Objective:To evaluate the effects of primary anti-dengue virus envelop protein domain 3(DENV-ED3)antibodies on secondary heterotypic anti-DENV ED3 antibody responses and the status of anti-DENV antibody responses agai...Objective:To evaluate the effects of primary anti-dengue virus envelop protein domain 3(DENV-ED3)antibodies on secondary heterotypic anti-DENV ED3 antibody responses and the status of anti-DENV antibody responses against multivalent DENV ED3s in mice.Methods:Four different DENV-ED3s were purified and their biophysical characteristics were confirmed.Swiss albino mice aged 3-4 weeks were immunized with four different DENV-ED3s and the anti-ED3 IgG responses were determined by ELISA.Results:Firstly,the primary 1ED3-2ED3-3ED3 cross-reactive anti-DENV1 ED3 response boosted the secondary anti-2ED3 and anti-3ED3 antibody responses.In contrast,primary anti-2ED3 and anti-3ED3 antibodies neither had cross-recognition of 1ED3,nor had any effect on secondary anti-1ED3 response.Besides,the strict serospecificity of the anti-4ED3 sera did not affect other secondary anti-DENV ED3 responses.Secondly,1ED3,2ED3,and 3ED3 were co-dominantly immunogenic in trivalent ED3 formulations.However,the poorly immunogenic 4ED3 became almost non-immunogenic when injected after or together with 2ED3 and 3ED3,but showed slightly increased immunogenicity when injected with 1ED3,suggesting an adjuvanticity of 1ED3 on 4ED3’s immunogenicity.Conclusions:Although DENV1~4 ED3s share similar sequence homologies and structures,their immune induction potentials differ significantly in terms of immune magnitude,sero-specificity,and sero-cross-reactivity.Such intrinsic features of DENV1~4 ED3s may lead to‘antigen interference’,limiting both the understanding of dengue etiology and the success of dengue vaccine development,which needs to neutralize all four DENV serotypes equivalently.展开更多
Dear Editor,Dengue virus(DENV)is a positive-sense single-stranded RNA virus belonging to the Flaviviridae family,which causes dengue—a disease affecting over 400 million people annually worldwide.DENV is transmitted ...Dear Editor,Dengue virus(DENV)is a positive-sense single-stranded RNA virus belonging to the Flaviviridae family,which causes dengue—a disease affecting over 400 million people annually worldwide.DENV is transmitted through the bite of mosquitoes from the Aedes genus,primarily Aedes aegypti,and has a wide distribution in tropical and subtropical areas(de Souza et al.,2022).展开更多
Dengue virus(DENV)is a mosquito-borne virus with a rapid spread to humans,causing mild to potentially fatal illness in hundreds of millions of people each year.Due to the large number of serotypes of the virus,there r...Dengue virus(DENV)is a mosquito-borne virus with a rapid spread to humans,causing mild to potentially fatal illness in hundreds of millions of people each year.Due to the large number of serotypes of the virus,there remains an unmet need to develop protective vaccines for a broad spectrum of the virus.Here,we constructed a modified mRNA vaccine containing envelope domain III(E-DIII)and non-structural protein 1(NS1)coated with lipid nanoparticles.This multi-target vaccine induced a robust antiviral immune response and increased neutralizing antibody titers that blocked all four types of DENV infection in vitro without significant antibodydependent enhancement(ADE).In addition,there was more bias for Th1 than Th2 in the exact E-DIII and NS1-specific T cell responses after a single injection.Importantly,intramuscular immunization limited DENV transmission in vivo and eliminated vascular leakage.Our findings highlight that chimeric allogeneic structural and non-structural proteins can be effective targets for DENV vaccine and that they can prevent the further development of congenital DENV syndrome.展开更多
