ABSTRACT
Infection with SARS-CoV-2 results in clinical outcomes ranging from silent or benign infection in most individuals to critical pneumonia and death in a few. Genetic studies in patients have established that critical cases can result from inborn errors of TLR3- or TLR7-dependent type I interferon immunity, or from preexisting autoantibodies neutralizing primarily IFN-α and/or IFN-ω. These findings are consistent with virological studies showing that multiple SARS-CoV-2 proteins interfere with pathways of induction of, or response to, type I interferons. They are also congruent with cellular studies and mouse models that found that type I interferons can limit SARS-CoV-2 replication in vitro and in vivo, while their absence or diminution unleashes viral growth. Collectively, these findings point to insufficient type I interferon during the first days of infection as a general mechanism underlying critical COVID-19 pneumonia, with implications for treatment and directions for future research.
Subject(s)
COVID-19 , Interferon Type I , Mice , Humans , Animals , Interferons/pharmacology , SARS-CoV-2ABSTRACT
COVID-19 exhibits extensive patient-to-patient heterogeneity. To link immune response variation to disease severity and outcome over time, we longitudinally assessed circulating proteins as well as 188 surface protein markers, transcriptome, and T cell receptor sequence simultaneously in single peripheral immune cells from COVID-19 patients. Conditional-independence network analysis revealed primary correlates of disease severity, including gene expression signatures of apoptosis in plasmacytoid dendritic cells and attenuated inflammation but increased fatty acid metabolism in CD56dimCD16hi NK cells linked positively to circulating interleukin (IL)-15. CD8+ T cell activation was apparent without signs of exhaustion. Although cellular inflammation was depressed in severe patients early after hospitalization, it became elevated by days 17-23 post symptom onset, suggestive of a late wave of inflammatory responses. Furthermore, circulating protein trajectories at this time were divergent between and predictive of recovery versus fatal outcomes. Our findings stress the importance of timing in the analysis, clinical monitoring, and therapeutic intervention of COVID-19.
Subject(s)
COVID-19/immunology , Cytokines/metabolism , Dendritic Cells/metabolism , Gene Expression/immunology , Killer Cells, Natural/metabolism , Severity of Illness Index , Adult , Aged , Aged, 80 and over , Biomarkers/metabolism , COVID-19/mortality , Case-Control Studies , Dendritic Cells/cytology , Female , Humans , Killer Cells, Natural/cytology , Longitudinal Studies , Male , Middle Aged , Transcriptome/immunology , Young AdultABSTRACT
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.
Subject(s)
Coronavirus Infections/genetics , Coronavirus Infections/immunology , Genetic Predisposition to Disease , Pneumonia, Viral/genetics , Pneumonia, Viral/immunology , Age Factors , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/physiopathology , Disease Resistance , Genetic Association Studies , Genetic Diseases, Inborn/immunology , Genetic Variation , Genome, Human , Host-Pathogen Interactions , Humans , Infections/genetics , Infections/immunology , Infections/physiopathology , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/physiopathology , SARS-CoV-2ABSTRACT
SARS-CoV-2 infections display tremendous interindividual variability, ranging from asymptomatic infections to life-threatening disease. Inborn errors of, and autoantibodies directed against, type I interferons (IFNs) account for about 20% of critical COVID-19 cases among SARS-CoV-2-infected individuals. By contrast, the genetic and immunological determinants of resistance to infection per se remain unknown. Following the discovery that autosomal recessive deficiency in the DARC chemokine receptor confers resistance to Plasmodium vivax, autosomal recessive deficiencies of chemokine receptor 5 (CCR5) and the enzyme FUT2 were shown to underlie resistance to HIV-1 and noroviruses, respectively. Along the same lines, we propose a strategy for identifying, recruiting, and genetically analyzing individuals who are naturally resistant to SARS-CoV-2 infection.
