Enhanced fitness of SARS-CoV-2 variants of concern
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ABSTRACT:
PROVIDER: PRJEB45736 | ENA |
REPOSITORIES: ENA
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Project description:A new phase of the COVID-19 pandemic has started as SARS-CoV-2 variants with increased transmissibility are emerging globally, calling for the development of reliable platforms to rapidly phenotype viruses. Currently, no rapid phenotyping system exists that both accurately models human biology and can be standardized properly. Organoids accurately model viral target cells in vivo, can be established from many tissues, passaged indefinitely, biobanked and shared. We found that the British variant (clade B.1.1.7), compared to an ancestral 614G-containing clade B virus, produced higher levels of infectious virus late in infection and had a higher replicative fitness in human airway, alveolar and intestinal organoid models. Our findings unveil extended shedding as a correlate of fitness for SARS-CoV-2, possibly explaining the rapid emergence of SARS-CoV-2 B.1.1.7. Combined with genomic surveillance systems, virus phenotyping using standardized organoid models may be implemented into public health decision making.
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Project description:Clonal hematopoiesis (CH) results from enhanced fitness of a mutant hematopoietic stem and progenitor cell (HSPC), but how such clones expand is unclear. Here, we developed a technique that combines mosaic mutagenesis with color labeling of HSPCs to study how acquired mutations affect clonal fitness in a native environment. Mutations in CH-associated genes, like asxl1, promoted clonal dominance. Single-cell transcriptional analysis revealed that mutations stimulated expression of proinflammatory genes in mature myeloid cells and anti-inflammatory genes in progenitor cells of the mutant clone. Biallelic loss of one such immunomodulator, nr4a1, abrogated the ability of asxl1-mutant clones to establish clonal dominance. These results support a model where clonal fitness of mutant clones is driven by enhanced resistance to inflammatory signals from their mutant mature cell progeny.
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Project description:Clonal hematopoiesis (CH) results from enhanced fitness of a mutant hematopoietic stem and progenitor cell (HSPC), but how such clones expand is unclear. Here, we developed a technique that combines mosaic mutagenesis with color labeling of HSPCs to study how acquired mutations affect clonal fitness in a native environment. Mutations in CH-associated genes, like asxl1, promoted clonal dominance. Single-cell transcriptional analysis revealed that mutations stimulated expression of proinflammatory genes in mature myeloid cells and anti-inflammatory genes in progenitor cells of the mutant clone. Biallelic loss of one such immunomodulator, nr4a1, abrogated the ability of asxl1-mutant clones to establish clonal dominance. These results support a model where clonal fitness of mutant clones is driven by enhanced resistance to inflammatory signals from their mutant mature cell progeny.
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Project description:Emergence of SARS-CoV-2 variants of concern (VOCs), including the globally successful Alpha (B.1.1.7) variant, suggests viral adaptation to enhance human-to-human transmission. Although much effort has focused on characterisation of spike changes, Alpha mutations outside spike likely contribute to adaptation. Here we used RNAseq as well as viral replication assays to show that Alpha isolates more effectively suppress innate immune responses (ISGs as assessed by RNA) in airway epithelial cells, compared to first wave isolates. We found that Alpha has dramatically increased subgenomic RNA and protein levels of N, Orf9b and Orf6, all known innate immune antagonists.
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Project description:Resistance to inflammation underlies enhanced fitness in clonal hematopoiesis [II]
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