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1
Blair, Paul, Maryam Keshtkar-Jahromi, Kevin Psoter, Ronald Reisler, Travis Warren, Sara Johnston, Arthur Goff, Lydia Downey, Sina Bavari, and Anthony Cardile. "Virulence of Marburg Virus Angola Compared to Mt. Elgon (Musoke) in Macaques: A Pooled Survival Analysis." Viruses 10, no. 11 (November 21, 2018): 658. http://dx.doi.org/10.3390/v10110658.
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Angola variant (MARV/Ang) has replaced Mt. Elgon variant Musoke isolate (MARV/MtE-Mus) as the consensus standard variant for Marburg virus research and is regarded as causing a more aggressive phenotype of disease in animal models; however, there is a dearth of published evidence supporting the higher virulence of MARV/Ang. In this retrospective study, we used data pooled from eight separate studies in nonhuman primates experimentally exposed with either 1000 pfu intramuscular (IM) MARV/Ang or MARV/MtE-Mus between 2012 and 2017 at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID). Multivariable Cox proportional hazards regression was used to evaluate the association of variant type with time to death, the development of anorexia, rash, viremia, and 10 select clinical laboratory values. A total of 47 cynomolgus monkeys were included, of which 18 were exposed to MARV/Ang in three separate studies and 29 to MARV/MtE-Mus in five studies. Following universally fatal Marburg virus exposure, compared to MARV/MtE-Mus, MARV/Ang was associated with an increased risk of death (HR = 22.10; 95% CI: 7.08, 68.93), rash (HR = 5.87; 95% CI: 2.76, 12.51) and loss of appetite (HR = 35.10; 95% CI: 7.60, 162.18). Our data demonstrate an increased virulence of MARV/Ang compared to MARV/MtE-Mus variant in the 1000 pfu IM cynomolgus macaque model.
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Bozhanova, Nina G., Amandeep K. Sangha, Alexander M. Sevy, Pavlo Gilchuk, Kai Huang, Rachel S. Nargi, Joseph X. Reidy, et al. "Discovery of Marburg virus neutralizing antibodies from virus-naïve human antibody repertoires using large-scale structural predictions." Proceedings of the National Academy of Sciences 117, no. 49 (November 23, 2020): 31142–48. http://dx.doi.org/10.1073/pnas.1922654117.
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Marburg virus (MARV) disease is lethal, with fatality rates up to 90%. Neutralizing antibodies (Abs) are promising drug candidates to prevent or treat the disease. Current efforts are focused in part on vaccine development to induce such MARV-neutralizing Abs. We analyzed the antibody repertoire from healthy unexposed and previously MARV-infected individuals to assess if naïve repertoires contain suitable precursor antibodies that could become neutralizing with a limited set of somatic mutations. We computationally searched the human Ab variable gene repertoire for predicted structural homologs of the neutralizing Ab MR78 that is specific to the receptor binding site (RBS) of MARV glycoprotein (GP). Eight Ab heavy-chain complementarity determining region 3 (HCDR3) loops from MARV-naïve individuals and one from a previously MARV-infected individual were selected for testing as HCDR3 loop chimeras on the MR78 Ab framework. Three of these chimerized antibodies bound to MARV GP. We then tested a full-length native Ab heavy chain encoding the same 17-residue-long HCDR3 loop that bound to the MARV GP the best among the chimeric Abs tested. Despite only 57% amino acid sequence identity, the Ab from a MARV-naïve donor recognized MARV GP and possessed neutralizing activity against the virus. Crystallization of both chimeric and full-length native heavy chain-containing Abs provided structural insights into the mechanism of binding for these types of Abs. Our work suggests that the MARV GP RBS is a promising candidate for epitope-focused vaccine design to induce neutralizing Abs against MARV.
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Enterlein, Sven, Viktor Volchkov, Michael Weik, Larissa Kolesnikova, Valentina Volchkova, Hans-Dieter Klenk, and Elke Mühlberger. "Rescue of Recombinant Marburg Virus from cDNA Is Dependent on Nucleocapsid Protein VP30." Journal of Virology 80, no. 2 (January 15, 2006): 1038–43. http://dx.doi.org/10.1128/jvi.80.2.1038-1043.2006.
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ABSTRACT Here we report recovery of infectious Marburg virus (MARV) from a full-length cDNA clone. Compared to the wild-type virus, recombinant MARV showed no difference in terms of morphology of virus particles, intracellular distribution in infected cells, and growth kinetics. The nucleocapsid protein VP30 of MARV and Ebola virus (EBOV) contains a Zn-binding motif which is important for the function of VP30 as a transcriptional activator in EBOV, whereas its role for MARV is unclear. It has been reported previously that MARV VP30 is able to support transcription in an EBOV-specific minigenome system. When the Zn-binding motif was destroyed, MARV VP30 was shown to be inactive in the EBOV system. While it was not possible to rescue recombinant MARV when the VP30 plasmid was omitted from transfection, MARV VP30 with a destroyed Zn-binding motif and EBOV VP30 were able to mediate virus recovery. In contrast, rescue of recombinant EBOV was not supported by EBOV VP30 containing a mutated Zn-binding domain.
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Daddario-DiCaprio, Kathleen M., Thomas W. Geisbert, Joan B. Geisbert, Ute Ströher, Lisa E. Hensley, Allen Grolla, Elizabeth A. Fritz, Friederike Feldmann, Heinz Feldmann, and Steven M. Jones. "Cross-Protection against Marburg Virus Strains by Using a Live, Attenuated Recombinant Vaccine." Journal of Virology 80, no. 19 (October 1, 2006): 9659–66. http://dx.doi.org/10.1128/jvi.00959-06.
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ABSTRACT Marburg virus (MARV) has been associated with sporadic episodes of hemorrhagic fever, including a recent highly publicized outbreak in Angola that produced severe disease and significant mortality in infected patients. MARV is also considered to have potential as a biological weapon. Recently, we reported the development of a promising attenuated, replication-competent vaccine against MARV based on recombinant vesicular stomatitis virus (VSV) expressing the glycoprotein of the Musoke strain of MARV (VSVΔG/MARVGP-Musoke). We used this vaccine to demonstrate complete protection of cynomolgus monkeys against a homologous MARV challenge. While these results are highly encouraging, an effective vaccine would need to confer protection against all relevant strains of MARV. Here, we evaluated the protective efficacy of the VSVΔG/MARVGP-Musoke vaccine against two heterologous MARV strains, the seemingly more pathogenic Angola strain and the more distantly related Ravn strain. In this study, seven cynomolgus monkeys were vaccinated with the VSVΔG/MARVGP-Musoke vector. Three of these animals were challenged with the Angola strain, three with the Ravn strain, and a single animal with the Musoke strain of MARV. Two animals served as controls and were each injected with a nonspecific VSV vector; these controls were challenged with the Angola and Ravn strains, respectively. Both controls succumbed to challenge by day 8. However, none of the specifically vaccinated animals showed any evidence of illness either from the vaccination or from the MARV challenges and all of these animals survived. These data suggest that the VSVΔG/MARVGP-Musoke vaccine should be sufficient to protect against all known MARV strains.
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Warfield, Kelly L., Steven B. Bradfute, Jay Wells, Loreen Lofts, Meagan T. Cooper, D. Anthony Alves, Daniel K. Reed, Sean A. VanTongeren, Christine A. Mech, and Sina Bavari. "Development and Characterization of a Mouse Model for Marburg Hemorrhagic Fever." Journal of Virology 83, no. 13 (April 15, 2009): 6404–15. http://dx.doi.org/10.1128/jvi.00126-09.
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ABSTRACT The lack of a mouse model has hampered an understanding of the pathogenesis and immunity of Marburg hemorrhagic fever (MHF), the disease caused by marburgvirus (MARV), and has created a bottleneck in the development of antiviral therapeutics. Primary isolates of the filoviruses, i.e., ebolavirus (EBOV) and MARV, are not lethal to immunocompetent adult mice. Previously, pathological, virologic, and immunologic evaluation of a mouse-adapted EBOV, developed by sequential passages in suckling mice, identified many similarities between this model and EBOV infections in nonhuman primates. We recently demonstrated that serially passaging virus recovered from the liver homogenates of MARV-infected immunodeficient (SCID) mice was highly successful in reducing the time to death in these mice from 50 to 70 days to 7 to 10 days after challenge with the isolate MARV-Ci67, -Musoke, or -Ravn. In this study, we extended our findings to show that further sequential passages of MARV-Ravn in immunocompetent mice caused the MARV to kill BALB/c mice. Serial sampling studies to characterize the pathology of mouse-adapted MARV-Ravn revealed that this model is similar to the guinea pig and nonhuman primate MHF models. Infection of BALB/c mice with mouse-adapted MARV-Ravn caused uncontrolled viremia and high viral titers in the liver, spleen, lymph node, and other organs; profound lymphopenia; destruction of lymphocytes within the spleen and lymph nodes; and marked liver damage and thrombocytopenia. Sequencing the mouse-adapted MARV-Ravn strain revealed differences in 16 predicted amino acids from the progenitor virus, although the exact changes required for adaptation are unclear at this time. This mouse-adapted MARV strain can now be used to develop and evaluate novel vaccines and therapeutics and may also help to provide a better understanding of the virulence factors associated with MARV.
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Fowler, Trent, Sandra Bamberg, Peggy Möller, Hans-Dieter Klenk, Thomas F. Meyer, Stephan Becker, and Thomas Rudel. "Inhibition of Marburg virus protein expression and viral release by RNA interference." Journal of General Virology 86, no. 4 (April 1, 2005): 1181–88. http://dx.doi.org/10.1099/vir.0.80622-0.
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High mortality rates and lack of an available vaccine against Marburg haemorrhagic fever (MHF) highlight the need for a defensive therapy against MHF and greater knowledge of the causative agent, the Marburg virus (MARV). Here, RNA interference (RNAi) is employed to destroy MARV transcripts, disrupting replication and allowing analysis of various roles of MARV proteins. Small interfering RNAs (siRNAs) homologous to three MARV transcripts (NP, VP35 and VP30) were co-transfected into cells with plasmids encoding the corresponding nucleocapsid proteins. The resulting decrease in MARV nucleocapsid-protein levels was shown to be specific, as siRNA that was not homologous to the MARV genome did not decrease the levels of viral nucleocapsid proteins. Additionally, transcript levels of double-stranded RNA (dsRNA)-sensor proteins, the dsRNA-activated protein kinase and 2′,5′-oligoadenylate synthetase 1 remained unchanged, suggesting that the decrease in viral proteins was not a result of activation of the antiviral properties of the interferon system. Subsequently, siRNAs were shown to reduce intracellular viral proteins in MARV-infected cells and viral material released into the medium. Targeted reduction of VP30 downregulated the intracellular levels of all other viral proteins, suggesting that VP30 plays an essential role for transcription/replication. The efficient reduction of MARV replication also suggests that RNAi may provide an agent against MHF.