Subject(s)
COVID-19/genetics , Disease Resistance/genetics , Genetic Predisposition to Disease , SARS-CoV-2/pathogenicity , Animals , COVID-19/immunology , COVID-19/virology , Genetic Heterogeneity , Host-Pathogen Interactions , Humans , Phenotype , Protective Factors , Risk Assessment , Risk Factors , SARS-CoV-2/immunologyABSTRACT
Mutations that impact immune cell migration and result in immune deficiency illustrate the importance of cell movement in host defense. In humans, loss-of-function mutations in DOCK8, a guanine exchange factor involved in hematopoietic cell migration, lead to immunodeficiency and, paradoxically, allergic disease. Here, we demonstrate that, like humans, Dock8-/- mice have a profound type 2 CD4+ helper T (TH2) cell bias upon pulmonary infection with Cryptococcus neoformans and other non-TH2 stimuli. We found that recruited Dock8-/-CX3CR1+ mononuclear phagocytes are exquisitely sensitive to migration-induced cell shattering, releasing interleukin (IL)-1ß that drives granulocyte-macrophage colony-stimulating factor (GM-CSF) production by CD4+ T cells. Blocking IL-1ß, GM-CSF or caspase activation eliminated the type-2 skew in mice lacking Dock8. Notably, treatment of infected wild-type mice with apoptotic cells significantly increased GM-CSF production and TH2 cell differentiation. This reveals an important role for cell death in driving type 2 signals during infection, which may have implications for understanding the etiology of type 2 CD4+ T cell responses in allergic disease.
Subject(s)
Guanine Nucleotide Exchange Factors/deficiency , Lymphocyte Activation/genetics , Lymphocyte Activation/immunology , Th2 Cells/immunology , Th2 Cells/metabolism , Animals , Biomarkers , Caspases/metabolism , Cell Movement/genetics , Cell Movement/immunology , Cytokines/genetics , Cytokines/metabolism , Disease Susceptibility , Gene Expression , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Humans , Immunophenotyping , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Mice , Mice, Knockout , Myeloid Cells/immunology , Myeloid Cells/metabolism , Phagocytes/immunology , Phagocytes/metabolism , Signal TransductionABSTRACT
Proteasomes and lysosomes constitute the major cellular systems that catabolize proteins to recycle free amino acids for energy and new protein synthesis. Tripeptidyl peptidase II (TPPII) is a large cytosolic proteolytic complex that functions in tandem with the proteasome-ubiquitin protein degradation pathway. We found that autosomal recessive TPP2 mutations cause recurrent infections, autoimmunity, and neurodevelopmental delay in humans. We show that a major function of TPPII in mammalian cells is to maintain amino acid levels and that TPPII-deficient cells compensate by increasing lysosome number and proteolytic activity. However, the overabundant lysosomes derange cellular metabolism by consuming the key glycolytic enzyme hexokinase-2 through chaperone-mediated autophagy. This reduces glycolysis and impairs the production of effector cytokines, including IFN-γ and IL-1ß. Thus, TPPII controls the balance between intracellular amino acid availability, lysosome number, and glycolysis, which is vital for adaptive and innate immunity and neurodevelopmental health.
Subject(s)
Adaptive Immunity , Aminopeptidases/metabolism , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism , Glycolysis , Immunity, Innate , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/metabolism , Proteolysis , Serine Endopeptidases/metabolism , Amino Acid Sequence , Aminopeptidases/chemistry , Animals , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/chemistry , Female , Humans , Immunologic Deficiency Syndromes/immunology , Lysosomes/metabolism , Male , Models, Molecular , Molecular Sequence Data , Pedigree , Sequence Alignment , Serine Endopeptidases/chemistryABSTRACT
BACKGROUND: Functional T-cell responses are essential for virus clearance and long-term protection after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, whereas certain clinical factors, such as older age and immunocompromise, are associated with worse outcome. OBJECTIVE: We sought to study the breadth and magnitude of T-cell responses in patients with coronavirus disease 2019 (COVID-19) and in individuals with inborn errors of immunity (IEIs) who had received COVID-19 mRNA vaccine. METHODS: Using high-throughput sequencing and bioinformatics tools to characterize the T-cell receptor ß repertoire signatures in 540 individuals after SARS-CoV-2 infection, 31 IEI recipients of COVID-19 mRNA vaccine, and healthy controls, we quantified HLA class I- and class II-restricted SARS-CoV-2-specific responses and also identified several HLA allele-clonotype motif associations in patients with COVID-19, including a subcohort of anti-type 1 interferon (IFN-1)-positive patients. RESULTS: Our analysis revealed that elderly patients with COVID-19 with critical disease manifested lower SARS-CoV-2 T-cell clonotype diversity as well as T-cell responses with reduced magnitude, whereas the SARS-CoV-2-specific clonotypes targeted a broad range of HLA class I- and class II-restricted epitopes across the viral proteome. The presence of anti-IFN-I antibodies was associated with certain HLA alleles. Finally, COVID-19 mRNA immunization induced an increase in the breadth of SARS-CoV-2-specific clonotypes in patients with IEIs, including those who had failed to seroconvert. CONCLUSIONS: Elderly individuals have impaired capacity to develop broad and sustained T-cell responses after SARS-CoV-2 infection. Genetic factors may play a role in the production of anti-IFN-1 antibodies. COVID-19 mRNA vaccines are effective in inducing T-cell responses in patients with IEIs.