Dengue virus(DENV)is a positive-sense single-stranded RNA virus belonging to the genus Flavivirus within the Flaviviridae family.Four serotypes,DENV 1-4,are distributed globally[1].Hanoi metropolitan city is an endemi...Dengue virus(DENV)is a positive-sense single-stranded RNA virus belonging to the genus Flavivirus within the Flaviviridae family.Four serotypes,DENV 1-4,are distributed globally[1].Hanoi metropolitan city is an endemic hotspot for DENV transmission in Vietnam[2,3].The largest outbreak occurred in 2017,with more than 36000 cases and 7 deaths reported,causing by all four serotypes with the predominance of DENV1,following by DENV2[4,5].During the following dengue season,we collected 390 blood and serum samples from 197 hospitalized patients in a national hospital in Hanoi city,Northern Vietnam to identify the circulating DENV serotypes responsible for the 2018-2019 outbreak.展开更多
Dengue viruses(DENV)have spread throughout the world and pose a huge threat to human life.The most widespread serotype is type 2 DENV(DENV 2),which has no specific treatment.NS2B-NS3 protease plays a pivotal role in D...Dengue viruses(DENV)have spread throughout the world and pose a huge threat to human life.The most widespread serotype is type 2 DENV(DENV 2),which has no specific treatment.NS2B-NS3 protease plays a pivotal role in DENV replication because of its function in cleavage of the viral polyprotein;thus,it is considered a promising target for antiviral discovery.In this study,we developed a high-throughput screening system based on the NS2B-NS3 protease to identify candidates from an FDA-approved drug library.Eltrombopag was screened out of 3273 drugs,and demonstrated inhibition on DENV 2 at the micromolar level in vitro,significantly reducing viral loads in the targeted organs of challenged mice following intraperitoneal injection.Further mechanistic analysis showed that eltrombopag allosterically binds to the DENV 2 NS2B-NS3 protease in a reversible,noncompetitive manner,therefore inhibiting DENV 2 at the post-infection stage.In addition,eltrombopag inhibited the NS2B-NS3 proteases of DENV 4 and Zika virus,suggesting its potential as a broadspectrum antiviral agent.This study repurposed eltrombopag as a promising antiviral agent against DENV,providing an alternative for antiviral development against flaviviruses.展开更多
基金supported by a GARE-MOE,Bangladesh(Grant No.:LS201615)visiting scholar funding of GIR TUAT to M.M.I.Japanese government(Monbukagakusho:MEXT)Ph.D.scholarship to M.D.I.and S.Y.
文摘Objective:To evaluate the effects of primary anti-dengue virus envelop protein domain 3(DENV-ED3)antibodies on secondary heterotypic anti-DENV ED3 antibody responses and the status of anti-DENV antibody responses against multivalent DENV ED3s in mice.Methods:Four different DENV-ED3s were purified and their biophysical characteristics were confirmed.Swiss albino mice aged 3-4 weeks were immunized with four different DENV-ED3s and the anti-ED3 IgG responses were determined by ELISA.Results:Firstly,the primary 1ED3-2ED3-3ED3 cross-reactive anti-DENV1 ED3 response boosted the secondary anti-2ED3 and anti-3ED3 antibody responses.In contrast,primary anti-2ED3 and anti-3ED3 antibodies neither had cross-recognition of 1ED3,nor had any effect on secondary anti-1ED3 response.Besides,the strict serospecificity of the anti-4ED3 sera did not affect other secondary anti-DENV ED3 responses.Secondly,1ED3,2ED3,and 3ED3 were co-dominantly immunogenic in trivalent ED3 formulations.However,the poorly immunogenic 4ED3 became almost non-immunogenic when injected after or together with 2ED3 and 3ED3,but showed slightly increased immunogenicity when injected with 1ED3,suggesting an adjuvanticity of 1ED3 on 4ED3’s immunogenicity.Conclusions:Although DENV1~4 ED3s share similar sequence homologies and structures,their immune induction potentials differ significantly in terms of immune magnitude,sero-specificity,and sero-cross-reactivity.Such intrinsic features of DENV1~4 ED3s may lead to‘antigen interference’,limiting both the understanding of dengue etiology and the success of dengue vaccine development,which needs to neutralize all four DENV serotypes equivalently.
