The Experts below are selected from a list of 498 Experts worldwide ranked by ideXlab platform
Yoshihiro Kawaoka - One of the best experts on this subject based on the ideXlab platform.
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A Critical Domain of Ebolavirus Envelope Glycoprotein Determines Glycoform and Infectivity
Nature Publishing Group, 2018Co-Authors: Haruhiko Fujihira, Ayato Takada, Yoshihiro Kawaoka, Katsuaki Usami, Keita Matsuno, Hideyuki Takeuchi, Kaori Denda-nagai, Jun-ichi Furukawa, Yasuro Shinohara, Tatsuro IrimuraAbstract:Abstract Ebolaviruses comprises 5 species that exert varying degrees of mortality/infectivity in humans with Reston Ebolaviruses (REBOV) showing the lowest and Zaire Ebolaviruses (ZEBOV) showing the highest. However, the molecular basis of this differential mortality/infectivity remains unclear. Here, we report that the structural features of ebolavirus envelope glycoproteins (GPs) and one of their counter receptors, macrophage galactose-type calcium-type lectin (MGL/CD301), play crucial roles in determining viral infectivity. The low infectivity of REBOV mediated by the interaction between GPs and MGL/CD301 dramatically increased when the N-terminal 18 amino acids (33rd through 50th) of GPs were replaced with that of ZEBOV. Furthermore, structural analysis of glycans of GPs revealed that N-glycans were more extended in REBOV than in ZEBOV. N-glycan extension was reversed by the replacement of aforementioned N-terminal 18 amino acid residues. Therefore, these data strongly suggest that extended N-glycans on GPs reduce MGL/CD301-mediated viral infectivity by hindering the interaction between GPs and MGL/CD301 preferentially binds O-glycans
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ebolavirus s foibles
Cell, 2017Co-Authors: Seiya Yamayoshi, Yoshihiro KawaokaAbstract:Ebola virus disease poses a global health threat. Here, two studies by Wec et al. and Zhao et al. identified vulnerability in an internal fusion loop of an ebolavirus glycoprotein. Monoclonal antibodies elicited from immunization and isolated from a human survivor that recognized epitopes in this area neutralized all five Ebolaviruses, guiding the development of a pan-ebolavirus immunotherapy.
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A shared structural solution for neutralizing Ebolaviruses
2016Co-Authors: João M. Dias, Marnie L. Fusco, Dafna M. Abelson, Majidat A. Muhammad, Samantha E. Zak, Anthony C. Wong, Peter Halfmann, Ana I. Kuehne, Shridhar Bale, Yoshihiro KawaokaAbstract:Sudan virus (genus ebolavirus) is lethal, yet no monoclonal antibody is known to neutralize it. Here we describe antibody 16F6 that neutralizes Sudan virus and present its structure bound to the trimeric viral glycoprotein. Unexpectedly, the 16F6 epitope overlaps that of KZ52, the only other antibody against the GP1,2 core to be visualized. Further, both antibodies against this key GP1– GP2-bridging epitope neutralize at a post-internalization step, likely fusion. Ebolaviruses (family Filoviridae), cause severe hemorrhagic fever with up to 90 % fatality. Five antigenically distinct Ebolaviruses have been identified that differ in genomic sequence by ~35–45%: Sudan, Ebola, Taï Forest, Reston, and Bundibugyo. However, almost all human deaths result from infection with either Sudan virus (SUDV; formerly known as Sudan ebolavirus) or Ebola virus (EBOV; formerly known as Zaire ebolavirus). In October 2000, a new variant of SUDV, termed Gulu (SUDV-Gul)1, emerged in the Gulu district of northwestern Uganda. It triggered the largest outbreak of Ebola hemorrhagic fever yet described, involving at least 425 individuals, of whom 224 died2. Multiple monoclonal Correspondence should be addressed to J.M. Dy
Marnie L. Fusco - One of the best experts on this subject based on the ideXlab platform.