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Polezhaeva, O. A., A. V. Zybkina, A. V. Zaikovskaya, O. V. P’yankov, S. A. P’yankov, A. V. Semenova, G. V. Semenova, and D. N. Shcherbakov. "Preparation of Class Y Immunoglobulins that Neutralize the Marburg Virus." Problems of Particularly Dangerous Infections, no. 4 (February 7, 2021): 86–91. http://dx.doi.org/10.21055/0370-1069-2020-4-86-91.
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The aim was to study the possibility of inducing Marburg-neutralizing chicken antibodies (MARV) using various immunogens.Materials and methods. Recombinant vaccinia virus expressing the surface glycoprotein (GP) transgene MARV of Musoke strain and pseudovirus particles exhibiting GP of three strains of MARV – Popp, Musoke and DRC2000 based on lentivirus and recombinant strain of vesicular stomatitis virus (VSV) were used as immunogens. Two groups of birds were involved in the study. Chickens were immunized 9 times: first time they were injected with the recombinant vaccinia virus, and then 8 times – with pseudovirus particles (based on lentivirus and a recombinant strain of the vesicular stomatitis virus). The accumulation of specific antibodies was evaluated by enzyme-linked immunosorbent assay (ELISA). We used recombinant VSV exhibiting GP MARV, and natural MARV strain Popp for the analysis of accumulation of neutralizing antibodies.Results and discussion. We have developed an effective immunization schedule for chickens with three recombinant constructs presenting GP MARV, which results in the induction of chicken IgY antibodies against Marburg virus with a titer in ELISA from 1:100 to 1:1 million. The obtained IgY neutralize MARV pseudoviruses (Popp, DRC2000, Musoke) at a dilution of 1/256 to 1/1024 and the natural MARV virus of the Popp strain at a dilution of 1/8. More stable results were demonstrated by immunization using Freund’s incomplete adjuvant.
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Arnold, Catherine, Jonathan Guito, Louis Altamura, Sean Lovett, Elyse Nagle, Gustavo Palacios, Mariano Sanchez-Lockhart, and Jonathan Towner. "Transcriptomics Reveal Antiviral Gene Induction in the Egyptian Rousette Bat Is Antagonized In Vitro by Marburg Virus Infection." Viruses 10, no. 11 (November 2, 2018): 607. http://dx.doi.org/10.3390/v10110607.
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The Egyptian rousette bat (ERB) is the only known Marburg virus (MARV) reservoir host. ERBs develop a productive MARV infection with low viremia and shedding but no overt disease, suggesting this virus is efficiently controlled by ERB antiviral responses. This dynamic would contrast with humans, where MARV-mediated interferon (IFN) antagonism early in infection is thought to contribute to the severe, often fatal disease. The newly-annotated ERB genome and transcriptome have now enabled us to use a custom-designed NanoString nCounter ERB CodeSet in conjunction with RNA-seq to investigate responses in a MARV-infected ERB cell line. Both transcriptomic platforms correlated well and showed that MARV inhibited the antiviral program in ERB cells, while an IFN antagonism-impaired MARV was less efficient at suppressing the response gene induction, phenotypes previously reported for primate cells. Interestingly, and despite the expansion of IFN loci in the ERB genome, neither MARV showed specific induction of almost any IFN gene. However, we detected an upregulation of putative, unannotated ERB antiviral paralogs, as well as an elevated basal expression in uninfected ERB cells of key antiviral genes.
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Hamilton Spence, Erin, Monica Huff, Karen Shattuck, Amy Vickers, Nadezda Yun, and Slobodan Paessler. "Ebola Virus and Marburg Virus in Human Milk Are Inactivated by Holder Pasteurization." Journal of Human Lactation 33, no. 2 (January 30, 2017): 351–54. http://dx.doi.org/10.1177/0890334416685564.
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Background: Potential donors of human milk are screened for Ebola virus (EBOV) using standard questions, but testing for EBOV and Marburg virus (MARV) is not part of routine serological testing performed by milk banks. Research aim: This study tested the hypothesis that EBOV would be inactivated in donor human milk (DHM) by standard pasteurization techniques (Holder) used in all North American nonprofit milk banks. Methods: Milk samples were obtained from a nonprofit milk bank. They were inoculated with EBOV (Zaire strain) and MARV (Angola strain) and processed by standard Holder pasteurization technique. Plaque assays for EBOV and MARV were performed to detect the presence of virus after pasteurization. Results: Neither EBOV nor MARV was detectable by viral plaque assay in DHM or culture media samples, which were pasteurized by the Holder process. Conclusion: EBOV and MARV are safely inactivated in human milk by standard Holder pasteurization technique. Screening for EBOV or MARV beyond questionnaire and self-deferral is not needed to ensure safety of DHM for high-risk infants.
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Saito, Takeshi, Junki Maruyama, Noriyo Nagata, Mao Isono, Kosuke Okuya, Yoshihiro Takadate, Yurie Kida, et al. "A Surrogate Animal Model for Screening of Ebola and Marburg Glycoprotein-Targeting Drugs Using Pseudotyped Vesicular Stomatitis Viruses." Viruses 12, no. 9 (August 22, 2020): 923. http://dx.doi.org/10.3390/v12090923.
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Filoviruses, including Ebola virus (EBOV) and Marburg virus (MARV), cause severe hemorrhagic fever in humans and nonhuman primates with high mortality rates. There is no approved therapy against these deadly viruses. Antiviral drug development has been hampered by the requirement of a biosafety level (BSL)-4 facility to handle infectious EBOV and MARV because of their high pathogenicity to humans. In this study, we aimed to establish a surrogate animal model that can be used for anti-EBOV and -MARV drug screening under BSL-2 conditions by focusing on the replication-competent recombinant vesicular stomatitis virus (rVSV) pseudotyped with the envelope glycoprotein (GP) of EBOV (rVSV/EBOV) and MARV (rVSV/MARV), which has been investigated as vaccine candidates and thus widely used in BSL-2 laboratories. We first inoculated mice, rats, and hamsters intraperitoneally with rVSV/EBOV and found that only hamsters showed disease signs and succumbed within 4 days post-infection. Infection with rVSV/MARV also caused lethal infection in hamsters. Both rVSV/EBOV and rVSV/MARV were detected at high titers in multiple organs including the liver, spleen, kidney, and lungs of infected hamsters, indicating acute and systemic infection resulting in fatal outcomes. Therapeutic effects of passive immunization with an anti-EBOV neutralizing antibody were specifically observed in rVSV/EBOV-infected hamsters. Thus, this animal model is expected to be a useful tool to facilitate in vivo screening of anti-filovirus drugs targeting the GP molecule.
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Enterlein, Sven, Kristina M. Schmidt, Michael Schümann, Dominik Conrad, Verena Krähling, Judith Olejnik, and Elke Mühlberger. "The Marburg Virus 3′ Noncoding Region Structurally and Functionally Differs from That of Ebola Virus." Journal of Virology 83, no. 9 (February 18, 2009): 4508–19. http://dx.doi.org/10.1128/jvi.02429-08.
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ABSTRACT We have previously shown that the first transcription start signal (TSS) of Zaire Ebola virus (ZEBOV) is involved in formation of an RNA secondary structure regulating VP30-dependent transcription activation. Interestingly, transcription of Marburg virus (MARV) minigenomes occurs independently of VP30. In this study, we analyzed the structure of the MARV 3′ noncoding region and its influence on VP30 necessity. Secondary structure formation of the TSS of the first gene was experimentally determined and showed substantial differences from the structure formed by the ZEBOV TSS. Chimeric MARV minigenomes mimicking the ZEBOV-specific RNA secondary structure were neither transcribed nor replicated. Mapping of the MARV genomic replication promoter revealed that the region homologous to the sequence involved in formation of the regulatory ZEBOV RNA structure is part of the MARV promoter. The MARV promoter is contained within the first 70 nucleotides of the genome and consists of two elements separated by a spacer region, comprising the TSS of the first gene. Mutations within the spacer abolished transcription activity and led to increased replication, indicating competitive transcription and replication initiation. The second promoter element is located within the nontranslated region of the first gene and consists of a stretch of three UN5 hexamers. Recombinant full-length MARV clones, in which the three conserved U residues were substituted, could not be rescued, underlining the importance of the UN5 hexamers for replication activity. Our data suggest that differences in the structure of the genomic replication promoters might account for the different transcription strategies of Marburg and Ebola viruses.
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Vanmechelen, Bert, Joren Stroobants, Kurt Vermeire, and Piet Maes. "Development of a T7-Independent MARV Minigenome System." Proceedings 50, no. 1 (June 9, 2020): 27. http://dx.doi.org/10.3390/proceedings2020050027.
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Marburg virus (MARV) is the only known pathogenic filovirus that does not belong to the genus Ebolavirus. It causes a severe hemorrhagic fever that is associated with a high mortality rate (>80%). The potential for filoviruses to cause devastating outbreaks, in combination with the lack of licensed therapeutics and vaccines for Marburg virus disease, illustrates the need for more MARV research. However, research involving MARV is hindered by its dependency on access to high-containment laboratories. Virus alternatives such as minigenomes have proven to be a useful tool to study virus replication and transcription at lower biosafety levels, and can be used for antiviral compound screening. All currently available MARV minigenomes are dependent on the addition of an ectopic T7 RNA polymerase that can drive minigenome expression. While this allows for high expression levels, the ectopic expression of a T7 polymerase is not feasible in all cell types, and acts as a confounding factor in compound screening assays. We have developed an alternative MARV minigenome system that is controlled by an RNA polymerase II promoter, which is natively expressed in most mammalian cell types. We show here that this novel minigenome can be used in a wide range of cell types, and can be easily amended to a 96-well format to be used for high-throughput compound screening, thereby providing a valuable alternative to previously developed MARV minigenomes.
