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Heinz Feldmann - One of the best experts on this subject based on the ideXlab platform.
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Stat1-Deficient Mice Are Not an Appropriate Model for Efficacy Testing of Recombinant
2016Co-Authors: Vesicular Stomatitis, Lisa Kercher, Joshua Marceau, Anthony York, Julie Callsion, Donald J. Gardner, Andrea Marzi, Thomas W Geisbert, Heinz FeldmannAbstract:Stat1−/ − mice lack a response to interferon α, β, and γ, allowing for replication of nonadapted wild-type (wt) Ebolavirus and Marburgvirus. We sought to establish a mouse model for efficacy testing of live attenuated re-combinant vesicular stomatitis virus (rVSV)–based filovirus vaccine vectors using wt Ebolavirus and Marburg-virus challenge strains. While infection of immunocompetent mice with different rVSV-based filovirus vectors did not cause disease, infection of Stat1−/ − mice with the same vectors resulted in systemic infection and lethal outcome for the majority of tested rVSVs. Despite differences in viral loads, organ tropism was remarkably similar between rVSV filovirus vaccine vectors and rVSVwt, with the exception of the brain. In conclusion, Stat1−/−mice are not an appropriate immunocompromised mouse model for efficacy testing of live attenuated, replication-competent rVSV vaccine vectors. Keywords. Vesicular stomatitis virus; Ebolavirus; Marburgvirus; vaccine; Stat1-deficient mice. Ebolavirus and Marburgvirus, members of the family Filoviridae, cause viral hemorrhagic fever in nonhuman primates and humans [1]. While outbreaks of filovirus hemorrhagic fever have occurred mainly in their en-demic area in Central Africa, currently, the biggest doc-umented Ebola virus (EBOV) outbreak is still ongoing in West African countries such as Guinea, Liberia and Sierra Leone. Not only has the virus spread from there into neighboring Mali, it was also introduced to Sene
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Stat1-Deficient Mice Are Not an Appropriate Model for Efficacy Testing of Recombinant Vesicular Stomatitis Virus–Based Filovirus Vaccines
The Journal of Infectious Diseases, 2015Co-Authors: Andrea Marzi, Lisa Kercher, Joshua Marceau, Anthony York, Julie Callsion, Donald J. Gardner, Thomas W Geisbert, Heinz FeldmannAbstract:: Stat1(-/-) mice lack a response to interferon α, β, and γ, allowing for replication of nonadapted wild-type (wt) Ebolavirus and Marburgvirus. We sought to establish a mouse model for efficacy testing of live attenuated recombinant vesicular stomatitis virus (rVSV)-based filovirus vaccine vectors using wt Ebolavirus and Marburgvirus challenge strains. While infection of immunocompetent mice with different rVSV-based filovirus vectors did not cause disease, infection of Stat1(-/-) mice with the same vectors resulted in systemic infection and lethal outcome for the majority of tested rVSVs. Despite differences in viral loads, organ tropism was remarkably similar between rVSV filovirus vaccine vectors and rVSVwt, with the exception of the brain. In conclusion, Stat1(-/-) mice are not an appropriate immunocompromised mouse model for efficacy testing of live attenuated, replication-competent rVSV vaccine vectors.
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Stat1-Deficient Mice Are Not an Appropriate Model for Efficacy Testing of Recombinant Vesicular Stomatitis Virus-Based Filovirus Vaccines.
The Journal of infectious diseases, 2015Co-Authors: Andrea Marzi, Lisa Kercher, Joshua Marceau, Anthony York, Julie Callsion, Donald J. Gardner, Thomas W Geisbert, Heinz FeldmannAbstract:Stat1(-/-) mice lack a response to interferon α, β, and γ, allowing for replication of nonadapted wild-type (wt) Ebolavirus and Marburgvirus. We sought to establish a mouse model for efficacy testing of live attenuated recombinant vesicular stomatitis virus (rVSV)-based filovirus vaccine vectors using wt Ebolavirus and Marburgvirus challenge strains. While infection of immunocompetent mice with different rVSV-based filovirus vectors did not cause disease, infection of Stat1(-/-) mice with the same vectors resulted in systemic infection and lethal outcome for the majority of tested rVSVs. Despite differences in viral loads, organ tropism was remarkably similar between rVSV filovirus vaccine vectors and rVSVwt, with the exception of the brain. In conclusion, Stat1(-/-) mice are not an appropriate immunocompromised mouse model for efficacy testing of live attenuated, replication-competent rVSV vaccine vectors.
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Ebola — A Growing Threat?
The New England Journal of Medicine, 2014Co-Authors: Heinz FeldmannAbstract:The latest outbreak of ebolavirus in West Africa has demonstrated our public health systems' limited ability to respond to rare, highly virulent communicable diseases. Despite years of research on ebolavirus and Marburgvirus, we have no vaccines or treatments available.