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structural basis of pan ebolavirus neutralization by a human antibody against a conserved yet cryptic epitope
Mbio, 2018Co-Authors: Brandyn R West, Marnie L. Fusco, Crystal L Moyer, Liam B King, Jacob C Milligan, Sean Hui, Erica Ollmann SaphireAbstract:ABSTRACT Only one naturally occurring human antibody has been described thus far that is capable of potently neutralizing all five Ebolaviruses. Here we present two crystal structures of this rare, pan-ebolavirus neutralizing human antibody in complex with Ebola virus and Bundibugyo virus glycoproteins (GPs), respectively. The structures delineate the key protein and glycan contacts for binding that are conserved across the Ebolaviruses, explain the antibody’s unique broad specificity and neutralization activity, and reveal the likely mechanism behind a known escape mutation in the fusion loop region of GP2. We found that the epitope of this antibody, ADI-15878, extends along the hydrophobic paddle of the fusion loop and then dips down into a highly conserved pocket beneath the N-terminal tail of GP2, a mode of recognition unlike any other antibody elicited against Ebola virus, and likely critical for its broad activity. The fold of Bundibugyo virus glycoprotein, not previously visualized, is similar to the fold of Ebola virus GP, and ADI-15878 binds to each virus’s GP with a similar strategy and angle of attack. These findings will be useful in deployment of this antibody as a broad-spectrum therapeutic and in the design of immunogens that elicit the desired broadly neutralizing immune response against all members of the ebolavirus genus and filovirus family. IMPORTANCE There are five different members of the Ebolavirus genus. Provision of vaccines and treatments able to protect against any of the five Ebolaviruses is an important goal of public health. Antibodies are a desired result of vaccines and can be delivered directly as therapeutics. Most antibodies, however, are effective against only one or two, not all, of these pathogens. Only one human antibody has been thus far described to neutralize all five Ebolaviruses, antibody ADI-15878. Here we describe the molecular structure of ADI-15878 bound to the relevant target proteins of Ebola virus and Bundibugyo virus. We explain how it achieves its rare breadth of activity and propose strategies to design improved vaccines capable of eliciting more antibodies like ADI-15878.
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multifunctional pan ebolavirus antibody recognizes a site of broad vulnerability on the ebolavirus glycoprotein
Immunity, 2018Co-Authors: Pavlo Gilchuk, Edgar Davidson, Hannah L Turner, Bronwyn M Gunn, Philipp A Ilinykh, Natalia Kuzmina, Kai Huang, Aubrey L Bryan, Benjamin J Doranz, Marnie L. FuscoAbstract:Ebolaviruses cause severe disease in humans, and identification of monoclonal antibodies (mAbs) that are effective against multiple Ebolaviruses are important for therapeutics development. Here we describe a distinct class of broadly neutralizing human mAbs with protective capacity against three Ebolaviruses infectious for humans: Ebola (EBOV), Sudan (SUDV), and Bundibugyo (BDBV) viruses. We isolated mAbs from human survivors of ebolavirus disease and identified a potent mAb, EBOV-520, which bound to an epitope in the glycoprotein (GP) base region. EBOV-520 efficiently neutralized EBOV, BDBV, and SUDV and also showed protective capacity in relevant animal models of these infections. EBOV-520 mediated protection principally by direct virus neutralization and exhibited multifunctional properties. This study identified a potent naturally occurring mAb and defined key features of the human antibody response that may contribute to broad protection. This multifunctional mAb and related clones are promising candidates for development as broadly protective pan-ebolavirus therapeutic molecules.
