe COVID (from Brescia n=567, Monza 77 and Pavia: 43) for serum IL-18, IL-18BP and CXCL-9 and a subset for spike-2 protein levels and other inflammatory markers released from innate and adaptive immune cells and/or surrounding tissues. Our data showed overall reduced Type I IFN signaling and variably immune activation of NFKB and Type II IFN (IFN gamma) regulated genes in hospitalized patients but not in patients with milder disease and healthy controls (Abers et al. JCI Insight 2021).
The transcriptional score derived from the analysis of 28 type I IFNregulated genes, was increased in a subset of patient over healthy controls but the type I IFN score of COVID-19 patients was significantly lower than that observed in monogenic type I IFNopathies. We also found that the normalized transcriptional levels of IFNA2 of circulating leukocytes did not correlate with the protein IFN-2a blood levels. Furthermore, normalized IFNA2 transcripts only weakly correlated with the 28-gene type I IFN score in COVID-19 patients which was in contrast to their significant correlation in patients with monogenic IFNopathies together with the decreased numbers of circulating plasmacytoid DCs (pDCs) and impaired production of type I IFN by circulating pDCs in COVID-19 patients reported by others (10, 16, 19) suggested non-hematopoietic sources of IFN alpha in COVID patients.
A multivariable analysis of patients first samples revealed 12 biomarker-associated with systemic and monocyte activation (sTNFRSF1A, IL-6, CCL2, ferritin, IL-15), damage (MMP-9, soluble ST2 sST2), neutrophil activation (NGAL, S100A9) endothelial activation (sVEGFR1) and T cell activation (IL-2) correlated with disease severity and mortality. Among these, sST2, sTNFRSF1A, IL-10, and IL-15 were consistently higher throughout the hospitalization in patients who died versus those who recovered. (Abers et al. JCI Insight 2020).
The inadequately low IFN alpha response contributes to the severe disease manifestations of COVID19. In another consortium study a subset of patients with particularly low and therefore impaired IFN who had life-threatening coronavirus disease 2019 had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon- (IFN-), 13 types of IFN- or against both in 10.2% of the cohort patients at the onset of critical disease. 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 over 600 individuals with asymptomatic or mild SARS-CoV-2 infection. (Bastard et al. Science 2020). This study identified the presence of anti-type I IFN antibodies as risk factors that suppress the IFN response and with among other host factors predisposes to severe COVD19.
A longitudinal multi-institutional consortium study conducted in pediatric patients with acute COVID-19 (n=110) and with MIS-C (n=76) and compared to pediatric healthy controls (pHCs; n=76) showed that acute COVID-19 patients mounted a robust type I interferon (IFN) response gene signature, whereas prominent type II IFN-dependent and NF-B-dependent signatures, matrisome activation and increased levels of circulating spike protein were detected in MIS-C, with no correlation with SARS-CoV-2 PCR status around the time of admission. The study further showed transient expansion of TRBV11-2 T cell clonotypes in MIS-C that were associated with signatures of inflammation and T cell activation and were associated with the combination of HLA A*02, B*35 and C*04 alleles suggesting a genetic susceptibility to the development of MIS-C.
In a collaboration with the Chertow group evaluated innate immune responses to SARS-CoV-2 in the upper (URT) and lower respiratory tract (LRT) in intubated patients with severe respiratory infections admitted to the ICU in the early phase of the COVID pandemic. We simultaneously assessed expression of type I IFNs (IFNA2 and IFNB1) and Type II IFN (IFNG expression) and the induction of an type-I IFN and NF-B signature in nasopharynx, tracheal aspirates and blood. We compared innate immune responses in the upper respiratory tract (URT) of patients with mild COVID 19 (outpatient) and the hospitalized patients with severe COVID-19. We further characterized the weekly dynamics of these responses in the upper and lower respiratory tracts (LRTs) and in blood for compartmental differences. We observed significantly increased ISG and NF-B responses in the URT of mild compared with severe patients early during illness. This pattern was associated with increased IFNA2 and IFNG expression in the URT of mild patients, a trend toward increased IFNB1-expression and significantly increased STING/IRF3/cGAS expression in the URT of severe patients was seen. By-week across-compartment analysis in severe patients revealed significantly higher ISG responses in the blood compared with the URT and LRT of these patients during the first week of illness, despite significantly lower expression of IFNA2, IFNB1, and IFNG in blood. NF-B responses, however, were significantly elevated in the LRT compared with the URT and blood of severe patients during peak illness (week 2). Our data support that severe COVID-19 is associated with impaired interferon signaling in the URT during early illness and robust pro-inflammatory responses in the LRT during peak illness (Ramos-Benitez MJ et al. medRxiv doi: https://doi.org/10.1101/2022.11.08.22281846).
