Itaconate(ITA),an immunomodulatory metabolite with known anti-inflammatory properties,has underexplored therapeutic or prophylactic potential against coronavirus disease 2019(COVID-19).Using an interanimal transmissio...Itaconate(ITA),an immunomodulatory metabolite with known anti-inflammatory properties,has underexplored therapeutic or prophylactic potential against coronavirus disease 2019(COVID-19).Using an interanimal transmission golden hamster model of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)-induced acute lung injury,we first assessed ITA changes in dNS1-RBD-vaccinated hamsters via metabolomic profiling.Then,we evaluated prophylactic intranasal(20 mg/kg at 9,6,and 3 days before SARS-CoV-2 infection)and therapeutic intraperitoneal(100 mg/kg at 6,24,and 48 hours post-infection)ITA administration,assessed by histopathology,transcriptomic,and metabolomic profiling,followed by multi-omics integration,including gene expression clustering,pathway enrichment,and cytokine/chemokine–metabolites correlation analyses.Public bronchoalveolar lavage fluid(BALF)single-cell RNA-sequencing(scRNA-seq)datasets from COVID-19 patients were re-analyzed to explore macrophage heterogeneity.Intranasal dNS1-RBD vaccine upregulated ITA levels,prompting further exploration of its immunomodulatory role.Both prophylactic and therapeutic ITA treatments significantly mitigated weight loss and improved lung pathology.Correlation analyses implied a potential regulatory crosstalk between fatty acid b-oxidation(FAO)and reduced inflammatory response.Reanalysis of BALF scRNA-seq dataset highlighted transcriptional networks involving PPARG,RARA,BHLHE41,TCF7L2,and ESRRA—genes linked to macrophage self-renewal and metabolic homeostasis,which appeared to be preserved in ITA-treated hamsters.These findings underscore ITA’s role in modulating immunometabolic responses,particularly through FAO-driven macrophage reprogramming,to attenuate SARS-CoV-2-induced lung damage.Together,this study provides insights into host-directed therapies targeting metabolic reprogramming to mitigate COVID-19 severity.展开更多
基金funded by the National Natural Science Foun-dation of China(grant numbers 82322027 to T.Z.,82341043 to T.Z.,and 92369108 to J.Z.)the National Key Research and Development Program of China(grant number 2023YFC2307602 to J.Z.)+1 种基金the Natural Science Foundation of Beijing Municipal(grant number L234007 to T.Z.)the Fundamental Research Funds for the Central Universities(grant number 20720220003 to N.X.).
文摘Itaconate(ITA),an immunomodulatory metabolite with known anti-inflammatory properties,has underexplored therapeutic or prophylactic potential against coronavirus disease 2019(COVID-19).Using an interanimal transmission golden hamster model of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)-induced acute lung injury,we first assessed ITA changes in dNS1-RBD-vaccinated hamsters via metabolomic profiling.Then,we evaluated prophylactic intranasal(20 mg/kg at 9,6,and 3 days before SARS-CoV-2 infection)and therapeutic intraperitoneal(100 mg/kg at 6,24,and 48 hours post-infection)ITA administration,assessed by histopathology,transcriptomic,and metabolomic profiling,followed by multi-omics integration,including gene expression clustering,pathway enrichment,and cytokine/chemokine–metabolites correlation analyses.Public bronchoalveolar lavage fluid(BALF)single-cell RNA-sequencing(scRNA-seq)datasets from COVID-19 patients were re-analyzed to explore macrophage heterogeneity.Intranasal dNS1-RBD vaccine upregulated ITA levels,prompting further exploration of its immunomodulatory role.Both prophylactic and therapeutic ITA treatments significantly mitigated weight loss and improved lung pathology.Correlation analyses implied a potential regulatory crosstalk between fatty acid b-oxidation(FAO)and reduced inflammatory response.Reanalysis of BALF scRNA-seq dataset highlighted transcriptional networks involving PPARG,RARA,BHLHE41,TCF7L2,and ESRRA—genes linked to macrophage self-renewal and metabolic homeostasis,which appeared to be preserved in ITA-treated hamsters.These findings underscore ITA’s role in modulating immunometabolic responses,particularly through FAO-driven macrophage reprogramming,to attenuate SARS-CoV-2-induced lung damage.Together,this study provides insights into host-directed therapies targeting metabolic reprogramming to mitigate COVID-19 severity.