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Structural Basis of Pan-Ebolavirus Neutralization by a Human Antibody against a Conserved, yet Cryptic Epitope
'American Society for Microbiology', 2018Co-Authors: Brandyn R West, Marnie L. Fusco, Crystal L Moyer, Liam B King, Jacob C Milligan, Sean Hui, Erica Ollmann SaphireAbstract:There are five different members of the Ebolavirus genus. Provision of vaccines and treatments able to protect against any of the five Ebolaviruses is an important goal of public health. Antibodies are a desired result of vaccines and can be delivered directly as therapeutics. Most antibodies, however, are effective against only one or two, not all, of these pathogens. Only one human antibody has been thus far described to neutralize all five Ebolaviruses, antibody ADI-15878. Here we describe the molecular structure of ADI-15878 bound to the relevant target proteins of Ebola virus and Bundibugyo virus. We explain how it achieves its rare breadth of activity and propose strategies to design improved vaccines capable of eliciting more antibodies like ADI-15878.Only one naturally occurring human antibody has been described thus far that is capable of potently neutralizing all five Ebolaviruses. Here we present two crystal structures of this rare, pan-ebolavirus neutralizing human antibody in complex with Ebola virus and Bundibugyo virus glycoproteins (GPs), respectively. The structures delineate the key protein and glycan contacts for binding that are conserved across the Ebolaviruses, explain the antibody’s unique broad specificity and neutralization activity, and reveal the likely mechanism behind a known escape mutation in the fusion loop region of GP2. We found that the epitope of this antibody, ADI-15878, extends along the hydrophobic paddle of the fusion loop and then dips down into a highly conserved pocket beneath the N-terminal tail of GP2, a mode of recognition unlike any other antibody elicited against Ebola virus, and likely critical for its broad activity. The fold of Bundibugyo virus glycoprotein, not previously visualized, is similar to the fold of Ebola virus GP, and ADI-15878 binds to each virus’s GP with a similar strategy and angle of attack. These findings will be useful in deployment of this antibody as a broad-spectrum therapeutic and in the design of immunogens that elicit the desired broadly neutralizing immune response against all members of the ebolavirus genus and filovirus family
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RESEARCH ARTICLE Protective mAbs and Cross-Reactive mAbs Raised by Immunization with Engineered Marburg Virus
2016Co-Authors: Marnie L. Fusco, Robyn Cassan, Julia E Biggins, Takao Hashiguchi, Gene G Olinger, Do H. Kim, Kevin J. Whaley, Larry Zeitlin, B. WardAbstract:The filoviruses, which include the marburg- and Ebolaviruses, have caused multiple out-breaks among humans this decade. Antibodies against the filovirus surface glycoprotein (GP) have been shown to provide life-saving therapy in nonhuman primates, but such anti-bodies are generally virus-specific. Many monoclonal antibodies (mAbs) have been described against Ebola virus. In contrast, relatively few have been described against Mar-burg virus. Here we present ten mAbs elicited by immunization of mice using recombinant mucin-deleted GPs from different Marburg virus (MARV) strains. Surprisingly, two of the mAbs raised against MARV GP also cross-react with the mucin-deleted GP cores of all tested Ebolaviruses (Ebola, Sudan, Bundibugyo, Reston), but these epitopes are maske
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A shared structural solution for neutralizing Ebolaviruses
2016Co-Authors: João M. Dias, Marnie L. Fusco, Dafna M. Abelson, Majidat A. Muhammad, Samantha E. Zak, Anthony C. Wong, Peter Halfmann, Ana I. Kuehne, Shridhar Bale, Yoshihiro KawaokaAbstract:Sudan virus (genus ebolavirus) is lethal, yet no monoclonal antibody is known to neutralize it. Here we describe antibody 16F6 that neutralizes Sudan virus and present its structure bound to the trimeric viral glycoprotein. Unexpectedly, the 16F6 epitope overlaps that of KZ52, the only other antibody against the GP1,2 core to be visualized. Further, both antibodies against this key GP1– GP2-bridging epitope neutralize at a post-internalization step, likely fusion. Ebolaviruses (family Filoviridae), cause severe hemorrhagic fever with up to 90 % fatality. Five antigenically distinct Ebolaviruses have been identified that differ in genomic sequence by ~35–45%: Sudan, Ebola, Taï Forest, Reston, and Bundibugyo. However, almost all human deaths result from infection with either Sudan virus (SUDV; formerly known as Sudan ebolavirus) or Ebola virus (EBOV; formerly known as Zaire ebolavirus). In October 2000, a new variant of SUDV, termed Gulu (SUDV-Gul)1, emerged in the Gulu district of northwestern Uganda. It triggered the largest outbreak of Ebola hemorrhagic fever yet described, involving at least 425 individuals, of whom 224 died2. Multiple monoclonal Correspondence should be addressed to J.M. Dy
Heinz Feldmann - One of the best experts on this subject based on the ideXlab platform.