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Novel neutralizing monoclonal antibodies protect rodents against lethal filovirus challenges
Trials in Vaccinology, 2014Co-Authors: Caleb D. Marceau, Andrea Marzi, Heinz Feldmann, Surendra Negi, Humberto Hernandez, Julie Callison, Viktoriya Borisevich, Werner Braun, Jody D. Berry, Barry RockxAbstract:Filoviruses are the causative agents of lethal hemorrhagic fever in human and non-human primates (NHP). The family of Filoviridae is composed of three genera, Ebolavirus, Marburgvirus and Cuevavirus. There are currently no approved vaccines or antiviral therapeutics for the treatment of filovirus infections in humans. Passive transfer of neutralizing antibodies targeting the Ebola virus (EBOV) glycoprotein (GP) has proven effective in protecting mice, guinea pigs and NHP from lethal challenges with EBOV. In this study, we generated two neutralizing monoclonal antibodies (MAbs), termed S9 and M4 that recognize the GP of EBOV or multiple strains of Marburg virus (MARV), respectively. We characterized the putative binding site of S9 as a linear epitope on the glycan cap of the GP1 subunit of the EBOV-GP. The M4 antibody recognizes an unknown conformational epitope on MARV-GP. Additionally, we demonstrated the post-exposure protection potential of these antibodies in both the mouse and guinea pig models of filovirus infection. These data indicate that MAbs S9 and M4 would be good candidates for inclusion in an antibody cocktail for the treatment of filovirus infections.
Jonathan S Towner - One of the best experts on this subject based on the ideXlab platform.
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Novel activities by ebolavirus and Marburgvirus interferon antagonists revealed using a standardized in vitro reporter system.
Virology, 2016Co-Authors: Jonathan C. Guito, César G. Albariño, Ayan K. Chakrabarti, Jonathan S TownerAbstract:Filoviruses are highly lethal in humans and nonhuman primates, likely due to potent antagonism of host interferon (IFN) responses early in infection. Filoviral protein VP35 is implicated as the major IFN induction antagonist, while Ebola virus (EBOV) VP24 or Marburg virus (MARV) VP40 are known to block downstream IFN signaling. Despite progress elucidating EBOV and MARV antagonist function, those for most other filoviruses, including Reston (RESTV), Sudan (SUDV), Tai Forest (TAFV), Bundibugyo (BDBV) and Ravn (RAVV) viruses, remain largely neglected. Thus, using standardized vectors and reporter assays, we characterized activities by each IFN antagonist from all known ebolavirus and Marburgvirus species side-by-side. We uncover noncanonical suppression of IFN induction by ebolavirus VP24, differing potencies by MARV and RAVV proteins, and intriguingly, weaker antagonism by VP24 of RESTV. These underlying molecular explanations for differential virulence in humans could guide future investigations of more-neglected filoviruses as well as treatment and vaccine studies.
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No evidence for the involvement of the argasid tick Ornithodoros faini in the enzootic maintenance of Marburgvirus within Egyptian rousette bats Rousettus aegyptiacus
Parasites & Vectors, 2016Co-Authors: Amy J. Schuh, Tara K. Sealy, Dmitry A. Apanaskevich, Brian R Amman, Stuart T. Nichol, Jonathan S TownerAbstract:Background The cave-dwelling Egyptian rousette bat (ERB; Rousettus aegyptiacus ) was recently identified as a natural reservoir host of Marburgviruses. However, the mechanisms of transmission for the enzootic maintenance of Marburgviruses within ERBs are unclear. Previous ecological investigations of large ERB colonies inhabiting Python Cave and Kitaka Mine, Uganda revealed that argasid ticks ( Ornithodoros faini ) are hematophagous ectoparasites of ERBs. Yet, their potential role as transmission vectors for Marburgvirus has not been sufficiently assessed. Findings In the present study, 3,125 O. faini were collected during April 2013 from the rock crevices of Python Cave, Uganda. None of the ticks tested positive for Marburgvirus-specific RNA by Q-RT-PCR. The probability of failure to detect Marburgvirus at a conservative prevalence of 0.1 % was 0.05. Conclusions The absence of Marburgvirus RNA in O. faini suggests they do not play a significant role in the transmission and enzootic maintenance of Marburgvirus within their natural reservoir host.
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No evidence for the involvement of the argasid tick Ornithodoros faini in the enzootic maintenance of Marburgvirus within Egyptian rousette bats Rousettus aegyptiacus
Parasites & Vectors, 2016Co-Authors: Amy J. Schuh, Tara K. Sealy, Dmitry A. Apanaskevich, Brian R Amman, Stuart T. Nichol, Jonathan S TownerAbstract:Background The cave-dwelling Egyptian rousette bat (ERB; Rousettus aegyptiacus) was recently identified as a natural reservoir host of Marburgviruses. However, the mechanisms of transmission for the enzootic maintenance of Marburgviruses within ERBs are unclear. Previous ecological investigations of large ERB colonies inhabiting Python Cave and Kitaka Mine, Uganda revealed that argasid ticks (Ornithodoros faini) are hematophagous ectoparasites of ERBs. Yet, their potential role as transmission vectors for Marburgvirus has not been sufficiently assessed.
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Geographic locations of Ebola HF outbreaks and phylogenetic relationships of representative filoviruses.