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Wijesinghe, Kaveesha J., and Robert V. Stahelin. "Investigation of the Lipid Binding Properties of the Marburg Virus Matrix Protein VP40." Journal of Virology 90, no. 6 (December 30, 2015): 3074–85. http://dx.doi.org/10.1128/jvi.02607-15.
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ABSTRACTMarburg virus (MARV), which belongs to the virus familyFiloviridae, causes hemorrhagic fever in humans and nonhuman primates that is often fatal. MARV is a lipid-enveloped virus that during the replication process extracts its lipid coat from the plasma membrane of the host cell it infects. MARV carries seven genes, one of which encodes its matrix protein VP40 (mVP40), which regulates the assembly and budding of the virions. Currently, little information is available on mVP40 lipid binding properties. Here, we have investigated thein vitroand cellular mechanisms by which mVP40 associates with lipid membranes. mVP40 associates with anionic membranes in a nonspecific manner that is dependent upon the anionic charge density of the membrane. These results are consistent with recent structural determination of mVP40, which elucidated an mVP40 dimer with a flat and extensive cationic lipid binding interface.IMPORTANCEMarburg virus (MARV) is a lipid-enveloped filamentous virus from the familyFiloviridae. MARV was discovered in 1967, and yet little is known about how its seven genes are used to assemble and form a new viral particle in the host cell it infects. The MARV matrix protein VP40 (mVP40) underlies the inner leaflet of the virus and regulates budding from the host cell plasma membrane.In vitroand cellular assays in this study investigated the mechanism by which mVP40 associates with lipids. The results demonstrate that mVP40 interactions with lipid vesicles or the inner leaflet of the plasma membrane are electrostatic but nonspecific in nature and are dependent on the anionic charge density of the membrane surface. Small molecules that can disrupt lipid trafficking or reduce the anionic charge of the plasma membrane interface may be useful in inhibiting assembly and budding of MARV.
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Freydank, Helmut. "MARV IV 119 – ein Vertrag?" Altorientalische Forschungen 39, no. 2 (December 2012): 226–34. http://dx.doi.org/10.1524/aofo.2012.0015.
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Gosse, Van. "Remembering and Honoring Marv Gettleman." Radical History Review 2017, no. 129 (October 2017): 197–98. http://dx.doi.org/10.1215/01636545-4187098.
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Koch, Benjamin, Patricia Schult-Dietrich, Stefan Büttner, Bijan Dilmaghani, Dario Lohmann, Patrick C. Baer, Ursula Dietrich, and Helmut Geiger. "Lectin Affinity Plasmapheresis for Middle East Respiratory Syndrome-Coronavirus and Marburg Virus Glycoprotein Elimination." Blood Purification 46, no. 2 (2018): 126–33. http://dx.doi.org/10.1159/000487224.
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Background/Aims: Middle East respiratory syndrome coronavirus (MERS-CoV) and Marburg virus (MARV) are among the World Health Organization’s top 8 emerging pathogens. Both zoonoses share nonspecific early symptoms, a high lethality rate, and a reduced number of specific treatment options. Therefore, we evaluated extracorporeal virus and glycoprotein (GP) elimination by lectin affinity plasmapheresis (LAP). Methods: For both MERS-CoV (pseudovirus) as well as MARV (GPs), 4 LAP devices (Mini Hemopurifiers, Aethlon Medical, San Diego, CA, USA) and 4 negative controls were tested. Samples were collected every 30 min and analyzed for reduction in virus infectivity by a flow cytometry-based infectivity assay (MERS-CoV) and in soluble GP content (MARV) by an immunoassay. Results: The experiments show a time-dependent clearance of MERS-CoV of up to 80% within 3 h (pseudovirus). Up to 70% of MARV-soluble GPs were eliminated at the same time. Substantial saturation of the binding resins was detected within the first treatment hour. Conclusion: MERS-CoV (pseudovirus) and MARV soluble GPs are eliminated by LAP in vitro. Considering the high lethality and missing established treatment options, LAP should be evaluated in vivo. Especially early initiation, continuous therapy, and timed cartridge exchanges could be of importance.
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Stonier, Spencer W., Andrew S. Herbert, Ana I. Kuehne, Ariel Sobarzo, Polina Habibulin, Chen V. Abramovitch Dahan, Rebekah M. James, et al. "Marburg virus survivor immune responses are Th1 skewed with limited neutralizing antibody responses." Journal of Experimental Medicine 214, no. 9 (July 19, 2017): 2563–72. http://dx.doi.org/10.1084/jem.20170161.
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Until recently, immune responses in filovirus survivors remained poorly understood. Early studies revealed IgM and IgG responses to infection with various filoviruses, but recent outbreaks have greatly expanded our understanding of filovirus immune responses. Immune responses in survivors of Ebola virus (EBOV) and Sudan virus (SUDV) infections have provided the most insight, with T cell responses as well as detailed antibody responses having been characterized. Immune responses to Marburg virus (MARV), however, remain almost entirely uncharacterized. We report that immune responses in MARV survivors share characteristics with EBOV and SUDV infections but have some distinct differences. MARV survivors developed multivariate CD4+ T cell responses but limited CD8+ T cell responses, more in keeping with SUDV survivors than EBOV survivors. In stark contrast to SUDV survivors, rare neutralizing antibody responses in MARV survivors diminished rapidly after the outbreak. These results warrant serious consideration for any vaccine or therapeutic that seeks to be broadly protective, as different filoviruses may require different immune responses to achieve immunity.
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Oda, Shun-ichiro, Takeshi Noda, Kaveesha J. Wijesinghe, Peter Halfmann, Zachary A. Bornholdt, Dafna M. Abelson, Tammy Armbrust, Robert V. Stahelin, Yoshihiro Kawaoka, and Erica Ollmann Saphire. "Crystal Structure of Marburg Virus VP40 Reveals a Broad, Basic Patch for Matrix Assembly and a Requirement of the N-Terminal Domain for Immunosuppression." Journal of Virology 90, no. 4 (December 9, 2015): 1839–48. http://dx.doi.org/10.1128/jvi.01597-15.
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ABSTRACTMarburg virus (MARV), a member of the filovirus family, causes severe hemorrhagic fever with up to 90% lethality. MARV matrix protein VP40 is essential for assembly and release of newly copied viruses and also suppresses immune signaling in the infected cell. Here we report the crystal structure of MARV VP40. We found that MARV VP40 forms a dimer in solution, mediated by N-terminal domains, and that formation of this dimer is essential for budding of virus-like particles. We also found the N-terminal domain to be necessary and sufficient for immune antagonism. The C-terminal domains of MARV VP40 are dispensable for immunosuppression but are required for virus assembly. The C-terminal domains are only 16% identical to those of Ebola virus, differ in structure from those of Ebola virus, and form a distinct broad and flat cationic surface that likely interacts with the cell membrane during virus assembly.IMPORTANCEMarburg virus, a cousin of Ebola virus, causes severe hemorrhagic fever, with up to 90% lethality seen in recent outbreaks. Molecular structures and visual images of the proteins of Marburg virus are essential for the development of antiviral drugs. One key protein in the Marburg virus life cycle is VP40, which both assembles the virus and suppresses the immune system. Here we provide the molecular structure of Marburg virus VP40, illustrate differences from VP40 of Ebola virus, and reveal surfaces by which Marburg VP40 assembles progeny and suppresses immune function.
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Mckinnon, John, Zachary Osborn, Tom Taylor, Jun Ying Zhou, Danijela Lucic, Katelyn Clark, Katrina Williams, and Linoj Samuel. "Comparison of Roche TaqMan v.2.0, Abbott RealTime and Modified Abbott Residual Viremia Assays in Testing of Routine Samples for Viremia Monitoring in HIV Care." Open Forum Infectious Diseases 4, suppl_1 (2017): S359. http://dx.doi.org/10.1093/ofid/ofx163.872.
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Abstract Background Routine HIV RNA clinical monitoring frequently reports virermia (VL) as detectable, quantifiable <50 or blips >50 c/mL. To assess whether the results represent true increases or just assay variability, we designed comparisons of the Roche COBAS AmpliPrep / COBAS TaqMan HIV-1 Test version 2.0 (TM) and the Abbott RealTime HIV-1 assay (RT) to a residual viremia (RV) assay with a limit of detection of 3 c/mL, the Modified Abbott Residual Viremia assay (MARV). Methods HIV suppressed patients on stable therapy presenting for routine visits at the HIV clinic in Henry Ford Hospital (HFH) were prospectively enrolled. Blood samples and questionnaires were obtained at each visit. Paired plasma samples were processed and analyzed per manufacturer instructions; HFH clinical laboratory processed the samples using the TM assay and the McKinnon Research Laboratory performed the FDA approved RT assay and RV testing using the MARV assay. Parametric and non-parametric analyses were conducted as indicated. Results 124 HIV patients are reported with a mean age of 51, mostly male (84%) and African American (64%). Mean CD4 cell counts were 661 cells/mm3. TM assay results for 196 plasma samples were not detectable (ND) 119 (61%), detectable (DT) 61 (31%) and quantifiable viremia (QV) >20 c/mL 16 (8%). 5 patients had QV over 50 c/mL. 60 tested patients (49.5%) had at least one sample either DT or QV. TM results were not correlated to CD4 cell counts, antiretrovirals, medical conditions or reported adherence (avg. 97%). 174 RT and 187 MARV paired tests were ND on 142 (81%) / 121 (65%), DT on 34 (17%) RT, and quantifiable in 0% / 34 (33%) of the samples respectively. Higher VL detection by the TM was shown compared with the RT (P = 0.005) and MARV (P < 0.001) assays. Mean QV by the MARV was 5.0 vs.. 55 c/mL on the TM assay (P < 0.001). VL for all assays trends correlated when compared for ND, DT and >20 copies/mL (P < 0.001). Bland-Altman plots show higher VL detected by TM as compared with MARV (P < 0.001) and good correlation between RT and MARV assays (P = 0.6). Conclusion HIV viremia is more frequently reported by TM assay as compared with the RT assay and was significantly higher than VL detected by the MARV assay. Over detection of VL by the TM assay may impact clinical decision making and increase cost of care. Disclosures J. Mckinnon, Abbott Molecular: Speaker’s Bureau, Grant recipient, Research grant and Speaker honorarium D. Lucic, Abbott Molecular: Employee, Salary
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Geisbert, Thomas W., Michael Bailey, Joan B. Geisbert, Clement Asiedu, Mario Roederer, Maria Grazia-Pau, Jerome Custers, et al. "Vector Choice Determines Immunogenicity and Potency of Genetic Vaccines against Angola Marburg Virus in Nonhuman Primates." Journal of Virology 84, no. 19 (July 21, 2010): 10386–94. http://dx.doi.org/10.1128/jvi.00594-10.
