Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is a‘highly transmissible respiratory pathogen,leading to severe multiorgan damage.However,knowledge regarding SARS-CoV-2-induced cellular alterations is lim...Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is a‘highly transmissible respiratory pathogen,leading to severe multiorgan damage.However,knowledge regarding SARS-CoV-2-induced cellular alterations is limited.In this study,we report that SARSCoV-2 aberrantly elevates mitochondrial bioenergetics and activates the EGFR-mediated cell survival signal cascade during the early stage of viral infection.SARS-CoV-2 causes an increase in mitochondrial transmembrane potential via the SARS-CoV-2 RNAnucleocapsid cluster,thereby abnormally promoting mitochondrial elongation and the OXPHOS process,followed by enhancing ATP production.Furthermore,SARS-CoV-2 activates the EGFR signal cascade and subsequently induces mitochondrial EGFR trafficking,contributing to abnormal OXPHOS process and viral propagation.Approved EGFR inhibitors remarkably reduce SARS-CoV-2 propagation,among which vandetanib exhibits the highest antiviral efficacy.Treatment of SARS-CoV-2-infected cells with vandetanib decreases SARS-CoV-2-induced EGFR trafficking to the mitochondria and restores SARS-CoV-2-induced aberrant elevation in OXPHOS process and ATP generation,thereby resulting in the reduction of SARS-CoV-2 propagation.Furthermore,oral administration of vandetanib to SARS-CoV-2-infected hACE2 transgenic mice reduces SARS-CoV-2 propagation in lung tissue and mitigates SARS-CoV-2-induced lung inflammation.Vandetanib also exhibits potent antiviral activity against various SARS-CoV-2 variants of concern,including alpha,beta,delta and omicron,in in vitro cell culture experiments.Taken together,our findings provide novel insight into SARS-CoV-2-induced alterations in mitochondrial dynamics and EGFR trafficking during the early stage of viral infection and their roles in robust SARS-CoV-2 propagation,suggesting that EGFR is an attractive host target for combating COVID-19.展开更多
The composition of commensal bacteria plays a critical role in controlling immune responses in the intestine.Studies have shown that specific bacterial strains may have the capacity to enhance host immune defense agai...The composition of commensal bacteria plays a critical role in controlling immune responses in the intestine.Studies have shown that specific bacterial strains may have the capacity to enhance host immune defense against gastrointestinal viral infections.While norovirus is known to be the most common cause of gastroenteritis,leading to an estimated 200,000 deaths every year,identification of bacterial strains with protective effects against norovirus infection remains elusive.Here,we discovered Lactobacillus salivarius HHuMin-U(HHuMin-U)as a potent antiviral strain against norovirus infection.HHuMin-U significantly suppressed murine norovirus replication and lowered viral RNA titers in macrophages.The transcriptome sequencing(RNA sequencing)analysis revealed that HHuMin-U markedly enhanced the expression level of antiviral interferon-stimulated genes compared to mock treatment.HHuMin-U treatment dose-dependently induced type I interferons(IFN-αand IFN-β)and tumor necrosis factor-αproduction in mouse and human macrophages,promoting antiviral innate responses against norovirus infection.Investigation on the molecular mechanism demonstrated that HHuMin-U can activate nuclear factorκB and TANK-binding kinase 1(TBK1)–interferon regulatory factor 3 signaling pathways,leading to the phosphorylation of signal transducer and activator of transcription 1 and signal transducer and activator of transcription 2,the key mediators of interferon-stimulated genes.Finally,oral administration of HHuMin-U increased IFN-βlevels in the ileum of mice and altered the gut microbiome profile.These results suggest the species/strain-specific importance of gut microbial composition for antiviral immune responses and the potential use of HHuMin-U as a probiotic agent.展开更多
基金supported in part by the National Research Council of Science&Technology grant by the Korea government(CRC-16-01-KRICT)the Korea Research Institute of Chemical Technology(KRICT)(KK2333-20)+1 种基金the National Research Foundation of Korea(NRF-2021M3E5E3080540,RS-2023-00248135)the BK 21 FOUR Program by the Chungnam National University Research Grant,2023.
文摘Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is a‘highly transmissible respiratory pathogen,leading to severe multiorgan damage.However,knowledge regarding SARS-CoV-2-induced cellular alterations is limited.In this study,we report that SARSCoV-2 aberrantly elevates mitochondrial bioenergetics and activates the EGFR-mediated cell survival signal cascade during the early stage of viral infection.SARS-CoV-2 causes an increase in mitochondrial transmembrane potential via the SARS-CoV-2 RNAnucleocapsid cluster,thereby abnormally promoting mitochondrial elongation and the OXPHOS process,followed by enhancing ATP production.Furthermore,SARS-CoV-2 activates the EGFR signal cascade and subsequently induces mitochondrial EGFR trafficking,contributing to abnormal OXPHOS process and viral propagation.Approved EGFR inhibitors remarkably reduce SARS-CoV-2 propagation,among which vandetanib exhibits the highest antiviral efficacy.Treatment of SARS-CoV-2-infected cells with vandetanib decreases SARS-CoV-2-induced EGFR trafficking to the mitochondria and restores SARS-CoV-2-induced aberrant elevation in OXPHOS process and ATP generation,thereby resulting in the reduction of SARS-CoV-2 propagation.Furthermore,oral administration of vandetanib to SARS-CoV-2-infected hACE2 transgenic mice reduces SARS-CoV-2 propagation in lung tissue and mitigates SARS-CoV-2-induced lung inflammation.Vandetanib also exhibits potent antiviral activity against various SARS-CoV-2 variants of concern,including alpha,beta,delta and omicron,in in vitro cell culture experiments.Taken together,our findings provide novel insight into SARS-CoV-2-induced alterations in mitochondrial dynamics and EGFR trafficking during the early stage of viral infection and their roles in robust SARS-CoV-2 propagation,suggesting that EGFR is an attractive host target for combating COVID-19.
基金a National Research Foundation of Korea(NRF)grant funded by the Korean Government(Ministry of Science,ICT and Future Planning)(2020R1A2C1010703).
文摘The composition of commensal bacteria plays a critical role in controlling immune responses in the intestine.Studies have shown that specific bacterial strains may have the capacity to enhance host immune defense against gastrointestinal viral infections.While norovirus is known to be the most common cause of gastroenteritis,leading to an estimated 200,000 deaths every year,identification of bacterial strains with protective effects against norovirus infection remains elusive.Here,we discovered Lactobacillus salivarius HHuMin-U(HHuMin-U)as a potent antiviral strain against norovirus infection.HHuMin-U significantly suppressed murine norovirus replication and lowered viral RNA titers in macrophages.The transcriptome sequencing(RNA sequencing)analysis revealed that HHuMin-U markedly enhanced the expression level of antiviral interferon-stimulated genes compared to mock treatment.HHuMin-U treatment dose-dependently induced type I interferons(IFN-αand IFN-β)and tumor necrosis factor-αproduction in mouse and human macrophages,promoting antiviral innate responses against norovirus infection.Investigation on the molecular mechanism demonstrated that HHuMin-U can activate nuclear factorκB and TANK-binding kinase 1(TBK1)–interferon regulatory factor 3 signaling pathways,leading to the phosphorylation of signal transducer and activator of transcription 1 and signal transducer and activator of transcription 2,the key mediators of interferon-stimulated genes.Finally,oral administration of HHuMin-U increased IFN-βlevels in the ileum of mice and altered the gut microbiome profile.These results suggest the species/strain-specific importance of gut microbial composition for antiviral immune responses and the potential use of HHuMin-U as a probiotic agent.