Subject(s)
COVID-19 , Immunocompromised Host , SARS-CoV-2 , Humans , COVID-19/immunology , SARS-CoV-2/immunology , Male , Middle Aged , Female , Immunocompromised Host/immunology , Adult , Aged , T-Lymphocytes/immunology , COVID-19 Vaccines/immunology , Immunocompetence/immunologyABSTRACT
Interleukin (IL)-37, an antiinflammatory IL-1 family cytokine, is a key suppressor of innate immunity. IL-37 signaling requires the heterodimeric IL-18R1 and IL-1R8 receptor, which is abundantly expressed in the gastrointestinal tract. Here we report a 4-mo-old male from a consanguineous family with a homozygous loss-of-function IL37 mutation. The patient presented with persistent diarrhea and was found to have infantile inflammatory bowel disease (I-IBD). Patient cells showed increased intracellular IL-37 expression and increased proinflammatory cytokine production. In cell lines, mutant IL-37 was not stably expressed or properly secreted and was thus unable to functionally suppress proinflammatory cytokine expression. Furthermore, induced pluripotent stem cell-derived macrophages from the patient revealed an activated macrophage phenotype, which is more prone to lipopolysaccharide and IL-1ß stimulation, resulting in hyperinflammatory tumor necrosis factor production. Insights from this patient will not only shed light on monogenic contributions of I-IBD but may also reveal the significance of the IL-18 and IL-37 axis in colonic homeostasis.
Subject(s)
Gene Expression Regulation/immunology , Inflammatory Bowel Diseases , Interleukin-1 , Loss of Function Mutation , Macrophage Activation/immunology , Macrophages/immunology , Child, Preschool , Female , Humans , Induced Pluripotent Stem Cells/immunology , Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/immunology , Interleukin-1/genetics , Interleukin-1/immunology , Interleukin-18/genetics , Interleukin-18/immunology , Interleukin-1beta/genetics , Interleukin-1beta/immunology , Macrophage Activation/genetics , MaleABSTRACT
Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare primary cutaneous non-Hodgkin lymphoma involving CD8+ T cells, the genetic underpinnings of which remain incompletely understood. Here we report two unrelated patients with B cell Expansion with NF-κB and T cell Anergy (BENTA) disease and a novel presentation of SPTCL. Patient 1 presented early in life with recurrent infections and B cell lymphocytosis, linked to a novel gain-of-function (GOF) CARD11 mutation (p.Lys238del). He developed SPTCL-like lesions and membranoproliferative glomerulonephritis by age 2, treated successfully with cyclosporine. Patient 2 presented at 13 months with splenomegaly, lymphadenopathy, and SPTCL with evidence of hemophagocytic lymphohistiocytosis. Genetic analysis revealed two in cis germline GOF CARD11 variants (p.Glu121Asp/p.Gly126Ser). Autologous bone marrow transplant resulted in SPTCL remission despite persistent B cell lymphocytosis. These cases illuminate an unusual pathological manifestation for BENTA disease, suggesting that CARD11 GOF mutations can manifest in cutaneous CD4+and CD8+ T cell malignancies.