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ebolavirus an overview of molecular and clinical pathogenesis
Methods of Molecular Biology, 2017Co-Authors: Veronica Vine, Dana P Scott, Heinz FeldmannAbstract:Ebolaviruses cause severe, often fatal hemorrhagic fever in Central, East, and West Africa. Until recently, they have been viewed as rare but highly pathogenic infections with regional, but limited, global public health impact. This view has changed with the emergence of the first epidemic of Ebola hemorrhagic fever in West Africa. In this chapter we provide an introduction of the pathogenesis of Ebolaviruses as well as a description of clinical disease features. We also describe the current animal models used in ebolavirus research, detailing each model's unique strengths and weaknesses. We focus on Ebola virus representing the type species Zaire ebolavirus of the genus Ebolavirus, as most work relates to this pathogen.
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Natural Immunity to Ebola Virus in the Syrian Hamster Requires Antibody Responses
2016Co-Authors: Joseph Prescott, Darryl Falzarano, Heinz FeldmannAbstract:Most Ebolaviruses can cause severe disease in humans and other primates, with high case fatality rates during human outbreaks. Although these viruses have been studied for almost 4 decades, little is know regarding the mechanisms by which they cause disease and what is important for protection or treatment after infection. Be-cause of the sporadic nature of the outbreaks and difficulties accessing the populations affected by Ebolaviruses, little is also known about what constitutes an appropriate immune response to infection in humans that survive infection. Such knowledge would allow a targeted approach to therapies. In contrast to humans, rodents are protected from disease on infection with Ebolaviruses, although adapted versions of some of the viruses are le-thal in mice, hamsters and guinea pigs. Using the recently described hamster model, along with T-cell depletion strategies, we show that CD4+ T cells are required for natural immunity to Ebola virus infection and that CD4-dependent antibody responses are required for immunity in this model. Keywords. Ebola virus; immune response; antibody; T cell. Ebola virus (EBOV) is the prototypic etiologic agent of Ebola hemorrhagic fever (EHF) and is responsible for the current outbreak in West Africa, which has infected thousands of people, with a case-fatality rate of abou
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cytomegalovirus based vaccine expressing ebola virus glycoprotein protects nonhuman primates from ebola virus infection
Scientific Reports, 2016Co-Authors: Andrea Marzi, Elaine Haddock, Christopher J Parkins, Friederike Feldmann, Ilhem Messaoudi, Aisling A Murphy, Patrick W Hanley, Matthew J Emery, Flora Engelmann, Heinz FeldmannAbstract:Ebolaviruses pose significant public health problems due to their high lethality, unpredictable emergence, and localization to the poorest areas of the world. In addition to implementation of standard public health control procedures, a number of experimental human vaccines are being explored as a further means for outbreak control. Recombinant cytomegalovirus (CMV)-based vectors are a novel vaccine platform that have been shown to induce substantial levels of durable, but primarily T-cell-biased responses against the encoded heterologous target antigen. Herein, we demonstrate the ability of rhesus CMV (RhCMV) expressing Ebola virus (EBOV) glycoprotein (GP) to provide protective immunity to rhesus macaques against lethal EBOV challenge. Surprisingly, vaccination was associated with high levels of GP-specific antibodies, but with no detectable GP-directed cellular immunity.
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Discovery of an antibody for pan-ebolavirus therapy
Scientific Reports, 2016Co-Authors: Wakako Furuyama, Asuka Nanbo, Junki Maruyama, Hiroko Miyamoto, Osamu Noyori, Andrea Marzi, Manabu Igarashi, Reiko Yoshida, Elaine Haddock, Heinz FeldmannAbstract:During the latest outbreak of Ebola virus disease in West Africa, monoclonal antibody therapy (e.g., ZMapp) was utilized to treat patients. However, due to the antigenic differences among the five ebolavirus species, the current therapeutic monoclonal antibodies are only effective against viruses of the species Zaire ebolavirus. Although this particular species has indeed caused the majority of human infections in Central and, recently, West Africa, other ebolavirus species (e.g., Sudan ebolavirus and Bundibugyo ebolavirus) have also repeatedly caused outbreaks in Central Africa and thus should not be neglected in the development of countermeasures against Ebolaviruses. Here we report the generation of an ebolavirus glycoprotein-specific monoclonal antibody that effectively inhibits cellular entry of representative isolates of all known ebolavirus species in vitro and show its protective efficacy in mouse models of ebolavirus infections. This novel neutralizing monoclonal antibody targets a highly conserved internal fusion loop in the glycoprotein molecule and prevents membrane fusion of the viral envelope with cellular membranes. The discovery of this highly cross-neutralizing antibody provides a promising option for broad-acting ebolavirus antibody therapy and will accelerate the design of improved vaccines that can selectively elicit cross-neutralizing antibodies against multiple species of Ebolaviruses.
