The emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants has decreased the efficacy of SARs-CoV-2 vaccines in containing coronavirus disease 2019(CoVID-19)over time,and booster vaccination ...The emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants has decreased the efficacy of SARs-CoV-2 vaccines in containing coronavirus disease 2019(CoVID-19)over time,and booster vaccination strategies are urgently necessitated to achieve sufficient protection.Intranasal immunization can improvemucosal immunity,offer-ing protection against the infection and sustaining the spread of SARS-CoV-2.In this study,an intranasal booster of the RBD-HR vaccine after two doses of the mRNA vaccine significantly increased the levels of specific binding antibodies in serum,nasal lavage fluid,and bronchoal-veolar lavage fluid compared with only two doses of mRNA vaccine.After intranasal boosting with the RBD-HR vaccine,the levels of serum neutralizing antibodies against prototype and variant strains of SARS-Cov-2 pseudoviruses weremarkedly higher than those in mice receiving mRNA vaccine alone,and intranasal boosting with the RBD-HR vaccine also inhibited the bind-ing of RBD to hACE2 receptors.Furthermore,the heterologous intranasal immunization regimen promoted extensive memory T cell responses and activated CD103+dendritic cells in the respiratory mucosa,and potently enhanced the formation of T follicular helper cells and germinal center B cells in vital immune organs,including mediastinal lymph nodes,inguinal lymph nodes,and spleen.Collectively,these data infer that heterologous intranasal boosting with the RBD-HR vaccine elicited broad protective immunity against SARS-CoV-2 both locallyandsystemically.展开更多
For coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),15–30%of patients are likely to develop COVID-19-related acute respiratory distress syndrome(ARDS).There ar...For coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),15–30%of patients are likely to develop COVID-19-related acute respiratory distress syndrome(ARDS).There are still few effective and well-understood therapies available.Novel variants and short-lasting immunity are posing challenges to vaccine efficacy,so finding antiviral and antiinflammatory treatments remains crucial.Here,tripterin(TP),a traditional Chinese medicine,was encapsulated into liposome(TP lipo)to investigate its antiviral and antiinflammatory effects in severe COVID-19.By using two severe COVID-19 models in human ACE2-transgenic(hACE2)mice,an analysis of TP lipo’s effects on pulmonary immune responses was conducted.Pulmonary pathological alterations and viral burden were reduced by TP lipo treatment.TP lipo inhibits SARS-CoV-2 replication and hyperinflammation in infected cells and mice,two crucial events in severe COVID-19 pathophysiology,it is a promising drug candidate to treat SARS-CoV-2-induced ARDS.展开更多
Over the past decades,great interest has been given to biomimetic nanoparticles(BNPs)since the rise of targeted drug delivery systems and biomimetic nanotechnology.Biological vectors including cell membranes,extracell...Over the past decades,great interest has been given to biomimetic nanoparticles(BNPs)since the rise of targeted drug delivery systems and biomimetic nanotechnology.Biological vectors including cell membranes,extracellular vesicles(EVs),and viruses are considered promising candidates for targeted delivery owing to their biocompatibility and biodegradability.BNPs,the integration of biological vectors and functional agents,are anticipated to load cargos or camouflage synthetic nanoparticles to achieve targeted delivery.Despite their excellent intrinsic properties,natural vectors are deliberately modified to endow multiple functions such as good permeability,improved loading capability,and high specificity.Through structural modification and transformation of the vectors,they are pervasively utilized as more effective vehicles that can deliver contrast agents,chemotherapy drugs,nucleic acids,and genes to target sites for refractory disease therapy.This review summarizes recent adva门ces in targeted delivery vectors based on cell membranes,EVs,and viruses,highlighting the potential applications of BNPs in the fields of biomedical imaging and therapy industry,as well as discussing the possibility of clinical translation and exploitation trend of these BNPs.展开更多