Subject(s)
Immunologic Deficiency Syndromes , Lymphocytosis , Lymphoma, T-Cell , Panniculitis , Male , Humans , Child, Preschool , CD8-Positive T-Lymphocytes/pathology , Panniculitis/genetics , Panniculitis/pathology , Panniculitis/therapy , Lymphoma, T-Cell/genetics , Lymphoma, T-Cell/therapyABSTRACT
DOCK8 immunodeficiency syndrome (DIDS) is a progressive combined immunodeficiency that can be distinguished from other combined immunodeficiencies or hyperimmunoglobulinemia E syndromes in featuring (a) profound susceptibility to virus infections of the skin, with associated skin cancers, and (b) severe food allergies. The DOCK8 locus has many repetitive sequence elements that predispose to the generation of large germline deletions as well as recombination-mediated somatic DNA repair. Residual DOCK8 protein contributes to the variable disease phenotype. The severe virus infections of the skin, and probably also VZV-associated vasculopathy, reflect an important function of DOCK8, which is normally required to maintain lymphocyte shape integrity as the cells migrate through dense tissues. Loss of DOCK8 also causes immune deficits through other mechanisms including a milder generalized cell survival defect and skewing of T helper cell subsets. Recent work has uncovered the roles for DOCK8 in dendritic cell responses that can also help explain the virus susceptibility, as well as in regulatory T cells that might help explain autoimmunity in a minority of patients. Fortunately, hematopoietic stem cell transplantation cures the eczema and infection susceptibility of DIDS, but not necessarily the other disease manifestations including food allergies.
Subject(s)
Guanine Nucleotide Exchange Factors/genetics , Immunologic Deficiency Syndromes/immunology , T-Lymphocytes/immunology , Clustered Regularly Interspaced Short Palindromic Repeats , Disease Susceptibility , Eczema , Genetic Therapy , Hematopoietic Stem Cell Transplantation , Humans , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/therapy , Neoplasms, Squamous Cell , Pneumonia , Vasculitis, Central Nervous SystemABSTRACT
BACKGROUND: Seasonal influenza virus infection causes a range of disease severity, including lower respiratory tract infection with respiratory failure. We evaluated the association of common variants in interferon (IFN) regulatory genes with susceptibility to critical influenza infection in children. METHODS: We performed targeted sequencing of 69 influenza-associated candidate genes in 348 children from 24 US centers admitted to the intensive care unit with influenza infection and lacking risk factors for severe influenza infection (PICFlu cohort, 59.4% male). As controls, whole genome sequencing from 675 children with asthma (CAMP cohort, 62.5% male) was compared. We assessed functional relevance using PICFlu whole blood gene expression levels for the gene and calculated IFN gene signature score. RESULTS: Common variants in DDX58, encoding the retinoic acid-inducible gene I (RIG-I) receptor, demonstrated association above or around the Bonferroni-corrected threshold (synonymous variant rs3205166; intronic variant rs4487862). The intronic single-nucleotide polymorphism rs4487862 minor allele was associated with decreased DDX58 expression and IFN signature (P < .05 and P = .0009, respectively) which provided evidence supporting the genetic variants' impact on RIG-I and IFN immunity. CONCLUSIONS: We provide evidence associating common gene variants in DDX58 with susceptibility to severe influenza infection in children. RIG-I may be essential for preventing life-threatening influenza-associated disease.
Subject(s)
Communicable Diseases , Influenza, Human , Child , Humans , Male , Adolescent , Female , Influenza, Human/genetics , DEAD Box Protein 58/genetics , DEAD Box Protein 58/metabolism , Receptors, Immunologic/genetics , Polymorphism, Single Nucleotide , Interferons/geneticsABSTRACT
Binding levels and neutralization activity of anti-type 1 interferon autoantibodies peaked during acute coronavirus disease 2019 and markedly decreased thereafter. Most patients maintained some ability to neutralize type 1 interferon into convalescence despite lower levels of binding immunoglobulin G. Identifying these autoantibodies in healthy individuals before the development of critical viral disease may be challenging.