2013Co-Authors: Jonathan S Towner, Tara K. Sealy, Marina L. Khristova, Robert Downing, Ian W. Lipkin, César G. Albariño, Sean Conlan, Serena A. Reeder, Phenix-lan Quan, Jordan W. TapperoAbstract:(A) Map of Africa showing the sites of all known ebolavirus outbreaks denoted by colored circles for Zaire ebolavirus (yellow), Sudan ebolavirus (green), and Côte d'Ivoire ebolavirus (red). The expanded map of Uganda shows the location of the communities of Bundibugyo and Kikyo (black circles) in western Uganda, the site of the recent outbreak of Bundibugyo ebolavirus. Also shown on the Uganda map are the cities of Kampala (capital), Entebbe (international airport) and Gulu (the site of an outbreak of Sudan ebolavirus in 2000, the largest known Ebola HF outbreak on record). (B) Phylogenetic tree comparing full-length genomes of ebolavirus and Marburgvirus by Bayesian analysis. Posterior probabilities greater than 0.5 and maximum likelihood bootstrap values greater than 50 are indicated at the nodes.
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Molecular evolution of viruses of the family Filoviridae based on 97 whole genome sequences
Journal of Virology, 2012Co-Authors: Serena A. Carroll, Tara K. Sealy, Jonathan S Towner, Pierre E. Rollin, Marina L. Khristova, Laura K. Mcmullan, Felicity J. Burt, Robert Swanepoel, Stuart T. NicholAbstract:ABSTRACT Viruses in the Ebolavirus and Marburgvirus genera (family Filoviridae) have been associated with large outbreaks of hemorrhagic fever in human and nonhuman primates. The first documented cases occurred in primates over 45 years ago, but the amount of virus genetic diversity detected within bat populations, which have recently been identified as potential reservoir hosts, suggests that the filoviruses are much older. Here, detailed Bayesian coalescent phylogenetic analyses are performed on 97 whole-genome sequences, 55 of which are newly reported, to comprehensively examine molecular evolutionary rates and estimate dates of common ancestry for viruses within the family Filoviridae. Molecular evolutionary rates for viruses belonging to different species range from 0.46 × 10 −4 nucleotide substitutions/site/year for Sudan ebolavirus to 8.21 × 10 −4 nucleotide substitutions/site/year for Reston ebolavirus. Most recent common ancestry can be traced back only within the last 50 years for Reston ebolavirus and Zaire ebolavirus species and suggests that viruses within these species may have undergone recent genetic bottlenecks. Viruses within Marburg Marburgvirus and Sudan ebolavirus species can be traced back further and share most recent common ancestors approximately 700 and 850 years before the present, respectively. Examination of the whole family suggests that members of the Filoviridae, including the recently described Lloviu virus, shared a most recent common ancestor approximately 10,000 years ago. These data will be valuable for understanding the evolution of filoviruses in the context of natural history as new reservoir hosts are identified and, further, for determining mechanisms of emergence, pathogenicity, and the ongoing threat to public health.
Tara K. Sealy - One of the best experts on this subject based on the ideXlab platform.
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No evidence for the involvement of the argasid tick Ornithodoros faini in the enzootic maintenance of Marburgvirus within Egyptian rousette bats Rousettus aegyptiacus
Parasites & Vectors, 2016Co-Authors: Amy J. Schuh, Tara K. Sealy, Dmitry A. Apanaskevich, Brian R Amman, Stuart T. Nichol, Jonathan S TownerAbstract:Background The cave-dwelling Egyptian rousette bat (ERB; Rousettus aegyptiacus ) was recently identified as a natural reservoir host of Marburgviruses. However, the mechanisms of transmission for the enzootic maintenance of Marburgviruses within ERBs are unclear. Previous ecological investigations of large ERB colonies inhabiting Python Cave and Kitaka Mine, Uganda revealed that argasid ticks ( Ornithodoros faini ) are hematophagous ectoparasites of ERBs. Yet, their potential role as transmission vectors for Marburgvirus has not been sufficiently assessed. Findings In the present study, 3,125 O. faini were collected during April 2013 from the rock crevices of Python Cave, Uganda. None of the ticks tested positive for Marburgvirus-specific RNA by Q-RT-PCR. The probability of failure to detect Marburgvirus at a conservative prevalence of 0.1 % was 0.05. Conclusions The absence of Marburgvirus RNA in O. faini suggests they do not play a significant role in the transmission and enzootic maintenance of Marburgvirus within their natural reservoir host.
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No evidence for the involvement of the argasid tick Ornithodoros faini in the enzootic maintenance of Marburgvirus within Egyptian rousette bats Rousettus aegyptiacus
Parasites & Vectors, 2016Co-Authors: Amy J. Schuh, Tara K. Sealy, Dmitry A. Apanaskevich, Brian R Amman, Stuart T. Nichol, Jonathan S TownerAbstract:Background The cave-dwelling Egyptian rousette bat (ERB; Rousettus aegyptiacus) was recently identified as a natural reservoir host of Marburgviruses. However, the mechanisms of transmission for the enzootic maintenance of Marburgviruses within ERBs are unclear. Previous ecological investigations of large ERB colonies inhabiting Python Cave and Kitaka Mine, Uganda revealed that argasid ticks (Ornithodoros faini) are hematophagous ectoparasites of ERBs. Yet, their potential role as transmission vectors for Marburgvirus has not been sufficiently assessed.