Neutrophil extracellular traps(NETs)can capture and kill viruses,such as influenza viruses,human immunodeficiency virus(HIV),and respiratory syncytial virus(RSV),thus contributing to host defense.Contrary to our expec...Neutrophil extracellular traps(NETs)can capture and kill viruses,such as influenza viruses,human immunodeficiency virus(HIV),and respiratory syncytial virus(RSV),thus contributing to host defense.Contrary to our expectation,we show here that the histones released by NETosis enhance the infectivity of SARS-CoV-2,as found by using live SARS-CoV-2 and two pseudovirus systems as well as a mouse model.The histone H3 or H4 selectively binds to subunit 2 of the spike(S)protein,as shown by a biochemical binding assay,surface plasmon resonance and binding energy calculation as well as the construction of a mutant S protein by replacing four acidic amino acids.Sialic acid on the host cell surface is the key molecule to which histones bridge subunit 2 of the S protein.Moreover,histones enhance cell-cell fusion.Finally,treatment with an inhibitor of NETosis,histone H3 or H4,or sialic acid notably affected the levels of sgRNA copies and the number of apoptotic cells in a mouse model.These findings suggest that SARS-CoV-2 could hijack histones from neutrophil NETosis to promote its host cell attachment and entry process and may be important in exploring pathogenesis and possible strategies to develop new effective therapies for COVID-19.展开更多
The outbreak of coronavirus disease 2019(COVID-19)has posed great threats to global health and economy.Several effective vaccines are available now,but additional booster immunization is required to retain or increase...The outbreak of coronavirus disease 2019(COVID-19)has posed great threats to global health and economy.Several effective vaccines are available now,but additional booster immunization is required to retain or increase the immune responses owing to waning immunity and the emergency of new variant strains.The deficiency of intramuscularly delivered vaccines to induce mucosal immunity urged the development of mucosal vaccines.Here,we developed an adjuvanted intranasal RBD vaccine and monitored its long-term immunogenicity against both wild-type and mutant strains of severe acute respiratory syndrome coronavirus-2(SARSCoV-2),including Omicron variants,in mice.Three-dose intranasal immunization with this vaccine induced and maintained high levels of neutralizing IgG antibodies in the sera for at least 1 year.Strong mucosal immunity was also provoked,including mucosal secretory IgA and lung-resident memory T cells(TRM).We also demonstrated that the long-term persistence of lung TRM cells is a consequence of local T-cell proliferation,rather than T-cell migration from lymph nodes.Our data suggested that the adjuvanted intranasal RBD vaccine is a promising vaccine candidate to establish robust,long-lasting,and broad protective immunity against SARS-CoV-2 both systemically and locally.展开更多
The development of animal models for COVID-19 is essential for basic research and drug/vaccine screening.Previously reported COVID-19 animal models need to be established under a high biosafety level condition for the...The development of animal models for COVID-19 is essential for basic research and drug/vaccine screening.Previously reported COVID-19 animal models need to be established under a high biosafety level condition for the utilization of live SARS-CoV-2,which greatly limits its application in routine research.Here,we gen erate a mouse model of COVID-19 un der a gen eral laboratory condition that captures multiple characteristics of SARS-CoV-2-induced acute respiratory distress syndrome(ARDS)observed in huma ns.Briefly,human ACE2-tra nsge nic(MCE2)mice were in tratracheally in stilled with the formaldehyde-inactivated SARS-CoV-2,resulting in a rapid weight loss and detrimental changes in lung structure and function.The pulmonary pathologic changes were characterized by diffuse alveolar damage with pulmonary consolidation,hemorrhage,necrotic debris,and hyaline membrane formation.The production of fatal cytokines(IL-β,TNF-α,and IL-6)and the infiltration of activated neutrophils,inflammatory monocyte-macrophages,and T cells in the lung were also determined,suggesting the activation of an adaptive immune response.Therapeutic strategies,such as dexamethasone or passive antibody therapy,could effectively ameliorate the disease progression in this model.Therefore,the established mouse model for SARS-CoV-2-induced ARDS in the current study may provide a robust tool for researchers in the standard open laboratory to investigate the pathological mechanisms or develop new therapeutic strategies for COVID-19 and ARDS.展开更多
基金funded by the National Science Foundation for Excellent Young Scholars of China(No.32122052)the National Natural Science Foundation Regional Innovation and Development of China(No.U19A2003).