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natural immunity to ebola virus in the syrian hamster requires antibody responses
The Journal of Infectious Diseases, 2015Co-Authors: Joseph Prescott, Darryl Falzarano, Heinz FeldmannAbstract:Most Ebolaviruses can cause severe disease in humans and other primates, with high case fatality rates during human outbreaks. Although these viruses have been studied for almost 4 decades, little is know regarding the mechanisms by which they cause disease and what is important for protection or treatment after infection. Because of the sporadic nature of the outbreaks and difficulties accessing the populations affected by Ebolaviruses, little is also known about what constitutes an appropriate immune response to infection in humans that survive infection. Such knowledge would allow a targeted approach to therapies. In contrast to humans, rodents are protected from disease on infection with Ebolaviruses, although adapted versions of some of the viruses are lethal in mice, hamsters and guinea pigs. Using the recently described hamster model, along with T-cell depletion strategies, we show that CD4(+) T cells are required for natural immunity to Ebola virus infection and that CD4-dependent antibody responses are required for immunity in this model.
John Misasi - One of the best experts on this subject based on the ideXlab platform.
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camouflage and misdirection the full on assault of ebola virus disease
Cell, 2014Co-Authors: John Misasi, Nancy J SullivanAbstract:Ebolaviruses cause a severe hemorrhagic fever syndrome that is rapidly fatal to humans and nonhuman primates. Ebola protein interactions with host cellular proteins disrupt type I and type II interferon responses, RNAi antiviral responses, antigen presentation, T-cell-dependent B cell responses, humoral antibodies, and cell-mediated immunity. This multifaceted approach to evasion and suppression of innate and adaptive immune responses in their target hosts leads to the severe immune dysregulation and "cytokine storm" that is characteristic of fatal ebolavirus infection. Here, we highlight some of the processes by which Ebola interacts with its mammalian hosts to evade antiviral defenses.
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filoviruses require endosomal cysteine proteases for entry but exhibit distinct protease preferences
Journal of Virology, 2012Co-Authors: John Misasi, Kartik Chandran, Nancy J Sullivan, Jinyi Yang, Bryden Considine, Claire Marie Filone, Marceline Cote, Giulia Fabozzi, Lisa E. HensleyAbstract:ABSTRACT Filoviruses are enveloped viruses that cause sporadic outbreaks of severe hemorrhagic fever [CDC, MMWR Morb. Mortal. Wkly. Rep. 50:73–77, 2001; Colebunders and Borchert, J. Infect. 40:16–20, 2000; Colebunders et al., J. Infect. Dis. 196(Suppl. 2):S148–S153, 2007; Geisbert and Jahrling, Nat. Med. 10:S110-S121, 2004]. Previous studies revealed that endosomal cysteine proteases are host factors for ebolavirus Zaire (Chandran et al., Science 308:1643–1645, 2005; Schornberg et al., J. Virol. 80:4174–4178, 2006). In this report, we show that infection mediated by glycoproteins from other phylogenetically diverse filoviruses are also dependent on these proteases and provide additional evidence indicating that they cleave GP1 and expose the binding domain for the critical host factor Niemann-Pick C1. Using selective inhibitors and knockout-derived cell lines, we show that the Ebolaviruses Zaire and Cote d9Ivoire are strongly dependent on cathepsin B, while the Ebolaviruses Sudan and Reston and Marburg virus are not. Taking advantage of previous studies of cathepsin B inhibitor-resistant viruses (Wong et al., J. Virol. 84:163–175, 2010), we found that virus-specific differences in the requirement for cathepsin B are correlated with sequence polymorphisms at residues 47 in GP1 and 584 in GP2. We applied these findings to the analysis of additional ebolavirus isolates and correctly predicted that the newly identified ebolavirus species Bundibugyo, containing D47 and I584, is cathepsin B dependent and that ebolavirus Zaire-1995, the single known isolate of ebolavirus Zaire that lacks D47, is not. We also obtained evidence for virus-specific differences in the role of cathepsin L, including cooperation with cathepsin B. These studies strongly suggest that the use of endosomal cysteine proteases as host factors for entry is a general property of members of the family Filoviridae.
