The family Filoviridae, which includes the genera Marburgvirus and Ebolavirus, contains some of the most pathogenic viruses in humans and non-human primates （NHPs）, causing severe hemorrhagic fevers with high fatali...The family Filoviridae, which includes the genera Marburgvirus and Ebolavirus, contains some of the most pathogenic viruses in humans and non-human primates （NHPs）, causing severe hemorrhagic fevers with high fatality rates. Small animal models against filoviruses using mice, guinea pigs, hamsters, and ferrets have been developed with the goal of screening candidate vaccines and antivirals, before testing in the gold standard NHP models. In this review, we summarize the different animal models used to understand filovirus pathogenesis, and discuss the advantages and disadvantages of each model with respect to filovirus disease research.展开更多
Dear Editor, The 2015-2016 outbreak of Zika virus （ZIKV） fever, first reported in Brazil during early 2015 （Zanluca et al., 2015）, has infected millions of people and is a global public health concern. ZIKV infect...Dear Editor, The 2015-2016 outbreak of Zika virus （ZIKV） fever, first reported in Brazil during early 2015 （Zanluca et al., 2015）, has infected millions of people and is a global public health concern. ZIKV infections are associated with fetal microcephaly, as well as neurological complications in humans. The virus can be shed in the semen and vaginal secretions of humans, leading to sexual transmission, and unexpectedly ZIKV infections cause severe damage to the male reproductive organs in male mice （Govero et al., 2016; Ma et al., 2016）.展开更多
Due to their inability to generate a complete immune response, mice knockout for type I interferon （IFN） receptors （Ifnar-/-） are more susceptible to viral infections, and are thus commonly used for pathogenesis s...Due to their inability to generate a complete immune response, mice knockout for type I interferon （IFN） receptors （Ifnar-/-） are more susceptible to viral infections, and are thus commonly used for pathogenesis studies. This mouse model has been used to study many diseases caused by highly pathogenic viruses from many families, including the Flaviviridae, Filoviridae, Arenaviridae, Bunyaviridae, Henipaviridae, and Togaviridae. In this review, we summarize the findings from these animal studies, and discuss the pros and cons of using this model versus other known methods for studying pathogenesis in animals.展开更多
The Angolan strain of Marburg virus （MARV/Ang） can cause lethal disease in humans with a case fatality rate of up to 90%, but infection of immunocompetent rodents do not result in any observable symptoms. Our previo...The Angolan strain of Marburg virus （MARV/Ang） can cause lethal disease in humans with a case fatality rate of up to 90%, but infection of immunocompetent rodents do not result in any observable symptoms. Our previous work includes the development and characterization of a MARV/Ang variant that can cause lethal disease in mice （MARV/Ang-MA）, with the aim of using this tool to screen for promising prophylactic and therapeutic candidates. An intermediate animal model is needed to confirm any findings from mice studies before testing in the gold-standard non-human primate （NHP） model. In this study, we serially passaged the clinical isolate of MARV/Ang in the livers and spleens of guinea pigs until a variant emerged that causes 100% lethality in guinea pigs （MARV/Ang- GA）. Animals infected with MARV/Ang-GA showed signs of filovirus infection including lymphocytopenia, thrombocytopenia, and high viremia leading to spread to major organs, including the liver, spleen, lungs, and kidneys. The MARV/Ang-GA guinea pigs died between 7-9 days after infection, and the LD50 was calculated to be 1.1x10-1 TCID50 （median tissue culture infective dose）. Mutations in MARV/Ang-GA were identified and compared to sequences of known rodent-adapted MARV/Ang variants, which may benefit future studies characterizing important host adaptation sites in the MARV/Ang viral genome.展开更多
The development of monoclonal antibodies to treat disease caused by filoviruses,particularly Ebola virus,has risen steeply in recent years thanks to several key studies demonstrating their remarkable therapeutic poten...The development of monoclonal antibodies to treat disease caused by filoviruses,particularly Ebola virus,has risen steeply in recent years thanks to several key studies demonstrating their remarkable therapeutic potential.The increased drive to develop new and better monoclonal antibodies has necessarily seen an increase in animal model efficacy testing,which is critical to the pre-clinical development of any novel countermeasure.Primary and secondary efficacy testing against filoviruses typically makes use of one or more rodent models(mice,guinea pigs,and occasionally hamsters)or the more recently described ferret model,although the exact choice of model depends on the specific filovirus being evaluated.Indeed,no single small animal model exists for all filoviruses,and the use of any given model must consider the nature of that model as well as the nature of the therapeutic and the experimental objectives.Confirmatory evaluation,on the other hand,is performed in nonhuman primates(rhesus or cynomolgus macaques)regardless of the filovirus.In light of the number of different animal models that are currently used in monoclonal antibody efficacy testing,we sought to better understand how these efficacy tests are being performed by numerous different laboratories around the world.To this end,we review the animal models that are being used for antibody efficacy testing against filoviruses,and we highlight the challenge doses and routes of infection that are used.We also describe the various antibody treatment regimens,including antibody dose,route,and schedule of administration,that are used in these model systems.We do not identify any single best model or treatment regimen,and we do not advocate for field-wide protocol standardization.Instead,we hope to provide a comprehensive resource that will facilitate and enhance the continued pre-clinical development of novel monoclonal antibody therapeutics.展开更多