文摘Dear Editor,Dengue virus(DENV)is a positive-sense single-stranded RNA virus belonging to the Flaviviridae family,which causes dengue—a disease affecting over 400 million people annually worldwide.DENV is transmitted through the bite of mosquitoes from the Aedes genus,primarily Aedes aegypti,and has a wide distribution in tropical and subtropical areas(de Souza et al.,2022).
基金supported by the Strategic Priority Research Program of CAS (XDB29010000)partially financially supported by the Institute of Infectious Disease of Shenzhen Bay Laboratorysupported by the Youth Innovation Promotion Association of CAS (2019091)
文摘Dengue virus(DENV)is a mosquito-borne virus with a rapid spread to humans,causing mild to potentially fatal illness in hundreds of millions of people each year.Due to the large number of serotypes of the virus,there remains an unmet need to develop protective vaccines for a broad spectrum of the virus.Here,we constructed a modified mRNA vaccine containing envelope domain III(E-DIII)and non-structural protein 1(NS1)coated with lipid nanoparticles.This multi-target vaccine induced a robust antiviral immune response and increased neutralizing antibody titers that blocked all four types of DENV infection in vitro without significant antibodydependent enhancement(ADE).In addition,there was more bias for Th1 than Th2 in the exact E-DIII and NS1-specific T cell responses after a single injection.Importantly,intramuscular immunization limited DENV transmission in vivo and eliminated vascular leakage.Our findings highlight that chimeric allogeneic structural and non-structural proteins can be effective targets for DENV vaccine and that they can prevent the further development of congenital DENV syndrome.
基金the“Metropolitan Mosquitoes Project”funded by the Swedish Research Council for Environment,Agricultural Sciences and Spatial Planning(Formas,grant number 2016-00364).
文摘Dengue virus(DENV)is a positive-sense single-stranded RNA virus belonging to the genus Flavivirus within the Flaviviridae family.Four serotypes,DENV 1-4,are distributed globally[1].Hanoi metropolitan city is an endemic hotspot for DENV transmission in Vietnam[2,3].The largest outbreak occurred in 2017,with more than 36000 cases and 7 deaths reported,causing by all four serotypes with the predominance of DENV1,following by DENV2[4,5].During the following dengue season,we collected 390 blood and serum samples from 197 hospitalized patients in a national hospital in Hanoi city,Northern Vietnam to identify the circulating DENV serotypes responsible for the 2018-2019 outbreak.
基金supported by the National Natural Science Foundation of China(Grant No.82130101)the Youth Innovation Promotion Association of CAS(Grant No.2021333).
文摘Dengue viruses(DENV)have spread throughout the world and pose a huge threat to human life.The most widespread serotype is type 2 DENV(DENV 2),which has no specific treatment.NS2B-NS3 protease plays a pivotal role in DENV replication because of its function in cleavage of the viral polyprotein;thus,it is considered a promising target for antiviral discovery.In this study,we developed a high-throughput screening system based on the NS2B-NS3 protease to identify candidates from an FDA-approved drug library.Eltrombopag was screened out of 3273 drugs,and demonstrated inhibition on DENV 2 at the micromolar level in vitro,significantly reducing viral loads in the targeted organs of challenged mice following intraperitoneal injection.Further mechanistic analysis showed that eltrombopag allosterically binds to the DENV 2 NS2B-NS3 protease in a reversible,noncompetitive manner,therefore inhibiting DENV 2 at the post-infection stage.In addition,eltrombopag inhibited the NS2B-NS3 proteases of DENV 4 and Zika virus,suggesting its potential as a broadspectrum antiviral agent.This study repurposed eltrombopag as a promising antiviral agent against DENV,providing an alternative for antiviral development against flaviviruses.