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ABSTRACT The immunogenicity and durability of genetic vaccines are influenced by the composition of gene inserts and choice of delivery vector. DNA vectors are a promising vaccine approach showing efficacy when combined in prime-boost regimens with recombinant protein or viral vectors, but they have shown limited comparative efficacy as a stand-alone platform in primates, due possibly to suboptimal gene expression or cell targeting. Here, regimens using DNA plasmids modified for optimal antigen expression and recombinant adenovirus (rAd) vectors, all encoding the glycoprotein (GP) gene from Angola Marburg virus (MARV), were compared for their ability to provide immune protection against lethal MARV Angola infection. Heterologous DNA-GP/rAd5-GP prime-boost and single-modality rAd5-GP, as well as the DNA-GP-only vaccine, prevented death in all vaccinated subjects after challenge with a lethal dose of MARV Angola. The DNA/DNA vaccine induced humoral responses comparable to those induced by a single inoculation with rAd5-GP, as well as CD4+ and CD8+ cellular immune responses, with skewing toward CD4+ T-cell activity against MARV GP. Vaccine regimens containing rAd-GP, alone or as a boost, exhibited cellular responses with CD8+ T-cell dominance. Across vaccine groups, CD8+ T-cell subset dominance comprising cells exhibiting a tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ) double-positive functional phenotype was associated with an absence or low frequency of clinical symptoms, suggesting that both the magnitude and functional phenotype of CD8+ T cells may determine vaccine efficacy against infection by MARV Angola.
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Kajihara, Masahiro, Eri Nakayama, Andrea Marzi, Manabu Igarashi, Heinz Feldmann, and Ayato Takada. "Novel mutations in Marburg virus glycoprotein associated with viral evasion from antibody mediated immune pressure." Journal of General Virology 94, no. 4 (April 1, 2013): 876–83. http://dx.doi.org/10.1099/vir.0.049114-0.
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Marburg virus (MARV) and Ebola virus, members of the family Filoviridae, cause lethal haemorrhagic fever in humans and non-human primates. Although the outbreaks are concentrated mainly in Central Africa, these viruses are potential agents of imported infectious diseases and bioterrorism in non-African countries. Recent studies demonstrated that non-human primates passively immunized with virus-specific antibodies were successfully protected against fatal filovirus infection, highlighting the important role of antibodies in protective immunity for this disease. However, the mechanisms underlying potential evasion from antibody mediated immune pressure are not well understood. To analyse possible mutations involved in immune evasion in the MARV envelope glycoprotein (GP) which is the major target of protective antibodies, we selected escape mutants of recombinant vesicular stomatitis virus (rVSV) expressing MARV GP (rVSVΔG/MARVGP) by using two GP-specific mAbs, AGP127-8 and MGP72-17, which have been previously shown to inhibit MARV budding. Interestingly, several rVSVΔG/MARVGP variants escaping from the mAb pressure-acquired amino acid substitutions in the furin-cleavage site rather than in the mAb-specific epitopes, suggesting that these epitopes are recessed, not exposed on the uncleaved GP molecule, and therefore inaccessible to the mAbs. More surprisingly, some variants escaping mAb MGP72-17 lacked a large proportion of the mucin-like region of GP, indicating that these mutants efficiently escaped the selective pressure by deleting the mucin-like region including the mAb-specific epitope. Our data demonstrate that MARV GP possesses the potential to evade antibody mediated immune pressure due to extraordinary structural flexibility and variability.
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Koehler, Alexander, Larissa Kolesnikova, Ulla Welzel, Gordian Schudt, Astrid Herwig, and Stephan Becker. "A Single Amino Acid Change in the Marburg Virus Matrix Protein VP40 Provides a Replicative Advantage in a Species-Specific Manner." Journal of Virology 90, no. 3 (November 18, 2015): 1444–54. http://dx.doi.org/10.1128/jvi.02670-15.
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ABSTRACTMarburg virus (MARV) induces severe hemorrhagic fever in humans and nonhuman primates but only transient nonlethal disease in rodents. However, sequential passages of MARV in rodents boosts infection leading to lethal disease. Guinea pig-adapted MARV contains one mutation in the viral matrix protein VP40 at position 184 (VP40D184N). The contribution of the D184N mutation to the efficacy of replication in a new host is unknown. In the present study, we demonstrated that recombinant MARV containing the D184N mutation in VP40 [rMARVVP40(D184N)] grew to higher titers than wild-type recombinant MARV (rMARVWT) in guinea pig cells. Moreover, rMARVVP40(D184N)displayed higher infectivity in guinea pig cells. Comparative analysis of VP40 functions indicated that neither the interferon (IFN)-antagonistic function nor the membrane binding capabilities of VP40 were affected by the D184N mutation. However, the production of VP40-induced virus-like particles (VLPs) and the recruitment of other viral proteins to the budding site was improved by the D184N mutation in guinea pig cells, which resulted in the higher infectivity of VP40D184N-induced infectious VLPs (iVLPs) compared to that of VP40-induced iVLPs. In addition, the function of VP40 in suppressing viral RNA synthesis was influenced by the D184N mutation specifically in guinea pig cells, thus allowing greater rates of transcription and replication. Our results showed that the improved viral fitness of rMARVVP40(D184N)in guinea pig cells was due to the better viral assembly function of VP40D184Nand its lower inhibitory effect on viral transcription and replication rather than modulation of the VP40-mediated suppression of IFN signaling.IMPORTANCEThe increased virulence achieved by virus passaging in a new host was accompanied by mutations in the viral genome. Analyzing how these mutations affect the functions of viral proteins and the ability of the virus to grow within new host cells helps in the understanding of the molecular mechanisms increasing virulence. Using a reverse genetics approach, we demonstrated that a single mutation in MARV VP40 detected in a guinea pig-adapted MARV provided a replicative advantage of rMARVVP40(D184N)in guinea pig cells. Our studies show that this replicative advantage of rMARV VP40D184Nwas based on the improved functions of VP40 in iVLP assembly and in the regulation of transcription and replication rather than on the ability of VP40 to combat the host innate immunity.
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Khodzhaniyazov, Tirkish, and Luke Treadwell. "The Marv Hoard of Early Islamic Dirhams." Iran 36 (1998): 85. http://dx.doi.org/10.2307/4299977.
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Marzi, Andrea, Thomas Gramberg, Graham Simmons, Peggy Möller, Andrew J. Rennekamp, Mandy Krumbiegel, Martina Geier, et al. "DC-SIGN and DC-SIGNR Interact with the Glycoprotein of Marburg Virus and the S Protein of Severe Acute Respiratory Syndrome Coronavirus." Journal of Virology 78, no. 21 (November 1, 2004): 12090–95. http://dx.doi.org/10.1128/jvi.78.21.12090-12095.2004.
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ABSTRACT The lectins DC-SIGN and DC-SIGNR can augment viral infection; however, the range of pathogens interacting with these attachment factors is incompletely defined. Here we show that DC-SIGN and DC-SIGNR enhance infection mediated by the glycoprotein (GP) of Marburg virus (MARV) and the S protein of severe acute respiratory syndrome coronavirus and might promote viral dissemination. SIGNR1, a murine DC-SIGN homologue, also enhanced infection driven by MARV and Ebola virus GP and could be targeted to assess the role of attachment factors in filovirus infection in vivo.
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Cheng, Han, Calli M. Lear-Rooney, Lisa Johansen, Elizabeth Varhegyi, Zheng W. Chen, Gene G. Olinger, and Lijun Rong. "Inhibition of Ebola and Marburg Virus Entry by G Protein-Coupled Receptor Antagonists." Journal of Virology 89, no. 19 (July 22, 2015): 9932–38. http://dx.doi.org/10.1128/jvi.01337-15.
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ABSTRACTFiloviruses, consisting of Ebola virus (EBOV) and Marburg virus (MARV), are among the most lethal infectious threats to mankind. Infections by these viruses can cause severe hemorrhagic fevers in humans and nonhuman primates with high mortality rates. Since there is currently no vaccine or antiviral therapy approved for humans, there is an urgent need to develop prophylactic and therapeutic options for use during filoviral outbreaks and bioterrorist attacks. One of the ideal targets against filoviral infection and diseases is at the entry step, which is mediated by the filoviral glycoprotein (GP). In this report, we screened a chemical library of small molecules and identified numerous inhibitors, which are known G protein-coupled receptor (GPCR) antagonists targeting different GPCRs, including histamine receptors, 5-HT (serotonin) receptors, muscarinic acetylcholine receptor, and adrenergic receptor. These inhibitors can effectively block replication of both infectious EBOV and MARV, indicating a broad antiviral activity of the GPCR antagonists. The time-of-addition experiment and microscopic studies suggest that GPCR antagonists block filoviral entry at a step following the initial attachment but prior to viral/cell membrane fusion. These results strongly suggest that GPCRs play a critical role in filoviral entry and GPCR antagonists can be developed as an effective anti-EBOV/MARV therapy.IMPORTANCEInfection of Ebola virus and Marburg virus can cause severe illness in humans with a high mortality rate, and currently there is no FDA-approved vaccine or therapeutic treatment available. The 2013-2015 epidemic in West Africa underscores a lack of our understanding in the infection and pathogenesis of these viruses and the urgency of drug discovery and development. In this study, we have identified numerous inhibitors that are known G protein-coupled receptor (GPCR) antagonists targeting different GPCRs. These inhibitors can effectively block replication of both infectious EBOV and MARV, indicating a broad antiviral activity of the GPCR antagonists. Our results strongly suggest that GPCRs play a critical role in filoviral entry and GPCR antagonists can be developed as an effective anti-EBOV/MARV therapy.