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ebolavirus δ peptide immunoadhesins inhibit marburgvirus and ebolavirus cell entry
Journal of Virology, 2011Co-Authors: Sheli R. Radoshitzky, KELLY LYN WARFIELD, Steven B. Bradfute, Krishna P. Kota, Xiaoli Chi, Lian Dong, Jacqueline D. Gearhart, Cary Retterer, Philip J. Kranzusch, John MisasiAbstract:With the exception of Reston and Lloviu viruses, filoviruses (marburgviruses, Ebolaviruses, and "cuevaviruses") cause severe viral hemorrhagic fevers in humans. Filoviruses use a class I fusion protein, GP(1,2), to bind to an unknown, but shared, cell surface receptor to initiate virus-cell fusion. In addition to GP(1,2), Ebolaviruses and cuevaviruses, but not marburgviruses, express two secreted glycoproteins, soluble GP (sGP) and small soluble GP (ssGP). All three glycoproteins have identical N termini that include the receptor-binding region (RBR) but differ in their C termini. We evaluated the effect of the secreted ebolavirus glycoproteins on marburgvirus and ebolavirus cell entry, using Fc-tagged recombinant proteins. Neither sGP-Fc nor ssGP-Fc bound to filovirus-permissive cells or inhibited GP(1,2)-mediated cell entry of pseudotyped retroviruses. Surprisingly, several Fc-tagged Δ-peptides, which are small C-terminal cleavage products of sGP secreted by ebolavirus-infected cells, inhibited entry of retroviruses pseudotyped with Marburg virus GP(1,2), as well as Marburg virus and Ebola virus infection in a dose-dependent manner and at low molarity despite absence of sequence similarity to filovirus RBRs. Fc-tagged Δ-peptides from three Ebolaviruses (Ebola virus, Sudan virus, and Tai Forest virus) inhibited GP(1,2)-mediated entry and infection of viruses comparably to or better than the Fc-tagged RBRs, whereas the Δ-peptide-Fc of an ebolavirus nonpathogenic for humans (Reston virus) and that of an ebolavirus with lower lethality for humans (Bundibugyo virus) had little effect. These data indicate that Δ-peptides are functional components of ebolavirus proteomes. They join cathepsins and integrins as novel modulators of filovirus cell entry, might play important roles in pathogenesis, and could be exploited for the synthesis of powerful new antivirals.
Andrea Marzi - One of the best experts on this subject based on the ideXlab platform.
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the ebola virus glycoprotein and its immune responses across multiple vaccine platforms
Expert Review of Vaccines, 2020Co-Authors: Kyle Odonnell, Andrea MarziAbstract:Introduction: For over 40 years, Ebolaviruses have been responsible for sporadic outbreaks of severe and often fatal hemorrhagic fever in humans and nonhuman primates across western and central Afr...
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Ebolaviruses associated with differential pathogenicity induce distinct host responses in human macrophages
Journal of Virology, 2017Co-Authors: Judith Olejnik, Andrea Marzi, Adam J. Hume, Laure R Deflube, Hideki Ebihara, Adriana Forero, Whitney Manhart, Andrew Nishida, Michael G Katze, Angela L RasmussenAbstract:Ebola virus (EBOV) and Reston virus (RESTV) are members of the Ebolavirus genus which greatly differ in their pathogenicity. While EBOV causes a severe disease in humans characterized by a dysregulated inflammatory response and elevated cytokine and chemokine production, there are no reported disease-associated human cases of RESTV infection, suggesting that RESTV is nonpathogenic for humans. The underlying mechanisms determining the pathogenicity of different ebolavirus species are not yet known. In this study, we dissected the host response to EBOV and RESTV infection in primary human monocyte-derived macrophages (MDMs). As expected, EBOV infection led to a profound proinflammatory response, including strong induction of type I and type III interferons (IFNs). In contrast, RESTV-infected macrophages remained surprisingly silent. Early activation of IFN regulatory factor 3 (IRF3) and NF-κB was observed in EBOV-infected, but not in RESTV-infected, MDMs. In concordance with previous results, MDMs treated with inactivated EBOV and Ebola virus-like particles (VLPs) induced NF-κB activation mediated by Toll-like receptor 4 (TLR4) in a glycoprotein (GP)-dependent manner. This was not the case in cells exposed to live RESTV, inactivated RESTV, or VLPs containing RESTV GP, indicating that RESTV GP does not trigger TLR4 signaling. Our results suggest that the lack of