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.

Humans display substantial interindividual clinical variability after SARS-CoV-2 infection^1–3, the genetic and immunological basis of which has begun to be deciphered⁴. However, the extent and drivers of population differences in immune responses to SARS-CoV-2 remain unclear. Here we report single-cell RNA-sequencing data for peripheral blood mononuclear cells—from 222 healthy donors of diverse ancestries—that were stimulated with SARS-CoV-2 or influenza A virus. We show that SARS-CoV-2 induces weaker, but more heterogeneous, interferon-stimulated gene activity compared with influenza A virus, and a unique pro-inflammatory signature in myeloid cells. Transcriptional responses to viruses display marked population differences, primarily driven by changes in cell abundance including increased lymphoid differentiation associated with latent cytomegalovirus infection. Expression quantitative trait loci and mediation analyses reveal a broad effect of cell composition on population disparities in immune responses, with genetic variants exerting a strong effect on specific loci. Furthermore, we show that natural selection has increased population differences in immune responses, particularly for variants associated with SARS-CoV-2 response in East Asians, and document the cellular and molecular mechanisms by which Neanderthal introgression has altered immune functions, such as the response of myeloid cells to viruses. Finally, colocalization and transcriptome-wide association analyses reveal an overlap between the genetic basis of immune responses to SARS-CoV-2 and COVID-19 severity, providing insights into the factors contributing to current disparities in COVID-19 risk.

Humans display vast clinical variability upon SARS-CoV-2 infection ^1–3 , partly due to genetic and immunological factors ⁴ . However, the magnitude of population differences in immune responses to SARS-CoV-2 and the mechanisms underlying such variation remain unknown. Here we report single-cell RNA-sequencing data for peripheral blood mononuclear cells from 222 healthy donors of various ancestries stimulated with SARS-CoV-2 or influenza A virus. We show that SARS-CoV-2 induces a weaker, but more heterogeneous interferon-stimulated gene activity than influenza A virus, and a unique pro-inflammatory signature in myeloid cells. We observe marked population differences in transcriptional responses to viral exposure that reflect environmentally induced cellular heterogeneity, as illustrated by higher rates of cytomegalovirus infection, affecting lymphoid cells, in African-descent individuals. Expression quantitative trait loci and mediation analyses reveal a broad effect of cell proportions on population differences in immune responses, with genetic variants having a narrower but stronger effect on specific loci. Additionally, natural selection has increased immune response differentiation across populations, particularly for variants associated with SARS-CoV-2 responses in East Asians. We document the cellular and molecular mechanisms through which Neanderthal introgression has altered immune functions, such as its impact on the myeloid response in Europeans. Finally, colocalization analyses reveal an overlap between the genetic architecture of immune responses to SARS-CoV-2 and COVID-19 severity. Collectively, these findings suggest that adaptive evolution targeting immunity has also contributed to current disparities in COVID-19 risk.

Bases génétiques et évolutives de la variabilité interpopulationnelle de la réponse immunitaire au SARS-CoV-2: Tous les humains ne sont pas égaux face au SARS-CoV-2. Les bases génétiques et immunologiques de ces différences inter-individuelles commencent à être déchiffrées, mais les prédicteurs de différences immunitaires face au SARS-CoV-2 entre populations restent méconnus. Dans ce contexte, nous rapportons des données de séquençage d'ARN en résolution cellule unique sur des cellules mononucléaires du sang périphérique provenant de 222 donneurs sains de diverses origines, qui ont été stimulées par le SARS-CoV-2 ou le virus de la grippe. Nous montrons que le SARS-CoV-2 induit une activité moins forte, mais plus hétérogène, des gènes stimulés par l'interféron par rapport au virus de la grippe, ainsi qu'une signature pro-inflammatoire unique dans les cellules myéloïdes. Les réponses transcriptionnelles aux virus présentent des différences marquées entre populations, principalement dues à des changements dans la composition cellulaire, y compris une différenciation lymphoïde accrue associée à une infection latente par le cytomégalovirus. Les loci associés à des traits quantitatifs d’expression (eQTLs), ainsi que les analyses de médiation, révèlent un large effet de la composition cellulaire sur les disparités de réponses immunitaires entre populations, avec des variants génétiques exerçant un fort effet sur des loci spécifiques. De plus, nous montrons que la sélection naturelle a accru les différences de réponse immunitaire entre populations, en particulier pour les variants associés à la réponse au SARSCoV-2 chez les populations d’Asie de l’Est, et nous montrons les mécanismes cellulaires et moléculaires par lesquels l'introgression néandertalienne a modifié les fonctions immunitaires, telles que la réponse des cellules myéloïdes aux virus. Enfin, les analyses de colocalisation et d'association transcriptomique à l'échelle du génome révèlent un chevauchement entre la base génétique des réponses immunitaires au SARS-CoV-2 et la gravité de la COVID-19, fournissant des informations sur les facteurs contribuant aux disparités actuelles dans le risque de COVID-19.