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experimental inoculation of egyptian rousette bats rousettus aegyptiacus with viruses of the ebolavirus and Marburgvirus genera
Viruses, 2015Co-Authors: Mega E Jones, Amy J. Schuh, Tara K. Sealy, Sherif R. Zaki, Ia R Amma, Stua T Nichol, Jonatha S TowneAbstract:The Egyptian rousette bat (Rousettus aegyptiacus) is a natural reservoir for Marburgviruses and a consistent source of virus spillover to humans. Cumulative evidence suggests various bat species may also transmit ebolaviruses. We investigated the susceptibility of Egyptian rousettes to each of the five known ebolaviruses (Sudan, Ebola, Bundibugyo, Tai Forest, and Reston), and compared findings with Marburg virus. In a pilot study, groups of four juvenile bats were inoculated with one of the ebolaviruses or Marburg virus. In ebolavirus groups, viral RNA tissue distribution was limited, and no bat became viremic. Sudan viral RNA was slightly more widespread, spurring a second, 15-day Sudan virus serial euthanasia study. Low levels of Sudan viral RNA disseminated to multiple tissues at early time points, but there was no viremia or shedding. In contrast, Marburg virus RNA was widely disseminated, with viremia, oral and rectal shedding, and antigen in spleen and liver. This is the first experimental infection study comparing tissue tropism, viral shedding, and clinical and pathologic effects of six different filoviruses in the Egyptian rousette, a known Marburgvirus reservoir. Our results suggest Egyptian rousettes are unlikely sources for ebolaviruses in nature, and support a possible single filovirus—single reservoir host relationship.
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oral shedding of marburg virus in experimentally infected egyptian fruit bats rousettus aegyptiacus
Journal of Wildlife Diseases, 2015Co-Authors: Brian R Amman, Amy J. Schuh, Tara K. Sealy, Megan E B Jones, Luke S Uebelhoer, Brian H Bird, Joann D Colemanmccray, Brock E MartinAbstract:Abstract Marburg virus (Marburg Marburgvirus; MARV) causes sporadic outbreaks of Marburg hemorrhagic fever (MHF) in Africa. The Egyptian fruit bat (Rousettus aegyptiacus) has been identified as a natural reservoir based most-recently on the repeated isolation of MARV directly from bats caught at two locations in southwestern Uganda where miners and tourists separately contracted MHF from 2007–08. Despite learning much about the ecology of MARV through extensive field investigations, there remained unanswered questions such as determining the primary routes of virus shedding and the severity of disease, if any, caused by MARV in infected bats. To answer these questions and others, we experimentally infected captive-bred R. aegyptiacus with MARV under high (biosafety level 4) containment. These experiments have shown infection profiles consistent with R. aegyptiacus being a bona fide natural reservoir host for MARV and demonstrated routes of viral shedding capable of infecting humans and other animals.
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Marburgvirus resurgence in kitaka mine bat population after extermination attempts uganda
Emerging Infectious Diseases, 2014Co-Authors: Brian R Amman, Amy J. Schuh, Tara K. Sealy, Trevor Shoemaker, Luke Nyakarahuka, Anita K Mcelroy, Kimberly A Dodd, Stephen Balinandi, Patrick Atimnedi, Winyi KaboyoAbstract:To the Editor: Marburg virus (MARV) and Ravn virus (RAVV), collectively called Marburgviruses, cause Marburg hemorrhagic fever (MHF) in humans. In July 2007, 4 cases of MHF (1 fatal) occurred in miners at Kitaka Mine in southern Uganda. Later, MHF occurred in 2 tourists who visited Python Cave, ≈50 km from Kitaka Mine. One of the tourists was from the United States (December 2007) and 1 was from the Netherlands (July 2008); 1 case was fatal (1,2,3). The cave and the mine each contained 40,000–100,000 Rousettus aegyptiacus bats (Egyptian fruit bats). Longitudinal investigations of the outbreaks at both locations were initiated by the Viral Special Pathogens Branch of the Centers for Disease Control and Prevention (CDC, Atlanta, GA, USA, and Entebbe, Uganda) in collaboration with the Uganda Wildlife Authority (UWA) and the Uganda Virus Research Institute (UVRI). During these studies, genetically diverse MARVs and RAVVs were isolated directly from bat tissues, and infection levels of the 2 viruses were found to increase in juvenile bats on a predictable bi-annual basis (4,5). However, investigations at Kitaka Mine were stopped when the miners exterminated the bat colony by restricting egress from the cave with papyrus reed barriers and then entangling the bats in fishing nets draped over the exits. The trapping continued for weeks, and the entrances were then sealed with sticks and plastic. These depopulation efforts were documented by researchers from UVRI, the CDC, the National Institute of Communicable Diseases (Sandringham, South Africa), and UWA during site visits to Kitaka Mine (Technical Appendix Figure). In August 2008, thousands of dead bats were found piled in the forest, and by November 2008, there was no evidence of bats living in the mine; whether 100% extermination was achieved is unknown. CDC, UVRI, and UWA recommended against extermination, believing that any results would be temporary and that such efforts could exacerbate the problem if bat exclusion methods were not complete and permanent (6,7). In October 2012, the most recent known Marburgvirus outbreak was detected in Ibanda, a town in southwest Uganda. Ibanda is ≈20 km from the Kitaka Mine and is the urban center that serves smaller communities in the Kitaka area. This MHF outbreak was the largest in Ugandan history: 