immune activation in RESTV-infected MDMs contributes to lower pathogenicity by preventing the cytokine storm observed in EBOV infection. We further demonstrate that inhibition of TLR4 signaling abolishes EBOV GP-mediated NF-κB activation. This finding indicates that limiting the excessive TLR4-mediated proinflammatory response in EBOV infection should be considered as a potential supportive treatment option for EBOV disease.IMPORTANCE Emerging infectious diseases are a major public health concern, as exemplified by the recent devastating Ebola virus (EBOV) outbreak. Different ebolavirus species are associated with widely varying pathogenicity in humans, ranging from asymptomatic infections for Reston virus (RESTV) to severe disease with fatal outcomes for EBOV. In this comparative study of EBOV- and RESTV-infected human macrophages, we identified key differences in host cell responses. Consistent with previous data, EBOV infection is associated with a proinflammatory signature triggered by the surface glycoprotein (GP), which can be inhibited by blocking TLR4 signaling. In contrast, infection with RESTV failed to stimulate a strong host response in infected macrophages due to the inability of RESTV GP to stimulate TLR4. We propose that disparate proinflammatory host signatures contribute to the differences in pathogenicity reported for ebolavirus species and suggest that proinflammatory pathways represent an intriguing target for the development of novel therapeutics.
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cytomegalovirus based vaccine expressing ebola virus glycoprotein protects nonhuman primates from ebola virus infection
Scientific Reports, 2016Co-Authors: Andrea Marzi, Elaine Haddock, Christopher J Parkins, Friederike Feldmann, Ilhem Messaoudi, Aisling A Murphy, Patrick W Hanley, Matthew J Emery, Flora Engelmann, Heinz FeldmannAbstract:Ebolaviruses pose significant public health problems due to their high lethality, unpredictable emergence, and localization to the poorest areas of the world. In addition to implementation of standard public health control procedures, a number of experimental human vaccines are being explored as a further means for outbreak control. Recombinant cytomegalovirus (CMV)-based vectors are a novel vaccine platform that have been shown to induce substantial levels of durable, but primarily T-cell-biased responses against the encoded heterologous target antigen. Herein, we demonstrate the ability of rhesus CMV (RhCMV) expressing Ebola virus (EBOV) glycoprotein (GP) to provide protective immunity to rhesus macaques against lethal EBOV challenge. Surprisingly, vaccination was associated with high levels of GP-specific antibodies, but with no detectable GP-directed cellular immunity.
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Discovery of an antibody for pan-ebolavirus therapy
Scientific Reports, 2016Co-Authors: Wakako Furuyama, Asuka Nanbo, Junki Maruyama, Hiroko Miyamoto, Osamu Noyori, Andrea Marzi, Manabu Igarashi, Reiko Yoshida, Elaine Haddock, Heinz FeldmannAbstract:During the latest outbreak of Ebola virus disease in West Africa, monoclonal antibody therapy (e.g., ZMapp) was utilized to treat patients. However, due to the antigenic differences among the five ebolavirus species, the current therapeutic monoclonal antibodies are only effective against viruses of the species Zaire ebolavirus. Although this particular species has indeed caused the majority of human infections in Central and, recently, West Africa, other ebolavirus species (e.g., Sudan ebolavirus and Bundibugyo ebolavirus) have also repeatedly caused outbreaks in Central Africa and thus should not be neglected in the development of countermeasures against Ebolaviruses. Here we report the generation of an ebolavirus glycoprotein-specific monoclonal antibody that effectively inhibits cellular entry of representative isolates of all known ebolavirus species in vitro and show its protective efficacy in mouse models of ebolavirus infections. This novel neutralizing monoclonal antibody targets a highly conserved internal fusion loop in the glycoprotein molecule and prevents membrane fusion of the viral envelope with cellular membranes. The discovery of this highly cross-neutralizing antibody provides a promising option for broad-acting ebolavirus antibody therapy and will accelerate the design of improved vaccines that can selectively elicit cross-neutralizing antibodies against multiple species of Ebolaviruses.