Terms: <(IFN) α><(IFN)-α><(IFN)α><0-11 years old><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><92-kDa Gelatinase><92-kDa Type IV Collagenase><Acute><Admission><Admission activity><Adult><Adult Human><Age Years><Airway infections><Alferon><Alleles><Allelomorphs><Antibodies><Autoantibodies><Autoregulation><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Biological Markers><Blood><Blood Reticuloendothelial System><Blood Sample><Blood Serum><Blood leukocyte><Blood monocyte><Blood specimen><Body Tissues><CAGB><CCL2><CCL2 gene><CGCB><COVID><COVID crisis><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID-19><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infected patient><COVID-19 infection><COVID-19 pandemic><COVID-19 patient><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 virus><COVID-19 virus infection><COVID19><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 infection><COVID19 pandemic><COVID19 patient><COVID19 positive patient><COVID19 public health crisis><COVID19 virus><CSIF><CSIF-10><CV-19><CV19><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cessation of life><Chemokine, CC Motif, Ligand 2><Child><Child Youth><Childhood><Children (0-21)><China><Circulatory Collapse><Clinical><Co-Stimulator><CoV disease><CoV-2><CoV2><Collaborations><Complication><Conjunctivitis><Costimulator><Cytokine Synthesis Inhibitory Factor><Data><Death><Development><Diagnostic Findings><Disease><Disease Progression><Disorder><Dropsy><Edema><Emergencies><Emergency Situation><Endothelium><England><Epidermal Thymocyte Activating Factor><Exanthem><Exanthema><Ferritin><Fever><Gelatinase B><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Gene Transcription><Genes><Genetic Predisposition><Genetic Predisposition to Disease><Genetic Susceptibility><Genetic Transcription><Genetic propensity><HPGF><Hepatocyte-Stimulating Factor><Homeostasis><Hospital Admission><Hospitalization><Host Factor><Host Factor Protein><Hybridoma Growth Factor><Hydrops><IFN><IFN Alpha><IFN α><IFN-Gamma><IFN-Gamma-Inducing Factor Gene><IFN-beta 2><IFN-g><IFN-gamma-Inducing Factor><IFN-regulatory factor 3><IFN-α><IFN-γ><IFNA2><IFNA2 gene><IFNB2><IFNG><IFNa><IFNα><IFNγ><IGIF><IGIF Gene><IL-1><IL-1 Gamma><IL-1 Gamma Gene><IL-10><IL-15><IL-18><IL-18 Gene><IL-1g><IL-1g Gene><IL-2><IL-6><IL1><IL10><IL10A><IL15><IL15 Protein><IL18><IL18 Protein><IL18 gene><IL1F4><IL1F4 Gene><IL2 Protein><IL6 Protein><IMiD><IRF-3 protein><IRF3><IRF3 gene><IgG autoantibodies><Immune><Immune Cell Activation><Immune Interferon><Immune modulatory therapeutic><Immune system><Immunes><Immunoglobulin Enhancer-Binding Protein><Immunoglobulin G autoantibodies><Impairment><In Vitro><Individual><Infection><Inflammation><Inflammatory Response><Inherited Predisposition><Inherited Susceptibility><Innate Immune Response><Institution><Integration Host Factors><Interferon Alfa-n3><Interferon Gamma><Interferon Regulatory Factor 3><Interferon Type I><Interferon Type II><Interferon alpha><Interferon-Gamma-Inducing Factor Gene><Interferon-gamma-Inducing Factor><Interferon-α><Interferons><Interleukin 10 Precursor><Interleukin 18 (Interferon-Gamma-Inducing Factor)><Interleukin 18 (Interferon-Gamma-Inducing Factor) Gene><Interleukin 18 Proprotein><Interleukin 18 Proprotein Gene><Interleukin 2><Interleukin 2 Precursor><Interleukin I><Interleukin II><Interleukin-1><Interleukin-1 Gamma><Interleukin-1 Gamma Gene><Interleukin-10><Interleukin-15><Interleukin-15 Precursor><Interleukin-18><Interleukin-18 Precursor><Interleukin-18 Precursor Gene><Interleukin-2><Interleukin-6><Interleukine 2><Interleukine 2 Precursor><Interleukine II><Intracellular Communication and Signaling><Intubation><Kawasaki Disease><LCN2><LCN2 gene><LIAG><Leukocyte Interferon><Leukocytes><Leukocytes Reticuloendothelial System><Life><Lipocalin 2><Lower respiratory tract structure><Lung diseases><Lymphoblast Interferon><Lymphoblastoid Interferon><Lymphocyte Mitogenic Factor><Lymphocyte-Stimulating Hormone><MAC387><MCAF><MCP-1><MCP1><MGC12320><MGC12320 Gene><MGC9721><MGI-2><MIS-C><MMP-9><MMP-9 Protein><MRP14><Macrophage Cell Factor><Macrophage Gelatinase><Mainland China><Marrow leukocyte><Marrow monocyte><Matrix Metalloproteinase-9><Mediating><Mendelian disease><Mendelian disorder><Mendelian genetic disorder><Mitogenic Factor><Monitor><Monocyte Chemoattractant Protein-1><Monocyte Chemotactic Protein-1><Monocyte Chemotactic and Activating Factor><Monocyte Chemotactic and Activating Protein><Monocyte Chemotactive and Activating Factor><Monocyte Secretory Protein JE><Mucocutaneous Lymph Node Syndrome><Multiorgan Inflammatory Syndrome