Subject(s)
COVID-19 , Interferon Type I , Autoantibodies , Humans , Immunoglobulin G , Interferon-alphaABSTRACT
X-linked MAGT1 deficiency with increased susceptibility to Epstein-Barr virus (EBV) infection and N-linked glycosylation defect (XMEN) disease is an inborn error of immunity caused by loss-of-function mutations in the magnesium transporter 1 (MAGT1) gene. The original studies of XMEN patients focused on impaired magnesium regulation, leading to decreased EBV-cytotoxicity and the loss of surface expression of the activating receptor "natural killer group 2D" (NKG2D) on CD8+ T cells and NK cells. In vitro studies showed that supraphysiological supplementation of magnesium rescued these defects. Observational studies in 2 patients suggested oral magnesium supplementation could decrease EBV viremia. Hence, we performed a randomized, double-blind, placebo-controlled, crossover study in 2 parts. In part 1, patients received either oral magnesium L-threonate (MLT) or placebo for 12 weeks followed by 12 weeks of the other treatment. Part 2 began with 3 days of high-dose intravenous (IV) magnesium sulfate (MgSO4) followed by open-label MLT for 24 weeks. One EBV-infected and 3 EBV-naïve patients completed part 1. One EBV-naïve patient was removed from part 2 of the study due to asymptomatic elevation of liver enzymes during IV MgSO4. No change in EBV or NKG2D status was observed. In vitro magnesium supplementation experiments in cells from 14 XMEN patients failed to significantly rescue NKG2D expression and the clinical trial was stopped. Although small, this study indicates magnesium supplementation is unlikely to be an effective therapeutic option in XMEN disease.
Subject(s)
Cation Transport Proteins , Epstein-Barr Virus Infections , Neoplasms , X-Linked Combined Immunodeficiency Diseases , CD8-Positive T-Lymphocytes , Cation Transport Proteins/genetics , Cross-Over Studies , Dietary Supplements , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/drug therapy , Epstein-Barr Virus Infections/genetics , Herpesvirus 4, Human/physiology , Humans , Magnesium/metabolism , Magnesium/therapeutic use , Neoplasms/genetics , X-Linked Combined Immunodeficiency Diseases/geneticsABSTRACT
The International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) reports here the 2022 updated phenotypic classification, which accompanies and complements the most-recent genotypic classification. This phenotypic classification is aimed for clinicians at the bedside and focuses on clinical features and laboratory phenotypes of specific IEI. In this classification, 485 IEI underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity and auto-inflammation are described, including 55 novel monogenic defects and 1 autoimmune phenocopy. Therefore, all 485 diseases of the genetic classification are presented in this paper in the form of colored tables with essential clinical or immunological phenotype entries.
Subject(s)
Hypersensitivity , Immunologic Deficiency Syndromes , Neoplasms , Humans , Immunologic Deficiency Syndromes/genetics , Phenotype , GenotypeABSTRACT
We report the updated classification of inborn errors of immunity, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 55 novel monogenic gene defects, and 1 phenocopy due to autoantibodies, that have either been discovered since the previous update (published January 2020) or were characterized earlier but have since been confirmed or expanded in subsequent studies. While variants in additional genes associated with immune diseases have been reported in the literature, this update includes only those that the committee assessed that reached the necessary threshold to represent novel inborn errors of immunity. There are now a total of 485 inborn errors of immunity. These advances in discovering the genetic causes of human immune diseases continue to significantly further our understanding of molecular, cellular, and immunological mechanisms of disease pathogenesis, thereby simultaneously enhancing immunological knowledge and improving patient diagnosis and management. This report is designed to serve as a resource for immunologists and geneticists pursuing the molecular diagnosis of individuals with heritable immunological disorders and for the scientific dissection of cellular and molecular mechanisms underlying monogenic and related human immune diseases.
Subject(s)
Immune System Diseases , Immunologic Deficiency Syndromes , Humans , Immunologic Deficiency Syndromes/diagnosis , Phenotype , Research ReportABSTRACT
Rare, biallelic loss-of-function mutations in DOCK8 result in a combined immune deficiency characterized by severe and recurrent cutaneous infections, eczema, allergies, and susceptibility to malignancy, as well as impaired humoral and cellular immunity and hyper-IgE. The advent of next-generation sequencing technologies has enabled the rapid molecular diagnosis of rare monogenic diseases, including inborn errors of immunity. These advances have resulted in the implementation of gene-guided treatments, such as hematopoietic stem cell transplant for DOCK8 deficiency. However, putative disease-causing variants revealed by next-generation sequencing need rigorous validation to demonstrate pathogenicity. Here, we report the eventual diagnosis of DOCK8 deficiency in a consanguineous family due to a novel homozygous intronic deletion variant that caused aberrant exon splicing and subsequent loss of expression of DOCK8 protein. Remarkably, the causative variant was not initially detected by clinical whole-genome sequencing but was subsequently identified and validated by combining advanced genomic analysis, RNA-seq, and flow cytometry. This case highlights the need to adopt multipronged confirmatory approaches to definitively solve complex genetic cases that result from variants outside protein-coding exons and conventional splice sites.