15 laboratory-confirmed cases occurred (8). In November 2012, an ecologic investigation of the greater Ibanda/Kitaka area was initiated. The investigation included interviews with local authorities to locate all known R. aegyptiacus colonies in the area. Although minor colonies of small insectivorous bats were found, the only identifiable colony of R. aegyptiacus bats was found inside the re-opened Kitaka Mine, albeit at much reduced size, perhaps 1%–5% of that found before depopulation efforts. To determine whether the R. aegyptiacus bats that had repopulated Kitaka Mine were actively infected with Marburgviruses, we tested 400 bats by using previously described methods (4,5). Viral RNA was extracted from ≈100 mg of liver and spleen tissue by using the MagMAX Total Nucleic Acid Isolation Kit (Applied Biosystems, Foster City, CA, USA) according to the manufacturer’s recommended protocol. The Fisher exact test was conducted by using IBM SPSS Statistics, version 19.0 (IBM Corp., Armonk, NY, USA). Of the 400 R. aegyptiacus bats collected, 53 (13.3%) were positive for Marburgvirus RNA by quantitative reverse transcription PCR (32/233 [13.7%] adults and 21/167 [12.6%] juveniles; Technical Appendix Table); Marburgvirus was isolated from tissue samples from 9 of the 400 bats. The overall level of active infection was significantly higher than that found in Kitaka Mine during 2007–2008 (5.1%) (5) (Fisher exact test, p 0.5 for both), and overall, the presence of virus-specific IgG among the bats was 16.5%, a finding consistent with that in previous studies (4,5). Figure Phylogeny of concatenated Marburgvirus nucleoprotein (NP) and viral protein 35 (VP35) gene fragments as determined by using the maximum-likelihood method. Sequences from the NP (289–372 nt) and VP35 (203–213 nt) genes were amplified and ... Phylogenetic analysis of viral RNA genome fragment sequences in this study showed high Marburgvirus genetic diversity, including the presence of RAVVs and MARVs. Sequences for isolates from 3 bats were nearly identical to those of the MARV isolates obtained from patients in the 2012 Ibanda outbreak (8), suggesting that bats from Kitaka Mine were a likely source of the virus. Technical Appendix: Photographs taken during August 2008–September 2009 of bat extermination efforts at Kitaka Mine, and table showing demographic characteristics of bats captured during a Marburg hemorrhagic fever outbreak investigation at the mine in November 2012, Uganda. Click here to view.(124K, pdf)
Thomas W Geisbert - One of the best experts on this subject based on the ideXlab platform.
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Stat1-Deficient Mice Are Not an Appropriate Model for Efficacy Testing of Recombinant
2016Co-Authors: Vesicular Stomatitis, Lisa Kercher, Joshua Marceau, Anthony York, Julie Callsion, Donald J. Gardner, Andrea Marzi, Thomas W Geisbert, Heinz FeldmannAbstract:Stat1−/ − mice lack a response to interferon α, β, and γ, allowing for replication of nonadapted wild-type (wt) Ebolavirus and Marburgvirus. We sought to establish a mouse model for efficacy testing of live attenuated re-combinant vesicular stomatitis virus (rVSV)–based filovirus vaccine vectors using wt Ebolavirus and Marburg-virus challenge strains. While infection of immunocompetent mice with different rVSV-based filovirus vectors did not cause disease, infection of Stat1−/ − mice with the same vectors resulted in systemic infection and lethal outcome for the majority of tested rVSVs. Despite differences in viral loads, organ tropism was remarkably similar between rVSV filovirus vaccine vectors and rVSVwt, with the exception of the brain. In conclusion, Stat1−/−mice are not an appropriate immunocompromised mouse model for efficacy testing of live attenuated, replication-competent rVSV vaccine vectors. Keywords. Vesicular stomatitis virus; Ebolavirus; Marburgvirus; vaccine; Stat1-deficient mice. Ebolavirus and Marburgvirus, members of the family Filoviridae, cause viral hemorrhagic fever in nonhuman primates and humans [1]. While outbreaks of filovirus hemorrhagic fever have occurred mainly in their en-demic area in Central Africa, currently, the biggest doc-umented Ebola virus (EBOV) outbreak is still ongoing in West African countries such as Guinea, Liberia and Sierra Leone. Not only has the virus spread from there into neighboring Mali, it was also introduced to Sene
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Stat1-Deficient Mice Are Not an Appropriate Model for Efficacy Testing of Recombinant Vesicular Stomatitis Virus-Based Filovirus Vaccines.
The Journal of infectious diseases, 2015Co-Authors: Andrea Marzi, Lisa Kercher, Joshua Marceau, Anthony York, Julie Callsion, Donald J. Gardner, Thomas W Geisbert, Heinz FeldmannAbstract:Stat1(-/-) mice lack a response to interferon α, β, and γ, allowing for replication of nonadapted wild-type (wt) Ebolavirus and Marburgvirus. We sought to establish a mouse model for efficacy testing of live attenuated recombinant vesicular stomatitis virus (rVSV)-based filovirus vaccine vectors using wt Ebolavirus and Marburgvirus challenge strains. While infection of immunocompetent mice with different rVSV-based filovirus vectors did not cause disease, infection of Stat1(-/-) mice with the same vectors resulted in systemic infection and lethal outcome for the majority of tested rVSVs. Despite differences in viral loads, organ tropism was remarkably similar between rVSV filovirus vaccine vectors and rVSVwt, with the exception of the brain. In conclusion, Stat1(-/-) mice are not an appropriate immunocompromised mouse model for efficacy testing of live attenuated, replication-competent rVSV vaccine vectors.