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Kash, John C., Elke Mühlberger, Victoria Carter, Melanie Grosch, Olivia Perwitasari, Sean C. Proll, Matthew J. Thomas, Friedemann Weber, Hans-Dieter Klenk, and Michael G. Katze. "Global Suppression of the Host Antiviral Response by Ebola- and Marburgviruses: Increased Antagonism of the Type I Interferon Response Is Associated with Enhanced Virulence." Journal of Virology 80, no. 6 (March 15, 2006): 3009–20. http://dx.doi.org/10.1128/jvi.80.6.3009-3020.2006.
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ABSTRACT We studied the effect of filovirus infection on host cell gene expression by characterizing the regulation of gene expression responses in human liver cells infected with Zaire Ebolavirus (ZEBOV), Reston Ebolavirus (REBOV), and Marburgvirus (MARV), using transcriptional profiling and bioinformatics. Expression microarray analysis demonstrated that filovirus infection resulted in the up-regulation of immune-related genes and the down-regulation of many coagulation and acute-phase proteins. These studies further revealed that a common feature of filovirus virulence is suppression of key cellular antiviral responses, including TLR-, interferon (IFN) regulatory factor 3-, and PKR-related pathways. We further showed that ZEBOV and MARV were more potent antagonists of the IFN response and inhibited the expression of most of the IFN-stimulated genes (ISGs) observed in mock-infected IFN-α-2b treated cells, compared to REBOV infection, which activated more than 20% of these ISGs. Finally, we examined IFN-related gene expression in filovirus-infected cells treated with IFN-α-2b. These experiments revealed that a majority of genes induced in mock-infected cells treated with type I IFN were antagonized in treated ZEBOV- and MARV-infected cells, while in contrast, REBOV infection resulted in a significant increase in ISG expression. Analysis of STAT1 and -2 phosphorylation following IFN treatment showed a significant reduction of STAT phosphorylation for MARV but not for ZEBOV and REBOV, indicating that different mechanisms might be involved in antagonizing IFN signaling pathways by the different filovirus species. Taken together, these studies showed a correlation between antagonism of type I IFN responses and filovirus virulence.
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Kolesnikova, Larissa, Beate Berghöfer, Sandra Bamberg, and Stephan Becker. "Multivesicular Bodies as a Platform for Formation of the Marburg Virus Envelope." Journal of Virology 78, no. 22 (November 15, 2004): 12277–87. http://dx.doi.org/10.1128/jvi.78.22.12277-12287.2004.
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ABSTRACT The Marburg virus (MARV) envelope consists of a lipid membrane and two major proteins, the matrix protein VP40 and the glycoprotein GP. Both proteins use different intracellular transport pathways: GP utilizes the exocytotic pathway, while VP40 is transported through the retrograde late endosomal pathway. It is currently unknown where the proteins combine to form the viral envelope. In the present study, we identified the intracellular site where the two major envelope proteins of MARV come together as peripheral multivesicular bodies (MVBs). Upon coexpression with VP40, GP is redistributed from the trans-Golgi network into the VP40-containing MVBs. Ultrastructural analysis of MVBs suggested that they provide the platform for the formation of membrane structures that bud as virus-like particles from the cell surface. The virus-like particles contain both VP40 and GP. Single expression of GP also resulted in the release of particles, which are round or pleomorphic. Single expression of VP40 led to the release of filamentous structures that closely resemble viral particles and contain traces of endosomal marker proteins. This finding indicated a central role of VP40 in the formation of the filamentous structure of MARV particles, which is similar to the role of the related Ebola virusVP40. In MARV-infected cells, VP40 and GP are colocalized in peripheral MVBs as well. Moreover, intracellular budding of progeny virions into MVBs was frequently detected. Taken together, these results demonstrate an intracellular intersection between GP and VP40 pathways and suggest a crucial role of the late endosomal compartment for the formation of the viral envelope.
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Volkova, N. V., A. V. Ivanova, A. A. Isaeva, O. A. Polezhaeva, A. V. Zaykovskaya, D. N. Shcherbakov, and E. I. Kazachinskaya. "Obtaining Recombinant Antigens for the Development of Serological Diagnosis of Marburg Fever." Problems of Particularly Dangerous Infections, no. 4 (February 7, 2021): 47–52. http://dx.doi.org/10.21055/0370-1069-2020-4-47-52.
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Aim. Production of recombinant viral antigens of the main immunodominant proteins: glycoprotein (GPΔMLD), nucleoprotein (NP) and matrix protein (VP40) of the Marburg virus, as well as the study of their antigenic and immunogenic properties.Materials and methods. To create recombinant proteins GPΔMLD, NP and VP40 of the Marburg virus, synthesized nucleotide sequences encoding these proteins cloned into the pET21a expression vector were used. The immunogenic and antigenic properties of the obtained recombinant proteins were tested using a number of biomodels (mice, chickens, and guinea pigs).Results and discussion. Recombinant plasmids containing genes encoding proteins GPΔMLD, NP, VP40 of the Marburg virus, as well as Escherichia coli producing strains, with the yield of purified preparations of recombinant proteins GPΔMLD, NP, VP40 from one liter of culture fluid – 5, 10, and 10 μg were obtained, respectively. When mice are immunized, recombinant proteins GP, NP, and VP40 MARV induce the synthesis of high titer antibodies (recombinant proteins NP and VP40 – more than 409600, and recombinant protein GPΔMLD – 12800). Mouse antibodies specific to recombinant proteins interact in an enzyme-linked immunosorbent assay (ELISA) with the antigen of inactivated MARV. Antibodies of chickens immunized with virus-like particles containing the surface glycoprotein of the Marburg virus and antibodies of guinea pigs immunized with an experimental DNA vaccine containing the GPΔMLD MARV gene recognize the recombinant GPΔMLD protein and the viral protein in the inactivated MARV. The resulting recombinant proteins are immunogenic/antigenic and can be used for the development of enzymelinked immunosorbent assay systems.
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Radoshitzky, Sheli R., Lian Dong, Xiaoli Chi, Jeremiah C. Clester, Cary Retterer, Kevin Spurgers, Jens H. Kuhn, et al. "Infectious Lassa Virus, but Not Filoviruses, Is Restricted by BST-2/Tetherin." Journal of Virology 84, no. 20 (August 4, 2010): 10569–80. http://dx.doi.org/10.1128/jvi.00103-10.
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ABSTRACT Bone marrow stromal antigen 2 (BST-2/tetherin) is a cellular membrane protein that inhibits the release of HIV-1. We show for the first time, using infectious viruses, that BST-2 also inhibits egress of arenaviruses but has no effect on filovirus replication and spread. Specifically, infectious Lassa virus (LASV) release significantly decreased or increased in human cells in which BST-2 was either stably expressed or knocked down, respectively. In contrast, replication and spread of infectious Zaire ebolavirus (ZEBOV) and Lake Victoria marburgvirus (MARV) were not affected by these conditions. Replication of infectious Rift Valley fever virus (RVFV) and cowpox virus (CPXV) was also not affected by BST-2 expression. Elevated cellular levels of human or murine BST-2 inhibited the release of virus-like particles (VLPs) consisting of the matrix proteins of multiple highly virulent NIAID Priority Pathogens, including arenaviruses (LASV and Machupo virus [MACV]), filoviruses (ZEBOV and MARV), and paramyxoviruses (Nipah virus). Although the glycoproteins of filoviruses counteracted the antiviral activity of BST-2 in the context of VLPs, they could not rescue arenaviral (LASV and MACV) VLP release upon BST-2 overexpression. Furthermore, we did not observe colocalization of filoviral glycoproteins with BST-2 during infection with authentic viruses. None of the arenavirus-encoded proteins rescued budding of VLPs in the presence of BST-2. Our results demonstrate that BST-2 might be a broad antiviral factor with the ability to restrict release of a wide variety of human pathogens. However, at least filoviruses, RVFV, and CPXV are immune to its inhibitory effect.
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Fayzullayev, Farrux. "COVERAGE OF UBAYDULLAH'S ACTIVITIES IN HAFIZ TANISH BUKHARI'S "ABDULLANOMA"." JOURNAL OF LOOK TO THE PAST 4, no. 7 (July 30, 2021): 63–71. http://dx.doi.org/10.26739/2181-9599-2021-7-10.
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This article analyzes the work of Hafiz Tanish Bukhari in his work "Abdullanom", which provides information about the history of the 16th century, the activities of Ubaydullah, the master of his time, the great creative ruler of Shaybani, who left an important mark in the history of mankind. history of the Uzbek statehood. The military activities of Ubaydullah and his relationship with Zahiruddin Muhammad Babur and the ruler of Iran Ismail Safavi are highlighted. The source also touches upon Ubaydullah's diplomatic relations with neighboring countries.Index Terms.Shaybanikhan, Abdullanoma, tolgama, sarkard, Koran, Ubaidi, Najmi Soni, Ismail Safavi, Marv, Gijduvan
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Urata, Shuzo, Takeshi Noda, Yoshihiro Kawaoka, Shigeru Morikawa, Hideyoshi Yokosawa, and Jiro Yasuda. "Interaction of Tsg101 with Marburg Virus VP40 Depends on the PPPY Motif, but Not the PT/SAP Motif as in the Case of Ebola Virus, and Tsg101 Plays a Critical Role in the Budding of Marburg Virus-Like Particles Induced by VP40, NP, and GP." Journal of Virology 81, no. 9 (February 14, 2007): 4895–99. http://dx.doi.org/10.1128/jvi.02829-06.
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ABSTRACT Marburg virus (MARV) VP40 is a matrix protein that can be released from mammalian cells in the form of virus-like particles (VLPs) and contains the PPPY sequence, which is an L-domain motif. Here, we demonstrate that the PPPY motif is important for VP40-induced VLP budding and that VLP production is significantly enhanced by coexpression of NP and GP. We show that Tsg101 interacts with VP40 depending on the presence of the PPPY motif, but not the PT/SAP motif as in the case of Ebola virus, and plays an important role in VLP budding. These findings provide new insights into the mechanism of MARV budding.
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Geisbert, Thomas W., Joan B. Geisbert, Anders Leung, Kathleen M. Daddario-DiCaprio, Lisa E. Hensley, Allen Grolla, and Heinz Feldmann. "Single-Injection Vaccine Protects Nonhuman Primates against Infection with Marburg Virus and Three Species of Ebola Virus." Journal of Virology 83, no. 14 (April 22, 2009): 7296–304. http://dx.doi.org/10.1128/jvi.00561-09.