Subject(s)
Job Syndrome , Consanguinity , Guanine Nucleotide Exchange Factors/genetics , Homozygote , Humans , Job Syndrome/diagnosis , Job Syndrome/genetics , Mutation/genetics , Exome SequencingABSTRACT
BACKGROUND: Biallelic loss-of-function mutations in CARMIL2 cause combined immunodeficiency associated with dermatitis, inflammatory bowel disease (IBD), and EBV-related smooth muscle tumors. Clinical and immunological characterizations of the disease with long-term follow-up and treatment options have not been previously reported in large cohorts. We sought to determine the clinical and immunological features of CARMIL2 deficiency and long-term efficacy of treatment in controlling different disease manifestations. METHODS: The presenting phenotypes, long-term outcomes, and treatment responses were evaluated prospectively in 15 CARMIL2-deficient patients, including 13 novel cases. Lymphocyte subpopulations, protein expression, regulatory T (Treg), and circulating T follicular helper (cTFH ) cells were analyzed. Three-dimensional (3D) migration assay was performed to determine T-cell shape. RESULTS: Mean age at disease onset was 38 ± 23 months. Main clinical features were skin manifestations (n = 14, 93%), failure to thrive (n = 10, 67%), recurrent infections (n = 10, 67%), allergic symptoms (n = 8, 53%), chronic diarrhea (n = 4, 27%), and EBV-related leiomyoma (n = 2, 13%). Skin manifestations ranged from atopic and seborrheic dermatitis to psoriasiform rash. Patients had reduced proportions of memory CD4+ T cells, Treg, and cTFH cells. Memory B and NK cells were also decreased. CARMIL2-deficient T cells exhibited reduced T-cell proliferation and cytokine production following CD28 co-stimulation and normal morphology when migrating in a high-density 3D collagen gel matrix. IBD was the most severe clinical manifestation, leading to growth retardation, requiring multiple interventional treatments. All patients were alive with a median follow-up of 10.8 years (range: 3-17 years). CONCLUSION: This cohort provides clinical and immunological features and long-term follow-up of different manifestations of CARMIL2 deficiency.
Subject(s)
Inflammatory Bowel Diseases , Primary Immunodeficiency Diseases , Humans , Microfilament Proteins/genetics , Mutation , PhenotypeABSTRACT
Genetic defects of innate immunity impairing intestinal bacterial sensing are linked to the development of Inflammatory Bowel Disease (IBD). Although much evidence supports a role of the intestinal virome in gut homeostasis, most studies focus on intestinal viral composition rather than on host intestinal viral sensitivity. To demonstrate the association between the development of Very Early Onset IBD (VEOIBD) and variants in the IFIH1 gene which encodes MDA5, a key cytosolic sensor for viral nucleic acids. Whole exome sequencing (WES) was performed in two independent cohorts of children with VEOIBD enrolled in Italy (n = 18) and USA (n = 24). Luciferase reporter assays were employed to assess MDA5 activity. An enrichment analysis was performed on IFIH1 comparing 42 VEOIBD probands with 1527 unrelated individuals without gastrointestinal or immunological issues. We identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD from a combined cohort of 42 children. One subject, carrying a homozygous truncating variant resulting in complete LoF, experienced neonatal-onset, pan-gastrointestinal, IBD-like enteropathy plus multiple infectious episodes. The remaining seven subjects, affected by VEOIBD without immunodeficiency, were carriers of one LoF variant in IFIH1. Among these, two patients also carried a second hypomorphic variant, with partial function apparent when MDA5 was weakly stimulated. Furthermore, IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p = 0.007). Complete and partial MDA5 deficiency is associated with VEOIBD with variable penetrance and expressivity, suggesting a role for impaired intestinal viral sensing in IBD pathogenesis.