文摘The emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants has decreased the efficacy of SARs-CoV-2 vaccines in containing coronavirus disease 2019(CoVID-19)over time,and booster vaccination strategies are urgently necessitated to achieve sufficient protection.Intranasal immunization can improvemucosal immunity,offer-ing protection against the infection and sustaining the spread of SARS-CoV-2.In this study,an intranasal booster of the RBD-HR vaccine after two doses of the mRNA vaccine significantly increased the levels of specific binding antibodies in serum,nasal lavage fluid,and bronchoal-veolar lavage fluid compared with only two doses of mRNA vaccine.After intranasal boosting with the RBD-HR vaccine,the levels of serum neutralizing antibodies against prototype and variant strains of SARS-Cov-2 pseudoviruses weremarkedly higher than those in mice receiving mRNA vaccine alone,and intranasal boosting with the RBD-HR vaccine also inhibited the bind-ing of RBD to hACE2 receptors.Furthermore,the heterologous intranasal immunization regimen promoted extensive memory T cell responses and activated CD103+dendritic cells in the respiratory mucosa,and potently enhanced the formation of T follicular helper cells and germinal center B cells in vital immune organs,including mediastinal lymph nodes,inguinal lymph nodes,and spleen.Collectively,these data infer that heterologous intranasal boosting with the RBD-HR vaccine elicited broad protective immunity against SARS-CoV-2 both locallyandsystemically.
基金supported by the National Science Foundation for Excellent Young Scholars(No.32122052)the National Natural Science Foundation Regional Innovation and Development(No.U19A2003).
文摘For coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),15–30%of patients are likely to develop COVID-19-related acute respiratory distress syndrome(ARDS).There are still few effective and well-understood therapies available.Novel variants and short-lasting immunity are posing challenges to vaccine efficacy,so finding antiviral and antiinflammatory treatments remains crucial.Here,tripterin(TP),a traditional Chinese medicine,was encapsulated into liposome(TP lipo)to investigate its antiviral and antiinflammatory effects in severe COVID-19.By using two severe COVID-19 models in human ACE2-transgenic(hACE2)mice,an analysis of TP lipo’s effects on pulmonary immune responses was conducted.Pulmonary pathological alterations and viral burden were reduced by TP lipo treatment.TP lipo inhibits SARS-CoV-2 replication and hyperinflammation in infected cells and mice,two crucial events in severe COVID-19 pathophysiology,it is a promising drug candidate to treat SARS-CoV-2-induced ARDS.
基金This work was financially supported by the National Key Research and Development Program of China(2020YFC2008302)the Sichuan Science and Technology program(2019YFG0266)the 1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYJC18028,2021HXFH064)。
文摘Over the past decades,great interest has been given to biomimetic nanoparticles(BNPs)since the rise of targeted drug delivery systems and biomimetic nanotechnology.Biological vectors including cell membranes,extracellular vesicles(EVs),and viruses are considered promising candidates for targeted delivery owing to their biocompatibility and biodegradability.BNPs,the integration of biological vectors and functional agents,are anticipated to load cargos or camouflage synthetic nanoparticles to achieve targeted delivery.Despite their excellent intrinsic properties,natural vectors are deliberately modified to endow multiple functions such as good permeability,improved loading capability,and high specificity.Through structural modification and transformation of the vectors,they are pervasively utilized as more effective vehicles that can deliver contrast agents,chemotherapy drugs,nucleic acids,and genes to target sites for refractory disease therapy.This review summarizes recent adva门ces in targeted delivery vectors based on cell membranes,EVs,and viruses,highlighting the potential applications of BNPs in the fields of biomedical imaging and therapy industry,as well as discussing the possibility of clinical translation and exploitation trend of these BNPs.
基金supported by the National Science Foundation for Excellent Young Scholars (32122052)National Natural Science Foundation Regional Innovation and Development (No.U19A2003).