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ABSTRACT The filoviruses Marburg virus and Ebola virus cause severe hemorrhagic fever with high mortality in humans and nonhuman primates. Among the most promising filovirus vaccines under development is a system based on recombinant vesicular stomatitis virus (VSV) that expresses a single filovirus glycoprotein (GP) in place of the VSV glycoprotein (G). Here, we performed a proof-of-concept study in order to determine the potential of having one single-injection vaccine capable of protecting nonhuman primates against Sudan ebolavirus (SEBOV), Zaire ebolavirus (ZEBOV), Cote d'Ivoire ebolavirus (CIEBOV), and Marburgvirus (MARV). In this study, 11 cynomolgus monkeys were vaccinated with a blended vaccine consisting of equal parts of the vaccine vectors VSVΔG/SEBOVGP, VSVΔG/ZEBOVGP, and VSVΔG/MARVGP. Four weeks later, three of these animals were challenged with MARV, three with CIEBOV, three with ZEBOV, and two with SEBOV. Three control animals were vaccinated with VSV vectors encoding a nonfilovirus GP and challenged with SEBOV, ZEBOV, and MARV, respectively, and five unvaccinated control animals were challenged with CIEBOV. Importantly, none of the macaques vaccinated with the blended vaccine succumbed to a filovirus challenge. As expected, an experimental control animal vaccinated with VSVΔG/ZEBOVGP and challenged with SEBOV succumbed, as did the positive controls challenged with SEBOV, ZEBOV, and MARV, respectively. All five control animals challenged with CIEBOV became severely ill, and three of the animals succumbed on days 12, 12, and 14, respectively. The two animals that survived CIEBOV infection were protected from subsequent challenge with either SEBOV or ZEBOV, suggesting that immunity to CIEBOV may be protective against other species of Ebola virus. In conclusion, we developed an immunization scheme based on a single-injection vaccine that protects nonhuman primates against lethal challenge with representative strains of all human pathogenic filovirus species.
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Nakayama, Eri, Ayaka Yokoyama, Hiroko Miyamoto, Manabu Igarashi, Noriko Kishida, Keita Matsuno, Andrea Marzi, et al. "Enzyme-Linked Immunosorbent Assay for Detection of Filovirus Species-Specific Antibodies." Clinical and Vaccine Immunology 17, no. 11 (September 22, 2010): 1723–28. http://dx.doi.org/10.1128/cvi.00170-10.
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ABSTRACT Several enzyme-linked immunosorbent assays (ELISAs) for the detection of filovirus-specific antibodies have been developed. However, diagnostic methods to distinguish antibodies specific to the respective species of filoviruses, which provide the basis for serological classification, are not readily available. We established an ELISA using His-tagged secreted forms of the transmembrane glycoproteins (GPs) of five different Ebola virus (EBOV) species and one Marburg virus (MARV) strain as antigens for the detection of filovirus species-specific antibodies. The GP-based ELISA was evaluated by testing antisera collected from mice immunized with virus-like particles as well as from humans and nonhuman primates infected with EBOV or MARV. In our ELISA, little cross-reactivity of IgG antibodies was observed in most of the mouse antisera. Although sera and plasma from some patients and monkeys showed notable cross-reactivity with the GPs from multiple filovirus species, the highest reactions of IgG were uniformly detected against the GP antigen homologous to the virus species that infected individuals. We further confirmed that MARV-specific IgM antibodies were specifically detected in specimens collected from patients during the acute phase of infection. These results demonstrate the usefulness of our ELISA for diagnostics as well as ecological and serosurvey studies.
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Baker, Laura E., Jeffrey F. Ellena, Katarzyna B. Handing, Urszula Derewenda, Darkhan Utepbergenov, Daniel A. Engel, and Zygmunt S. Derewenda. "Molecular architecture of the nucleoprotein C-terminal domain from the Ebola and Marburg viruses." Acta Crystallographica Section D Structural Biology 72, no. 1 (January 1, 2016): 49–58. http://dx.doi.org/10.1107/s2059798315021439.
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TheFiloviridaefamily of negative-sense, single-stranded RNA (ssRNA) viruses is comprised of two species ofMarburgvirus(MARV and RAVV) and five species ofEbolavirus,i.e.Zaire (EBOV), Reston (RESTV), Sudan (SUDV), Taï Forest (TAFV) and Bundibugyo (BDBV). In each of these viruses the ssRNA encodes seven distinct proteins. One of them, the nucleoprotein (NP), is the most abundant viral protein in the infected cell and within the viral nucleocapsid. It is tightly associated with the viral RNA in the nucleocapsid, and during the lifecycle of the virus is essential for transcription, RNA replication, genome packaging and nucleocapsid assembly prior to membrane encapsulation. The structure of the unique C-terminal globular domain of the NP from EBOV has recently been determined and shown to be structurally unrelated to any other known protein [Dziubańskaet al.(2014),Acta Cryst. D70, 2420–2429]. In this paper, a study of the C-terminal domains from the NP from the remaining four species ofEbolavirus, as well as from the MARV strain ofMarburgvirus, is reported. As expected, the crystal structures of the BDBV and TAFV proteins show high structural similarity to that from EBOV, while the MARV protein behaves like a molten globule with a core residual structure that is significantly different from that of the EBOV protein.
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Bamberg, Sandra, Larissa Kolesnikova, Peggy Möller, Hans-Dieter Klenk, and Stephan Becker. "VP24 of Marburg Virus Influences Formation of Infectious Particles." Journal of Virology 79, no. 21 (November 1, 2005): 13421–33. http://dx.doi.org/10.1128/jvi.79.21.13421-13433.2005.
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ABSTRACT The highly pathogenic enveloped Marburg virus (MARV) is composed of seven structural proteins and the nonsegmented negative-sense viral RNA genome. Four proteins (NP, VP35, VP30, and L) make up the helical nucleocapsid, which is surrounded by a matrix that is composed of the viral proteins VP40 and VP24. VP40 is functionally homologous to the matrix proteins of other nonsegmented negative-strand RNA viruses. As yet, the function of VP24 remains elusive. In the present study we found that VP24 colocalized with inclusions in MARV-infected cells that contain preformed nucleocapsids and with nucleocapsids outside the inclusions. Coexpression studies revealed that VP24 is recruited into the inclusions by the presence of NP. Furthermore, VP24 displayed membrane-binding properties and was recruited into filamentous virus-like particles (VLPs) that are induced by VP40. The incorporation of VP24 altered neither the morphology of VLPs nor the budding efficiency of VLPs. When VP24 was silenced in MARV-infected cells by small interfering RNA technology, the release of viral particles was significantly reduced while viral transcription and replication were unimpaired. Our data support the idea that VP24 is essential for a process that takes place after replication and transcription and before budding of virus progeny. It is presumed that VP24 is necessary for the formation of transport-competent nucleocapsids and/or the interaction between the nucleocapsids and the budding sites at the plasma membrane.
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Yen, Benjamin C., and Christopher F. Basler. "Effects of Filovirus Interferon Antagonists on Responses of Human Monocyte-Derived Dendritic Cells to RNA Virus Infection." Journal of Virology 90, no. 10 (March 9, 2016): 5108–18. http://dx.doi.org/10.1128/jvi.00191-16.
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ABSTRACTDendritic cells (DCs) are major targets of filovirus infectionin vivo. Previous studies have shown that the filoviruses Ebola virus (EBOV) and Marburg virus (MARV) suppress DC maturationin vitro. Both viruses also encode innate immune evasion functions. The EBOV VP35 (eVP35) and the MARV VP35 (mVP35) proteins each can block RIG-I-like receptor signaling and alpha/beta interferon (IFN-α/β) production. The EBOV VP24 (eVP24) and MARV VP40 (mVP40) proteins each inhibit the production of IFN-stimulated genes (ISGs) by blocking Jak-STAT signaling; however, this occurs by different mechanisms, with eVP24 blocking nuclear import of tyrosine-phosphorylated STAT1 and mVP40 blocking Jak1 function. MARV VP24 (mVP24) has been demonstrated to modulate host cell antioxidant responses. Previous studies demonstrated that eVP35 is sufficient to strongly impair primary human monocyte-derived DC (MDDC) responses upon stimulation induced through the RIG-I-like receptor pathways. We demonstrate that mVP35, like eVP35, suppresses not only IFN-α/β production but also proinflammatory responses after stimulation of MDDCs with RIG-I activators. In contrast, eVP24 and mVP40, despite suppressing ISG production upon RIG-I activation, failed to block upregulation of maturation markers or T cell activation. mVP24, although able to stimulate expression of antioxidant response genes, had no measurable impact of DC function. These data are consistent with a model where filoviral VP35 proteins are the major suppressors of DC maturation during filovirus infection, whereas the filoviral VP24 proteins and mVP40 are insufficient to prevent DC maturation.IMPORTANCEThe ability to suppress the function of dendritic cells (DCs) likely contributes to the pathogenesis of disease caused by the filoviruses Ebola virus and Marburg virus. To clarify the basis for this DC suppression, we assessed the effect of filovirus proteins known to antagonize innate immune signaling pathways, including Ebola virus VP35 and VP24 and Marburg virus VP35, VP40, and VP24, on DC maturation and function. The data demonstrate that the VP35s from Ebola virus and Marburg virus are the major suppressors of DC maturation and that the effects on DCs of the remaining innate immune inhibitors are minor.
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Llop, Jaume. "MARV 6, 2 und die Eponymenfolgen des 12. Jahrhunderts." Zeitschrift für Assyriologie und vorderasiatische Archäologie 98, no. 1 (June 2008): 20–25. http://dx.doi.org/10.1515/za.2008.003.
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Müller, Stefanie, Peggy Möller, Matthew J. Bick, Stephanie Wurr, Stephan Becker, Stephan Günther, and Beate M. Kümmerer. "Inhibition of Filovirus Replication by the Zinc Finger Antiviral Protein." Journal of Virology 81, no. 5 (December 20, 2006): 2391–400. http://dx.doi.org/10.1128/jvi.01601-06.
