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1.
Nature ; 621(7977): 120-128, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37558883

RESUMO

Humans display substantial interindividual clinical variability after SARS-CoV-2 infection1-3, 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.


Assuntos
COVID-19 , Genética Populacional , SARS-CoV-2 , Análise da Expressão Gênica de Célula Única , Animais , Humanos , Diferenciação Celular , COVID-19/genética , COVID-19/imunologia , COVID-19/virologia , Citomegalovirus/fisiologia , População do Leste Asiático/genética , Introgressão Genética , Vírus da Influenza A/patogenicidade , Vírus da Influenza A/fisiologia , Interferons/imunologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Células Mieloides/imunologia , Homem de Neandertal/genética , Homem de Neandertal/imunologia , SARS-CoV-2/genética , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , SARS-CoV-2/fisiologia , Seleção Genética , Latência Viral
2.
Science ; 379(6632): eabo3627, 2023 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-36538032

RESUMO

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.


Assuntos
COVID-19 , Citocinas , Endorribonucleases , SARS-CoV-2 , Síndrome de Resposta Inflamatória Sistêmica , Criança , Humanos , COVID-19/imunologia , Citocinas/genética , Citocinas/imunologia , Endorribonucleases/genética , Endorribonucleases/metabolismo , RNA de Cadeia Dupla , SARS-CoV-2/genética , Síndrome de Resposta Inflamatória Sistêmica/genética
3.
Front Immunol ; 12: 768189, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34912340

RESUMO

There is considerable inter-individual and inter-population variability in response to viruses. The potential of monocytes to elicit type-I interferon responses has attracted attention to their role in viral infections. Here, we use single-cell RNA-sequencing to characterize the role of cellular heterogeneity in human variation of monocyte responses to influenza A virus (IAV) exposure. We show widespread inter-individual variability in the percentage of IAV-infected monocytes. Notably, individuals with high cellular susceptibility to IAV are characterized by a lower activation at basal state of an IRF/STAT-induced transcriptional network, which includes antiviral genes such as IFITM3, MX1 and OAS3. Upon IAV challenge, we find that cells escaping viral infection display increased mRNA expression of type-I interferon stimulated genes and decreased expression of ribosomal genes, relative to both infected cells and those never exposed to IAV. We also uncover a stronger resistance of CD16+ monocytes to IAV infection, together with CD16+ -specific mRNA expression of IL6 and TNF in response to IAV. Finally, using flow cytometry and bulk RNA-sequencing across 200 individuals of African and European ancestry, we observe a higher number of CD16+ monocytes and lower susceptibility to IAV infection among monocytes from individuals of African-descent. Based on these data, we hypothesize that higher basal monocyte activation, driven by environmental factors and/or weak-effect genetic variants, underlies the lower cellular susceptibility to IAV infection of individuals of African ancestry relative to those of European ancestry. Further studies are now required to investigate how such cellular differences in IAV susceptibility translate into population differences in clinical outcomes and susceptibility to severe influenza.


Assuntos
Vírus da Influenza A , Influenza Humana/etnologia , Monócitos/imunologia , Análise de Sequência de RNA , Análise de Célula Única , Adulto , População Negra , Citocinas/fisiologia , Proteínas Ligadas por GPI/análise , Humanos , Pessoa de Meia-Idade , Monócitos/virologia , Receptores de IgG/análise , Receptores de IgG/genética , Ribossomos/fisiologia , População Branca , Adulto Jovem
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