in Children><Multisystem Inflammatory Syndrome in Children><Myeloid Differentiation-Inducing Protein><NF-kB><NF-kappa B><NF-kappaB><NFKB><NGAL><NIAID><Nasopharynx><National Institute of Allergy and Infectious Disease><Neutrophil Activation><Neutrophil Gelatinase-Associated Lipocalin><Non-Polyadenylated RNA><Nuclear Factor kappa B><Nuclear Transcription Factor NF-kB><Oncogenic Lipocalin 24P3><Organ><Out-patients><Outpatients><Pathologic><Patients><Pattern><Peripheral><Phase><Physiological Homeostasis><Plasmacytoma Growth Factor><Population><Predisposing Factor><Production><Proteins><Pulmonary Diseases><Pulmonary Disorder><Pyrexia><RNA><RNA Expression><RNA Gene Products><Rash><Reporting><Respiratory Infections><Respiratory Tract Infections><Rhinopharynx><Ribonucleic Acid><Risk Factors><S100A9><S100A9 gene><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV-1><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 inhibitor><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 infection><SARS-CoV2 pandemic><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SCYA2><Sampling><Science><Screening procedure><Serum><Severe Acute Respiratory Coronavirus><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 inhibitor><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Severity of illness><Shock><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Signs and Symptoms><Skin Rash><Small Inducible Cytokine A2><Source><T Helper Factor><T cell growth factor><T-Cell Activation><T-Cell Growth Factor><T-Cell Stimulating Factor><T-Cells><T-Lymphocyte><Thymocyte Stimulating Factor><Time><Tissues><Toxic Shock><Toxic Shock Syndrome><Trachea><Trachea Proper><Transcript><Transcript Expression Analyses><Transcript Expression Analysis><Transcription><Transcription Factor NF-kB><Type V Collagenase><Upper respiratory tract><Uterocalin><Viral Gene Products><Viral Gene Proteins><Viral Proteins><White Blood Cells><White Cell><Whole Blood><World Health Organization><Wuhan coronavirus><activate T cells><adulthood><analyze gene expression><analyzing longitudinal><aspirate><autoimmune antibody><autoinflammatory diseases><autoinflammatory disorders><autoreactive antibody><bio-markers><biologic marker><biological signal transduction><biomarker><block SARS-CoV-2><block severe acute respiratory syndrome coronavirus 2><cardiac damage><child patients><circulatory shock><cohort><corona virus disease><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus 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biomarker><diagnostic marker><disease of the lung><disease severity><disease-causing mutation><disorder of the lung><febrile><febris><gastrointestinal symptom><gene expression analysis><gene expression assay><gene signatures><genetic etiology><genetic mechanism of disease><genetic signature><genetic vulnerability><genetically predisposed><hCoV19><heart damage><immune activation><immune modulating agents><immune modulating drug><immune modulating therapeutics><immune modulatory agents><immune modulatory drugs><immunomodulating agents><immunomodulating drugs><immunomodulator agent><immunomodulator drug><immunomodulator medication><immunomodulator prodrug><immunomodulator therapeutic><immunomodulatory agents><immunomodulatory drugs><immunomodulatory therapeutics><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><inflammation marker><inflammatory marker><inhibit SARS-CoV-2><inhibit severe acute respiratory syndrome coronavirus 2><innate immune pathways><insight><interferon beta 2><kappa B Enhancer Binding Protein><kids><lFN-Gamma><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><longitudinal analysis><lower respiratory tract><lung disorder><lymphocyte activating factor><monocyte><monogenic disease><monogenic disorder><mortality><multisystem inflammatory syndrome of children><nCoV2><nano-string><nanostring><nasopharnygeal><nuclear factor kappa beta><pandemic><pandemic disease><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient subgroups><patient subpopulations><patient subsets><patient subtypes><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><pediatric><pediatric inflammatory multisystem syndrome><pediatric patients><response><screening tools><self reactive antibody><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome-CoV><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><shocks><single-gene disease><single-gene disorder><systemic inflammation><systemic inflammatory response><thymus derived lymphocyte><transcriptional profiling><trend><upper airway tract><virus protein><white blood cell><white blood corpuscle><windpipe><youngster>