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ABSTRACT The zinc finger antiviral protein (ZAP) was recently shown to inhibit Moloney murine leukemia virus and Sindbis virus replication. We tested whether ZAP also acts against Ebola virus (EBOV) and Marburg virus (MARV). Antiviral effects were observed after infection of cells expressing the N-terminal part of ZAP fused to the product of the zeocin resistance gene (NZAP-Zeo) as well as after infection of cells inducibly expressing full-length ZAP. EBOV was inhibited by up to 4 log units, whereas MARV was inhibited between 1 to 2 log units. The activity of ZAP was dependent on the integrity of the second and fourth zinc finger motif, as tested with cell lines expressing NZAP-Zeo mutants. Heterologous expression of EBOV- and MARV-specific sequences fused to a reporter gene suggest that ZAP specifically targets L gene sequences. The activity of NZAP-Zeo in this assay was also dependent on the integrity of the second and fourth zinc finger motif. Time-course experiments with infectious EBOV showed that ZAP reduces the level of L mRNA before the level of genomic or antigenomic RNA is affected. Transient expression of ZAP decreased the activity of an EBOV replicon system by up to 95%. This inhibitory effect could be partially compensated for by overexpression of L protein. In conclusion, the data demonstrate that ZAP exhibits antiviral activity against filoviruses, presumably by decreasing the level of viral mRNA.
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Lin, Kenny L., Nancy A. Twenhafel, John H. Connor, Kathleen A. Cashman, Joshua D. Shamblin, Ginger C. Donnelly, Heather L. Esham, et al. "Temporal Characterization of Marburg Virus Angola Infection following Aerosol Challenge in Rhesus Macaques." Journal of Virology 89, no. 19 (July 22, 2015): 9875–85. http://dx.doi.org/10.1128/jvi.01147-15.
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ABSTRACTMarburg virus (MARV) infection is a lethal hemorrhagic fever for which no licensed vaccines or therapeutics are available. Development of appropriate medical countermeasures requires a thorough understanding of the interaction between the host and the pathogen and the resulting disease course. In this study, 15 rhesus macaques were sequentially sacrificed following aerosol exposure to the MARV variant Angola, with longitudinal changes in physiology, immunology, and histopathology used to assess disease progression. Immunohistochemical evidence of infection and resulting histopathological changes were identified as early as day 3 postexposure (p.e.). The appearance of fever in infected animals coincided with the detection of serum viremia and plasma viral genomes on day 4 p.e. High (>107PFU/ml) viral loads were detected in all major organs (lung, liver, spleen, kidney, brain, etc.) beginning day 6 p.e. Clinical pathology findings included coagulopathy, leukocytosis, and profound liver destruction as indicated by elevated liver transaminases, azotemia, and hypoalbuminemia. Altered cytokine expression in response to infection included early increases in Th2 cytokines such as interleukin 10 (IL-10) and IL-5 and late-stage increases in Th1 cytokines such as IL-2, IL-15, and granulocyte-macrophage colony-stimulating factor (GM-CSF). This study provides a longitudinal examination of clinical disease of aerosol MARV Angola infection in the rhesus macaque model.IMPORTANCEIn this study, we carefully analyzed the timeline of Marburg virus infection in nonhuman primates in order to provide a well-characterized model of disease progression following aerosol exposure.
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Bartlett, Maggie L., Peter A. Larson, Mariano Sanchez-Lockhart, and Gustavo Palacios. "Unique Features of Immunity within the Immunoglobulin Heavy Chain Locus of Egyptian Rousette Bats." Proceedings 50, no. 1 (August 11, 2020): 142. http://dx.doi.org/10.3390/proceedings2020050142.
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Marburg virus (MARV) presents with a hemorrhagic fever in primates but asymptomatically in its known reservoir, the Egyptian rousette bat (Rousettus aegyptiacus, ERB). Understanding the biological mechanisms that explain these differential outcomes could be used to develop efficient therapeutics against MARV disease in humans. Since one of the antiviral mechanisms to control viruses is the humoral response, we hypothesize that the B cell repertoire is unique to primates and contributes to the ERB’s ability to overcome MARV infection. Immunoglobulin (Ig) heavy and light chains undergo DNA rearrangement to generate a diverse repertoire. To be able to study B cell rearrangement, the accurate annotation of the Ig heavy chain (IGH) locus is needed. We implemented three complementary strategies to describe and annotate the IGH locus of ERBs. First, we identified and annotated genes at the IGH locus, utilizing the previously described genome and transcriptome of the ERB our group created in collaboration with the CDC and the University of Boston. Second, we sequenced the specific IgM transcriptome of B cells from ERB peripheral blood mononuclear cells (PBMCs), to confirm or identify new IGH germline genes. Third, we generated bacterial artificial chromosome (BAC) libraries to confirm and improve the layout of the IGH locus. We were able to resolve misassemblies of these regions and identify multiple gene expansions unique to ERBs that may contribute to their ability to generate B cell diversity and control infections. We found an expansion of genes associated with protection from various viruses in humans, differential expression of ERB isotypes across tissues, and two functional IgE genes.
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Emperador, Devy M., Laura T. Mazzola, Betsy Wonderly Trainor, Arlene Chua, and Cassandra Kelly-Cirino. "Diagnostics for filovirus detection: impact of recent outbreaks on the diagnostic landscape." BMJ Global Health 4, Suppl 2 (February 2019): e001112. http://dx.doi.org/10.1136/bmjgh-2018-001112.
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Ebolaviruses and Marburg virus (MARV) both belong to the family Filoviridae and cause severe haemorrhagic fever in humans. Due to high mortality rates and potential for spread from rural to urban regions, they are listed on the WHO R&D blueprint of high-priority pathogens. Recent ebolavirus outbreaks in Western and Central Africa have highlighted the importance of diagnostic testing in epidemic preparedness for these pathogens and led to the rapid development of a number of commercially available benchtop and point-of-care nucleic acid amplification tests as well as serological assays and rapid diagnostic tests. Despite these advancements, challenges still remain. While products approved under emergency use licenses during outbreak periods may continue to be used post-outbreak, a lack of clarity and incentive surrounding the regulatory approval pathway during non-outbreak periods has deterred many manufacturers from seeking full approvals. Waning of funding and poor access to samples after the 2014–2016 outbreak also contributed to cessation of development once the outbreak was declared over. There is a need for tests with improved sensitivity and specificity, and assays that can use alternative sample types could reduce the need for invasive procedures and expensive equipment, making testing in field conditions more feasible. For MARV, availability of diagnostic tests is still limited, restricted to a single ELISA test and assay panels designed to differentiate between multiple pathogens. It may be helpful to extend the target product profile for ebolavirus diagnostics to include MARV, as the viruses have many overlapping characteristics.
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Kamata, Teddy, Mohan Natesan, Kelly Warfield, M. Javad Aman, and Robert G. Ulrich. "Determination of Specific Antibody Responses to the Six Species of Ebola and Marburg Viruses by Multiplexed Protein Microarrays." Clinical and Vaccine Immunology 21, no. 12 (September 17, 2014): 1605–12. http://dx.doi.org/10.1128/cvi.00484-14.
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ABSTRACTInfectious hemorrhagic fevers caused by the Marburg and Ebola filoviruses result in human mortality rates of up to 90%, and there are no effective vaccines or therapeutics available for clinical use. The highly infectious and lethal nature of these viruses highlights the need for reliable and sensitive diagnostic methods. We assembled a protein microarray displaying nucleoprotein (NP), virion protein 40 (VP40), and glycoprotein (GP) antigens from isolates representing the six species of filoviruses for use as a surveillance and diagnostic platform. Using the microarrays, we examined serum antibody responses of rhesus macaques vaccinated with trivalent (GP, NP, and VP40) virus-like particles (VLP) prior to infection with the Marburg virus (MARV) (i.e.,Marburg marburgvirus) or the Zaire virus (ZEBOV) (i.e.,Zaire ebolavirus). The microarray-based assay detected a significant increase in antigen-specific IgG resulting from immunization, while a greater level of antibody responses resulted from challenge of the vaccinated animals with ZEBOV or MARV. Further, while antibody cross-reactivities were observed among NPs and VP40s of Ebola viruses, antibody recognition of GPs was very specific. The performance of mucin-like domain fragments of GP (GP mucin) expressed inEscherichia coliwas compared to that of GP ectodomains produced in eukaryotic cells. Based on results with ZEBOV and MARV proteins, antibody recognition of GP mucins that were deficient in posttranslational modifications was comparable to that of the eukaryotic cell-expressed GP ectodomains in assay performance. We conclude that the described protein microarray may translate into a sensitive assay for diagnosis and serological surveillance of infections caused by multiple species of filoviruses.
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Porter, Danielle P., Jessica M. Weidner, Laura Gomba, Roy Bannister, Christiana Blair, Robert Jordan, Jay Wells, et al. "Remdesivir (GS-5734) Is Efficacious in Cynomolgus Macaques Infected With Marburg Virus." Journal of Infectious Diseases 222, no. 11 (June 1, 2020): 1894–901. http://dx.doi.org/10.1093/infdis/jiaa290.
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Abstract Marburg virus (MARV) is a filovirus with documented human case-fatality rates of up to 90%. Here, we evaluated the therapeutic efficacy of remdesivir (GS-5734) in nonhuman primates experimentally infected with MARV. Beginning 4 or 5 days post inoculation, cynomolgus macaques were treated once daily for 12 days with vehicle, 5 mg/kg remdesivir, or a 10-mg/kg loading dose followed by 5 mg/kg remdesivir. All vehicle-control animals died, whereas 83% of animals receiving a 10-mg/kg loading dose of remdesivir survived, as did 50% of animals receiving a 5-mg/kg remdesivir regimen. Remdesivir-treated animals exhibited improved clinical scores, lower plasma viral RNA, and improved markers of kidney function, liver function, and coagulopathy versus vehicle-control animals. The small molecule remdesivir showed therapeutic efficacy in this Marburg virus disease model with treatment initiation 5 days post inoculation, supporting further assessment of remdesivir for the treatment of Marburg virus disease in humans.
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Urata, S., and J. Yasuda. "Regulation of Marburg virus (MARV) budding by Nedd4.1: a different WW domain of Nedd4.1 is critical for binding to MARV and Ebola virus VP40." Journal of General Virology 91, no. 1 (October 7, 2009): 228–34. http://dx.doi.org/10.1099/vir.0.015495-0.
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Saijo, Masayuki, Shigeru Morikawa, and Ichiro Kurane. "Diagnostic Systems for Viral Hemorrhagic Fevers and Emerging Viral Infections Prepared in the National Institute of Infectious Diseases." Journal of Disaster Research 4, no. 5 (October 1, 2009): 315–21. http://dx.doi.org/10.20965/jdr.2009.p0315.