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Stat1-Deficient Mice Are Not an Appropriate Model for Efficacy Testing of Recombinant Vesicular Stomatitis Virus–Based Filovirus Vaccines
The Journal of Infectious Diseases, 2015Co-Authors: Andrea Marzi, Lisa Kercher, Joshua Marceau, Anthony York, Julie Callsion, Donald J. Gardner, Thomas W Geisbert, Heinz FeldmannAbstract:: Stat1(-/-) mice lack a response to interferon α, β, and γ, allowing for replication of nonadapted wild-type (wt) Ebolavirus and Marburgvirus. We sought to establish a mouse model for efficacy testing of live attenuated recombinant vesicular stomatitis virus (rVSV)-based filovirus vaccine vectors using wt Ebolavirus and Marburgvirus challenge strains. While infection of immunocompetent mice with different rVSV-based filovirus vectors did not cause disease, infection of Stat1(-/-) mice with the same vectors resulted in systemic infection and lethal outcome for the majority of tested rVSVs. Despite differences in viral loads, organ tropism was remarkably similar between rVSV filovirus vaccine vectors and rVSVwt, with the exception of the brain. In conclusion, Stat1(-/-) mice are not an appropriate immunocompromised mouse model for efficacy testing of live attenuated, replication-competent rVSV vaccine vectors.
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A Single-Vector, Single-Injection Trivalent Filovirus Vaccine: Proof of Concept Study in Outbred Guinea Pigs
The Journal of Infectious Diseases, 2015Co-Authors: Chad E. Mire, Thomas W Geisbert, Joan B. Geisbert, Krystle N. Agans, Krista M. Versteeg, Natalia Mamaeva, John H. ConnorAbstract:The filoviruses, Marburg Marburgvirus (MARV), Zaire ebolavirus (ZEBOV), and Sudan ebolavirus (SEBOV), cause severe and often fatal hemorrhagic fever in humans and nonhuman primates (NHPs). Monovalent recombinant vesicular stomatitis virus (rVSV)-based vaccine vectors, which encode a filovirus glycoprotein (GP) in place of the VSV glycoprotein, have shown 100% efficacy against homologous filovirus challenge in rodent and NHP studies. Here, we examined the utility of a single-vector, single-injection trivalent rVSV vector expressing MARV, ZEBOV, and SEBOV GPs to protect against MARV-, ZEBOV-, and SEBOV-induced disease in outbred Hartley guinea pigs where we observed protection from effects of all 3 filoviruses.
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Proposal for a revised taxonomy of the family Filoviridae: Classification, names of taxa and viruses, and virus abbreviations
Archives of Virology, 2010Co-Authors: Jens H Kuhn, Ana I. Negredo, Viktor Volchkov, Clarence J. Peters, Hideki Ebihara, Antonio Tenorio, W. Ian Lipkin, Sergey V. Netesov, Thomas W Geisbert, Yoshihiro Kawaoka, Gustavo Palacios, Stephan Becker, Karl M. Johnson, Stuart T. Nichol, Peter B JahrlingAbstract:The taxonomy of the family Filoviridae (Marburgviruses and ebolaviruses) has changed several times since the discovery of its members, resulting in a plethora of species and virus names and abbreviations. The current taxonomy has only been partially accepted by most laboratory virologists. Confusion likely arose for several reasons: species names that consist of several words or which (should) contain diacritical marks, the current orthographic identity of species and virus names, and the similar pronunciation of several virus abbreviations in the absence of guidance for the correct use of vernacular names. To rectify this problem, we suggest (1) to retain the current species names Reston ebolavirus, Sudan ebolavirus, and Zaire ebolavirus, but to replace the name Cote d'Ivoire ebolavirus [sic] with Taï Forest ebolavirus and Lake Victoria Marburgvirus with Marburg Marburgvirus; (2) to revert the virus names of the type Marburgviruses and ebolaviruses to those used for decades in the field (Marburg virus instead of Lake Victoria Marburgvirus and Ebola virus instead of Zaire ebolavirus); (3) to introduce names for the remaining viruses reminiscent of jargon used by laboratory virologists but nevertheless different from species names (Reston virus, Sudan virus, Taï Forest virus), and (4) to introduce distinct abbreviations for the individual viruses (RESTV for Reston virus, SUDV for Sudan virus, and TAFV for Taï Forest virus), while retaining that for Marburg virus (MARV) and reintroducing that used over decades for Ebola virus (EBOV). Paying tribute to developments in the field, we propose (a) to create a new ebolavirus species (Bundibugyo ebolavirus) for one member virus (Bundibugyo virus, BDBV); (b) to assign a second virus to the species Marburg Marburgvirus (Ravn virus, RAVV) for better reflection of now available high-resolution phylogeny; and (c) to create a new tentative genus (Cuevavirus) with one tentative species (Lloviu cuevavirus) for the recently discovered Lloviu virus (LLOV). Furthermore, we explain the etymological derivation of individual names, their pronunciation, and their correct use, and we elaborate on demarcation criteria for each taxon and virus.