The onsite next generation sequencing(NGS)of Ebola virus(EBOV)genomes during the 2013–2016 Ebola epidemic in Western Africa provides an opportunity to trace the origin,transmission,and evolution of this virus.Herein,...The onsite next generation sequencing(NGS)of Ebola virus(EBOV)genomes during the 2013–2016 Ebola epidemic in Western Africa provides an opportunity to trace the origin,transmission,and evolution of this virus.Herein,we have diagnosed a cohort of EBOV patients in Sierra Leone in 2015,during the late phase of the outbreak.The surviving EBOV patients had a recovery process characterized by decreasing viremia,fever,and biochemical parameters.EBOV genomes sequenced through the longitudinal blood samples of these patients showed dynamic intra-host substitutions of the virus during acute infection,including the previously described short stretches of 13 serial TNC mutations.Remarkably,within individual patients,samples collected during the early phase of infection possessed Ts at these nucleotide sites,whereas they were replaced by Cs in samples collected in the later phase,suggesting that these short stretches of TNC mutations could emerge independently.In addition,up to a total of 35 nucleotide sites spanning the EBOV genome were mutated coincidently.Our study showed the dynamic intra-host adaptation of EBOV during patient recovery and gave more insight into the complex EBOV-host interactions.展开更多
The 2014-15 Ebola virus reported during March 2014 Guinea. has shown itself to （EBOV） outbreak, originally n the Western African nation of be resistant to traditional con- tainment methods, with over 28,000 infecti...The 2014-15 Ebola virus reported during March 2014 Guinea. has shown itself to （EBOV） outbreak, originally n the Western African nation of be resistant to traditional con- tainment methods, with over 28,000 infections and 11,000 deaths over 18 months. Recently, news that a Scottish nurse had relapsed to EBOV disease with neurological symptoms at 10 months after recovery have astonished experts. The prolonged nature of the outbreak has led to questions whether EBOV can become endemic in the human popula- tion, an undesirable outcome due to the large amount of resources required to keep this virus under control. In this commentary, we discuss aspects EBOV disease with those caused by pathogens considered endemic in humans, as well as factors which may contribute to sustained EBOV transmission in humans.展开更多
基金supported by the Public Health Agency of Canada(PHAC)partially supported by the NIH and CIHR grants to X.G.Qiu(U19 AI109762-1 and CIHR-IER-143487,respectively)+1 种基金the National Natural Science Foundation of China International Cooperation and Exchange Program(8161101193)National Science and Technology Major Project(2016ZX10004222)to G.Wong
文摘The family Filoviridae, which includes the genera Marburgvirus and Ebolavirus, contains some of the most pathogenic viruses in humans and non-human primates （NHPs）, causing severe hemorrhagic fevers with high fatality rates. Small animal models against filoviruses using mice, guinea pigs, hamsters, and ferrets have been developed with the goal of screening candidate vaccines and antivirals, before testing in the gold standard NHP models. In this review, we summarize the different animal models used to understand filovirus pathogenesis, and discuss the advantages and disadvantages of each model with respect to filovirus disease research.
文摘Dear Editor, The 2015-2016 outbreak of Zika virus （ZIKV） fever, first reported in Brazil during early 2015 （Zanluca et al., 2015）, has infected millions of people and is a global public health concern. ZIKV infections are associated with fetal microcephaly, as well as neurological complications in humans. The virus can be shed in the semen and vaginal secretions of humans, leading to sexual transmission, and unexpectedly ZIKV infections cause severe damage to the male reproductive organs in male mice （Govero et al., 2016; Ma et al., 2016）.
基金supported by the National Natural Science Foundation of China International Cooperation and Exchange Program(8161101193)the National Science and Technology Major Project(2016ZX10004222)to G.Wong
文摘Due to their inability to generate a complete immune response, mice knockout for type I interferon （IFN） receptors （Ifnar-/-） are more susceptible to viral infections, and are thus commonly used for pathogenesis studies. This mouse model has been used to study many diseases caused by highly pathogenic viruses from many families, including the Flaviviridae, Filoviridae, Arenaviridae, Bunyaviridae, Henipaviridae, and Togaviridae. In this review, we summarize the findings from these animal studies, and discuss the pros and cons of using this model versus other known methods for studying pathogenesis in animals.