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Given the real possibility of hemorrhagic fever viruses such as ebola (EBOV), Marburg (MARV), Crimean-Congo hemorrhagic fever (CCHFV), and Lassa (LASV) viruses being introduced into virus-free nations such as Japan, the need arises for concomitant diagnostics even where such diseases are not endemic. Hemorrhagic fever viruses classified as biosafety level-4 (BSL-4) pathogens can only be manipulated in BSL-4 laboratories, making it difficult for nations such as Japan, having no BSL-4 laboratories, to develop required diagnostic assays. To circumvent this problem, diagnostic assays with recombinant viral antigens have been developed at the National Institute of Infectious Diseases, Tokyo, Japan (NIID). Diagnostics such as enzyme immunoassays for detecting viral hemorrhagic antibodies and antigens were developed using recombinant nucleoproteins (rNPs) of EBOV, MARV, CCHFV, and LASV for use as antigens. Immunoglobulin-G (IgG)-linked immunosorbent assay (ELISA) and indirect immunofluorescence assay using rNPs were confirmed to be highly sensitive and specific in detecting these antibodies. Sandwich antigen (Ag) capture ELISA was also developed for detecting these antigens. The sections that follow detail diagnostics developed at the NIID.
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Mohamadzadeh, Mansour, Sadie S. Coberley, Gene G. Olinger, Warren V. Kalina, Gordon Ruthel, Claudette L. Fuller, Dana L. Swenson, William D. Pratt, Douglas B. Kuhns, and Alan L. Schmaljohn. "Activation of Triggering Receptor Expressed on Myeloid Cells-1 on Human Neutrophils by Marburg and Ebola Viruses." Journal of Virology 80, no. 14 (July 15, 2006): 7235–44. http://dx.doi.org/10.1128/jvi.00543-06.
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ABSTRACT Marburg virus (MARV) and Ebola virus (EBOV), members of the viral family Filoviridae, cause fatal hemorrhagic fevers in humans and nonhuman primates. High viral burden is coincident with inadequate adaptive immune responses and robust inflammatory responses, and virus-mediated dysregulation of early host defenses has been proposed. Recently, a novel class of innate receptors called the triggering receptors expressed in myeloid cells (TREM) has been discovered and shown to play an important role in innate inflammatory responses and sepsis. Here, we report that MARV and EBOV activate TREM-1 on human neutrophils, resulting in DAP12 phosphorylation, TREM-1 shedding, mobilization of intracellular calcium, secretion of proinflammatory cytokines, and phenotypic changes. A peptide specific to TREM-1 diminished the release of tumor necrosis factor alpha by filovirus-activated human neutrophils in vitro, and a soluble recombinant TREM-1 competitively inhibited the loss of cell surface TREM-1 that otherwise occurred on neutrophils exposed to filoviruses. These data imply direct activation of TREM-1 by filoviruses and also indicate that neutrophils may play a prominent role in the immune and inflammatory responses to filovirus infections.
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O'Hearn, Aileen, Minxiu Wang, Han Cheng, Calli M. Lear-Rooney, Katie Koning, Emily Rumschlag-Booms, Elizabeth Varhegyi, Gene Olinger, and Lijun Rong. "Role of EXT1 and Glycosaminoglycans in the Early Stage of Filovirus Entry." Journal of Virology 89, no. 10 (March 4, 2015): 5441–49. http://dx.doi.org/10.1128/jvi.03689-14.
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ABSTRACTFiloviruses, including both Ebola virus (EBOV) and Marburg virus (MARV), can infect humans and other animals, causing hemorrhagic fever with a high mortality rate. Entry of these viruses into the host is mediated by a single filoviral glycoprotein (GP). GP is composed of two subunits: GP1, which is responsible for attachment and binding to receptor(s) on susceptible cells, and GP2, which mediates viral and cell membrane fusion. Although numerous host factors have been implicated in the entry process, the initial attachment receptor(s) has not been well defined. In this report, we demonstrate that exostosin 1 (EXT1), which is involved in biosynthesis of heparan sulfate (HS), plays a role in filovirus entry. Expression knockdown of EXT1 by small interfering RNAs (siRNAs) impairs GP-mediated pseudoviral entry and that of infectious EBOV and MARV in tissue cultured cells. Furthermore, HS, heparin, and other related glycosaminoglycans (GAGs), to different extents, can bind to and block GP-mediated viral entry and that of infectious filoviruses. These results strongly suggest that HS and other related GAGs are attachment receptors that are utilized by filoviruses for entry and infection. These GAGs may have therapeutic potential in treating EBOV- and MARV-infected patients.IMPORTANCEInfection by Ebola virus and Marburg virus can cause severe illness in humans, with a high mortality rate, and currently there is no FDA-approved vaccine or therapeutic treatment available. The ongoing 2014 outbreak in West Africa underscores a lack of our understanding in the infection and pathogenesis of these viruses and the urgency of drug discovery and development. In this study, we provide several pieces of evidence that demonstrate that heparan sulfate and other closely related glycosaminoglycans are the molecules that are used by filoviruses for initial attachment. Furthermore, we demonstrate that these glycosaminoglycans can block entry of and infection by filoviruses. Thus, this work provides mechanistic insights on the early step of filoviral infection and suggests a possible therapeutic option for diseases caused by filovirus infection.
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Takadate, Yoshihiro, Rashid Manzoor, Takeshi Saito, Yurie Kida, Junki Maruyama, Tatsunari Kondoh, Hiroko Miyamoto, et al. "Receptor-Mediated Host Cell Preference of a Bat-Derived Filovirus, Lloviu Virus." Microorganisms 8, no. 10 (October 5, 2020): 1530. http://dx.doi.org/10.3390/microorganisms8101530.
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Lloviu virus (LLOV), a bat-derived filovirus that is phylogenetically distinct from human pathogenic filoviruses such as Ebola virus (EBOV) and Marburg virus (MARV), was discovered in Europe. However, since infectious LLOV has never been isolated, the biological properties of this virus remain poorly understood. We found that vesicular stomatitis virus (VSV) pseudotyped with the glycoprotein (GP) of LLOV (VSV–LLOV) showed higher infectivity in one bat (Miniopterus sp.)-derived cell line than in the other bat-derived cell lines tested, which was distinct from the tropism of VSV pseudotyped with EBOV (VSV–EBOV) and MARV GPs. We then focused on the interaction between GP and Niemann–Pick C1 (NPC1) protein, one of the cellular receptors of filoviruses. We introduced the Miniopterus bat and human NPC1 genes into NPC1-knockout Vero E6 cells and their susceptibilities to the viruses were compared. The cell line expressing the bat NPC1 showed higher susceptibility to VSV–LLOV than that expressing human NPC1, whereas the opposite preference was seen for VSV–EBOV. Using a site-directed mutagenesis approach, amino acid residues involved in the differential tropism were identified in the NPC1 and GP molecules. Our results suggest that the interaction between GP and NPC1 is an important factor in the tropism of LLOV to a particular bat species.
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Drelich, Aleksandra, Barbara Judy, Xi He, Qing Chang, Shangyi Yu, Xiang Li, Fanglin Lu, et al. "Exchange Protein Directly Activated by cAMP Modulates Ebola Virus Uptake into Vascular Endothelial Cells." Viruses 10, no. 10 (October 16, 2018): 563. http://dx.doi.org/10.3390/v10100563.
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Members of the family Filoviridae, including Ebola virus (EBOV) and Marburg virus (MARV), cause severe hemorrhagic fever in humans and nonhuman primates. Given their high lethality, a comprehensive understanding of filoviral pathogenesis is urgently needed. In the present studies, we revealed that the exchange protein directly activated by cAMP 1 (EPAC1) gene deletion protects vasculature in ex vivo explants from EBOV infection. Importantly, pharmacological inhibition of EPAC1 using EPAC-specific inhibitors (ESIs) mimicked the EPAC1 knockout phenotype in the ex vivo model. ESI treatment dramatically decreased EBOV infectivity in both ex vivo vasculature and in vitro vascular endothelial cells (ECs). Furthermore, postexposure protection of ECs against EBOV infection was conferred using ESIs. Protective efficacy of ESIs in ECs was observed also in MARV infection. Additional studies using a vesicular stomatitis virus pseudotype that expresses EBOV glycoprotein (EGP-VSV) confirmed that ESIs reduced infection in ECs. Ultrastructural studies suggested that ESIs blocked EGP-VSV internalization via inhibition of macropinocytosis. The inactivation of EPAC1 affects the early stage of viral entry after viral binding to the cell surface, but before early endosome formation, in a phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-dependent manner. Our study delineated a new critical role of EPAC1 during EBOV uptake into ECs.
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Hayman, David T. S. "Biannual birth pulses allow filoviruses to persist in bat populations." Proceedings of the Royal Society B: Biological Sciences 282, no. 1803 (March 22, 2015): 20142591. http://dx.doi.org/10.1098/rspb.2014.2591.
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Filoviruses Ebolavirus (EBOV) and Marburgvirus (MARV) cause haemorrhagic fevers with high mortality rates, posing significant threats to public health. To understand transmission into human populations, filovirus dynamics within reservoir host populations must be understood. Studies have directly linked filoviruses to bats, but the mechanisms allowing viral persistence within bat populations are poorly understood. Theory suggests seasonal birthing may decrease the probability of pathogen persistence within populations, but data suggest MARV may persist within colonies of seasonally breeding Egyptian fruit bats, Rousettus aegyptiacus . I synthesize available filovirus and bat data in a stochastic compartmental model to explore fundamental questions relating to filovirus ecology: can filoviruses persist within isolated bat colonies; do critical community sizes exist; and how do host–pathogen relationships affect spillover transmission potential? Synchronous annual breeding and shorter incubation periods did not allow filovirus persistence, whereas bi-annual breeding and longer incubation periods, such as reported for Egyptian fruit bats and EBOV in experimental studies, allowed persistence in colony sizes often found in nature. Serological data support the findings, with bats from species with two annual birth pulses more likely to be seropositive (odds ratio (OR) 4.4, 95% confidence interval (CI) 2.5–8.7) than those with one, suggesting that biannual birthing is necessary for filovirus persistence.