Amy J. Schuh - One of the best experts on this subject based on the ideXlab platform.
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No evidence for the involvement of the argasid tick Ornithodoros faini in the enzootic maintenance of Marburgvirus within Egyptian rousette bats Rousettus aegyptiacus
Parasites & Vectors, 2016Co-Authors: Amy J. Schuh, Tara K. Sealy, Dmitry A. Apanaskevich, Brian R Amman, Stuart T. Nichol, Jonathan S TownerAbstract:Background The cave-dwelling Egyptian rousette bat (ERB; Rousettus aegyptiacus ) was recently identified as a natural reservoir host of Marburgviruses. However, the mechanisms of transmission for the enzootic maintenance of Marburgviruses within ERBs are unclear. Previous ecological investigations of large ERB colonies inhabiting Python Cave and Kitaka Mine, Uganda revealed that argasid ticks ( Ornithodoros faini ) are hematophagous ectoparasites of ERBs. Yet, their potential role as transmission vectors for Marburgvirus has not been sufficiently assessed. Findings In the present study, 3,125 O. faini were collected during April 2013 from the rock crevices of Python Cave, Uganda. None of the ticks tested positive for Marburgvirus-specific RNA by Q-RT-PCR. The probability of failure to detect Marburgvirus at a conservative prevalence of 0.1 % was 0.05. Conclusions The absence of Marburgvirus RNA in O. faini suggests they do not play a significant role in the transmission and enzootic maintenance of Marburgvirus within their natural reservoir host.
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No evidence for the involvement of the argasid tick Ornithodoros faini in the enzootic maintenance of Marburgvirus within Egyptian rousette bats Rousettus aegyptiacus
Parasites & Vectors, 2016Co-Authors: Amy J. Schuh, Tara K. Sealy, Dmitry A. Apanaskevich, Brian R Amman, Stuart T. Nichol, Jonathan S TownerAbstract:Background The cave-dwelling Egyptian rousette bat (ERB; Rousettus aegyptiacus) was recently identified as a natural reservoir host of Marburgviruses. However, the mechanisms of transmission for the enzootic maintenance of Marburgviruses within ERBs are unclear. Previous ecological investigations of large ERB colonies inhabiting Python Cave and Kitaka Mine, Uganda revealed that argasid ticks (Ornithodoros faini) are hematophagous ectoparasites of ERBs. Yet, their potential role as transmission vectors for Marburgvirus has not been sufficiently assessed.
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experimental inoculation of egyptian rousette bats rousettus aegyptiacus with viruses of the ebolavirus and Marburgvirus genera
Viruses, 2015Co-Authors: Mega E Jones, Amy J. Schuh, Tara K. Sealy, Sherif R. Zaki, Ia R Amma, Stua T Nichol, Jonatha S TowneAbstract:The Egyptian rousette bat (Rousettus aegyptiacus) is a natural reservoir for Marburgviruses and a consistent source of virus spillover to humans. Cumulative evidence suggests various bat species may also transmit ebolaviruses. We investigated the susceptibility of Egyptian rousettes to each of the five known ebolaviruses (Sudan, Ebola, Bundibugyo, Tai Forest, and Reston), and compared findings with Marburg virus. In a pilot study, groups of four juvenile bats were inoculated with one of the ebolaviruses or Marburg virus. In ebolavirus groups, viral RNA tissue distribution was limited, and no bat became viremic. Sudan viral RNA was slightly more widespread, spurring a second, 15-day Sudan virus serial euthanasia study. Low levels of Sudan viral RNA disseminated to multiple tissues at early time points, but there was no viremia or shedding. In contrast, Marburg virus RNA was widely disseminated, with viremia, oral and rectal shedding, and antigen in spleen and liver. This is the first experimental infection study comparing tissue tropism, viral shedding, and clinical and pathologic effects of six different filoviruses in the Egyptian rousette, a known Marburgvirus reservoir. Our results suggest Egyptian rousettes are unlikely sources for ebolaviruses in nature, and support a possible single filovirus—single reservoir host relationship.
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oral shedding of marburg virus in experimentally infected egyptian fruit bats rousettus aegyptiacus
Journal of Wildlife Diseases, 2015Co-Authors: Brian R Amman, Amy J. Schuh, Tara K. Sealy, Megan E B Jones, Luke S Uebelhoer, Brian H Bird, Joann D Colemanmccray, Brock E MartinAbstract:Abstract Marburg virus (Marburg Marburgvirus; MARV) causes sporadic outbreaks of Marburg hemorrhagic fever (MHF) in Africa. The Egyptian fruit bat (Rousettus aegyptiacus) has been identified as a natural reservoir based most-recently on the repeated isolation of MARV directly from bats caught at two locations in southwestern Uganda where miners and tourists separately contracted MHF from 2007–08. Despite learning much about the ecology of MARV through extensive field investigations, there remained unanswered questions such as determining the primary routes of virus shedding and the severity of disease, if any, caused by MARV in infected bats. To answer these questions and others, we experimentally infected captive-bred R. aegyptiacus with MARV under high (biosafety level 4) containment. These experiments have shown infection profiles consistent with R. aegyptiacus being a bona fide natural reservoir host for MARV and demonstrated routes of viral shedding capable of infecting humans and other animals.