基金supported by the Public Health Agency of Canada(PHAC)partially supported by the NIH and CIHR grants to X.G.Qiu(U19 AI109762-1 and CIHR-IER-143487,respectively)+1 种基金grants from the National Natural Science Foundation of China International Cooperation and Exchange Program(8161101193)National Science and Technology Major Project(2016ZX10004222)to G.Wong
文摘The Angolan strain of Marburg virus （MARV/Ang） can cause lethal disease in humans with a case fatality rate of up to 90%, but infection of immunocompetent rodents do not result in any observable symptoms. Our previous work includes the development and characterization of a MARV/Ang variant that can cause lethal disease in mice （MARV/Ang-MA）, with the aim of using this tool to screen for promising prophylactic and therapeutic candidates. An intermediate animal model is needed to confirm any findings from mice studies before testing in the gold-standard non-human primate （NHP） model. In this study, we serially passaged the clinical isolate of MARV/Ang in the livers and spleens of guinea pigs until a variant emerged that causes 100% lethality in guinea pigs （MARV/Ang- GA）. Animals infected with MARV/Ang-GA showed signs of filovirus infection including lymphocytopenia, thrombocytopenia, and high viremia leading to spread to major organs, including the liver, spleen, lungs, and kidneys. The MARV/Ang-GA guinea pigs died between 7-9 days after infection, and the LD50 was calculated to be 1.1x10-1 TCID50 （median tissue culture infective dose）. Mutations in MARV/Ang-GA were identified and compared to sequences of known rodent-adapted MARV/Ang variants, which may benefit future studies characterizing important host adaptation sites in the MARV/Ang viral genome.
基金supported by the Public Health Agency of Canada。
文摘The development of monoclonal antibodies to treat disease caused by filoviruses,particularly Ebola virus,has risen steeply in recent years thanks to several key studies demonstrating their remarkable therapeutic potential.The increased drive to develop new and better monoclonal antibodies has necessarily seen an increase in animal model efficacy testing,which is critical to the pre-clinical development of any novel countermeasure.Primary and secondary efficacy testing against filoviruses typically makes use of one or more rodent models(mice,guinea pigs,and occasionally hamsters)or the more recently described ferret model,although the exact choice of model depends on the specific filovirus being evaluated.Indeed,no single small animal model exists for all filoviruses,and the use of any given model must consider the nature of that model as well as the nature of the therapeutic and the experimental objectives.Confirmatory evaluation,on the other hand,is performed in nonhuman primates(rhesus or cynomolgus macaques)regardless of the filovirus.In light of the number of different animal models that are currently used in monoclonal antibody efficacy testing,we sought to better understand how these efficacy tests are being performed by numerous different laboratories around the world.To this end,we review the animal models that are being used for antibody efficacy testing against filoviruses,and we highlight the challenge doses and routes of infection that are used.We also describe the various antibody treatment regimens,including antibody dose,route,and schedule of administration,that are used in these model systems.We do not identify any single best model or treatment regimen,and we do not advocate for field-wide protocol standardization.Instead,we hope to provide a comprehensive resource that will facilitate and enhance the continued pre-clinical development of novel monoclonal antibody therapeutics.
基金supported by the Megaproject for Infectious Disease Research of China(2016ZX10004222-003)the research of Ebola pathogen from the National Natural Science Foundation of China(NSFC,81590763)+4 种基金National Key Research and Development Program of China(2016YFC1200200 to Y.Shu)the Distinguished Young Scientist Program of the NSFC(81525017 to Y.Shu)the Excellent Young Scientist Program of the NSFC(81822040 to W.J.Liu)the Taishan Scholar Project of Shandong Province(ts201511056 to W.Shi)G.F.Gao is a primary principal investigator of the NSFC Innovative Research Group(81621091).
文摘The onsite next generation sequencing(NGS)of Ebola virus(EBOV)genomes during the 2013–2016 Ebola epidemic in Western Africa provides an opportunity to trace the origin,transmission,and evolution of this virus.Herein,we have diagnosed a cohort of EBOV patients in Sierra Leone in 2015,during the late phase of the outbreak.The surviving EBOV patients had a recovery process characterized by decreasing viremia,fever,and biochemical parameters.EBOV genomes sequenced through the longitudinal blood samples of these patients showed dynamic intra-host substitutions of the virus during acute infection,including the previously described short stretches of 13 serial TNC mutations.Remarkably,within individual patients,samples collected during the early phase of infection possessed Ts at these nucleotide sites,whereas they were replaced by Cs in samples collected in the later phase,suggesting that these short stretches of TNC mutations could emerge independently.In addition,up to a total of 35 nucleotide sites spanning the EBOV genome were mutated coincidently.Our study showed the dynamic intra-host adaptation of EBOV during patient recovery and gave more insight into the complex EBOV-host interactions.
文摘The 2014-15 Ebola virus reported during March 2014 Guinea. has shown itself to （EBOV） outbreak, originally n the Western African nation of be resistant to traditional con- tainment methods, with over 28,000 infections and 11,000 deaths over 18 months. Recently, news that a Scottish nurse had relapsed to EBOV disease with neurological symptoms at 10 months after recovery have astonished experts. The prolonged nature of the outbreak has led to questions whether EBOV can become endemic in the human popula- tion, an undesirable outcome due to the large amount of resources required to keep this virus under control. In this commentary, we discuss aspects EBOV disease with those caused by pathogens considered endemic in humans, as well as factors which may contribute to sustained EBOV transmission in humans.