文摘Neutrophil extracellular traps(NETs)can capture and kill viruses,such as influenza viruses,human immunodeficiency virus(HIV),and respiratory syncytial virus(RSV),thus contributing to host defense.Contrary to our expectation,we show here that the histones released by NETosis enhance the infectivity of SARS-CoV-2,as found by using live SARS-CoV-2 and two pseudovirus systems as well as a mouse model.The histone H3 or H4 selectively binds to subunit 2 of the spike(S)protein,as shown by a biochemical binding assay,surface plasmon resonance and binding energy calculation as well as the construction of a mutant S protein by replacing four acidic amino acids.Sialic acid on the host cell surface is the key molecule to which histones bridge subunit 2 of the S protein.Moreover,histones enhance cell-cell fusion.Finally,treatment with an inhibitor of NETosis,histone H3 or H4,or sialic acid notably affected the levels of sgRNA copies and the number of apoptotic cells in a mouse model.These findings suggest that SARS-CoV-2 could hijack histones from neutrophil NETosis to promote its host cell attachment and entry process and may be important in exploring pathogenesis and possible strategies to develop new effective therapies for COVID-19.
基金supported by the National Natural Science Foundation Regional Innovation and Development(No.U19A2003)the National Science Fund for Excellent Young Scholars National Science Fund for Excellent Young Scholars(No.32122052).
文摘The outbreak of coronavirus disease 2019(COVID-19)has posed great threats to global health and economy.Several effective vaccines are available now,but additional booster immunization is required to retain or increase the immune responses owing to waning immunity and the emergency of new variant strains.The deficiency of intramuscularly delivered vaccines to induce mucosal immunity urged the development of mucosal vaccines.Here,we developed an adjuvanted intranasal RBD vaccine and monitored its long-term immunogenicity against both wild-type and mutant strains of severe acute respiratory syndrome coronavirus-2(SARSCoV-2),including Omicron variants,in mice.Three-dose intranasal immunization with this vaccine induced and maintained high levels of neutralizing IgG antibodies in the sera for at least 1 year.Strong mucosal immunity was also provoked,including mucosal secretory IgA and lung-resident memory T cells(TRM).We also demonstrated that the long-term persistence of lung TRM cells is a consequence of local T-cell proliferation,rather than T-cell migration from lymph nodes.Our data suggested that the adjuvanted intranasal RBD vaccine is a promising vaccine candidate to establish robust,long-lasting,and broad protective immunity against SARS-CoV-2 both systemically and locally.
基金This work is supported by the National Natural Science Foundation Regional Innovation and Development(No.U19A2003)National Major Scientific and Technological Special Project for"Significant New Drugs Development"(No.2018ZX09733001)+1 种基金the Excellent Youth Foundation of Sichuan Scientific Committee Grant in China(No.2019JDJQ008)the Development Program of China(No.2016YFA0201402).
文摘The development of animal models for COVID-19 is essential for basic research and drug/vaccine screening.Previously reported COVID-19 animal models need to be established under a high biosafety level condition for the utilization of live SARS-CoV-2,which greatly limits its application in routine research.Here,we gen erate a mouse model of COVID-19 un der a gen eral laboratory condition that captures multiple characteristics of SARS-CoV-2-induced acute respiratory distress syndrome(ARDS)observed in huma ns.Briefly,human ACE2-tra nsge nic(MCE2)mice were in tratracheally in stilled with the formaldehyde-inactivated SARS-CoV-2,resulting in a rapid weight loss and detrimental changes in lung structure and function.The pulmonary pathologic changes were characterized by diffuse alveolar damage with pulmonary consolidation,hemorrhage,necrotic debris,and hyaline membrane formation.The production of fatal cytokines(IL-β,TNF-α,and IL-6)and the infiltration of activated neutrophils,inflammatory monocyte-macrophages,and T cells in the lung were also determined,suggesting the activation of an adaptive immune response.Therapeutic strategies,such as dexamethasone or passive antibody therapy,could effectively ameliorate the disease progression in this model.Therefore,the established mouse model for SARS-CoV-2-induced ARDS in the current study may provide a robust tool for researchers in the standard open laboratory to investigate the pathological mechanisms or develop new therapeutic strategies for COVID-19 and ARDS.