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Marburgvirus resurgence in kitaka mine bat population after extermination attempts uganda
Emerging Infectious Diseases, 2014Co-Authors: Brian R Amman, Amy J. Schuh, Tara K. Sealy, Trevor Shoemaker, Luke Nyakarahuka, Anita K Mcelroy, Kimberly A Dodd, Stephen Balinandi, Patrick Atimnedi, Winyi KaboyoAbstract:To the Editor: Marburg virus (MARV) and Ravn virus (RAVV), collectively called Marburgviruses, cause Marburg hemorrhagic fever (MHF) in humans. In July 2007, 4 cases of MHF (1 fatal) occurred in miners at Kitaka Mine in southern Uganda. Later, MHF occurred in 2 tourists who visited Python Cave, ≈50 km from Kitaka Mine. One of the tourists was from the United States (December 2007) and 1 was from the Netherlands (July 2008); 1 case was fatal (1,2,3). The cave and the mine each contained 40,000–100,000 Rousettus aegyptiacus bats (Egyptian fruit bats). Longitudinal investigations of the outbreaks at both locations were initiated by the Viral Special Pathogens Branch of the Centers for Disease Control and Prevention (CDC, Atlanta, GA, USA, and Entebbe, Uganda) in collaboration with the Uganda Wildlife Authority (UWA) and the Uganda Virus Research Institute (UVRI). During these studies, genetically diverse MARVs and RAVVs were isolated directly from bat tissues, and infection levels of the 2 viruses were found to increase in juvenile bats on a predictable bi-annual basis (4,5). However, investigations at Kitaka Mine were stopped when the miners exterminated the bat colony by restricting egress from the cave with papyrus reed barriers and then entangling the bats in fishing nets draped over the exits. The trapping continued for weeks, and the entrances were then sealed with sticks and plastic. These depopulation efforts were documented by researchers from UVRI, the CDC, the National Institute of Communicable Diseases (Sandringham, South Africa), and UWA during site visits to Kitaka Mine (Technical Appendix Figure). In August 2008, thousands of dead bats were found piled in the forest, and by November 2008, there was no evidence of bats living in the mine; whether 100% extermination was achieved is unknown. CDC, UVRI, and UWA recommended against extermination, believing that any results would be temporary and that such efforts could exacerbate the problem if bat exclusion methods were not complete and permanent (6,7). In October 2012, the most recent known Marburgvirus outbreak was detected in Ibanda, a town in southwest Uganda. Ibanda is ≈20 km from the Kitaka Mine and is the urban center that serves smaller communities in the Kitaka area. This MHF outbreak was the largest in Ugandan history: 15 laboratory-confirmed cases occurred (8). In November 2012, an ecologic investigation of the greater Ibanda/Kitaka area was initiated. The investigation included interviews with local authorities to locate all known R. aegyptiacus colonies in the area. Although minor colonies of small insectivorous bats were found, the only identifiable colony of R. aegyptiacus bats was found inside the re-opened Kitaka Mine, albeit at much reduced size, perhaps 1%–5% of that found before depopulation efforts. To determine whether the R. aegyptiacus bats that had repopulated Kitaka Mine were actively infected with Marburgviruses, we tested 400 bats by using previously described methods (4,5). Viral RNA was extracted from ≈100 mg of liver and spleen tissue by using the MagMAX Total Nucleic Acid Isolation Kit (Applied Biosystems, Foster City, CA, USA) according to the manufacturer’s recommended protocol. The Fisher exact test was conducted by using IBM SPSS Statistics, version 19.0 (IBM Corp., Armonk, NY, USA). Of the 400 R. aegyptiacus bats collected, 53 (13.3%) were positive for Marburgvirus RNA by quantitative reverse transcription PCR (32/233 [13.7%] adults and 21/167 [12.6%] juveniles; Technical Appendix Table); Marburgvirus was isolated from tissue samples from 9 of the 400 bats. The overall level of active infection was significantly higher than that found in Kitaka Mine during 2007–2008 (5.1%) (5) (Fisher exact test, p 0.5 for both), and overall, the presence of virus-specific IgG among the bats was 16.5%, a finding consistent with that in previous studies (4,5). Figure Phylogeny of concatenated Marburgvirus nucleoprotein (NP) and viral protein 35 (VP35) gene fragments as determined by using the maximum-likelihood method. Sequences from the NP (289–372 nt) and VP35 (203–213 nt) genes were amplified and ... Phylogenetic analysis of viral RNA genome fragment sequences in this study showed high Marburgvirus genetic diversity, including the presence of RAVVs and MARVs. Sequences for isolates from 3 bats were nearly identical to those of the MARV isolates obtained from patients in the 2012 Ibanda outbreak (8), suggesting that bats from Kitaka Mine were a likely source of the virus. Technical Appendix: Photographs taken during August 2008–September 2009 of bat extermination efforts at Kitaka Mine, and table showing demographic characteristics of bats captured during a Marburg hemorrhagic fever outbreak investigation at the mine in November 2012, Uganda. Click here to view.(124K, pdf)
