#Filovirus #Virulence in #Interferon α/β and γ Double Knockout Mice, and #Treatment with #Favipiravir (Viruses, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Viruses. 2019 Feb 3;11(2). pii: E137. doi: 10.3390/v11020137.

Filovirus Virulence in Interferon α/β and γ Double Knockout Mice, and Treatment with Favipiravir.

Comer JE1,2,3,4, Escaffre O5, Neef N6, Brasel T7,8,9, Juelich TL10, Smith JK11, Smith J12, Kalveram B13, Perez DD14, Massey S15, Zhang L16, Freiberg AN17,18,19,20.

Author information: 1 Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. jscomer@UTMB.edu. 2 Office of Regulated Nonclinical Studies, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. jscomer@UTMB.edu. 3 Sealy Institute for Vaccine Science, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. jscomer@UTMB.edu. 4 The Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. jscomer@UTMB.edu. 5 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. olescaff@utmb.edu. 6 Experimental Pathology Laboratories, Inc., Sterling, VA 20167, USA. nneef@7thwavelabs.com. 7 Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. trbrasel@utmb.edu. 8 Office of Regulated Nonclinical Studies, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. trbrasel@utmb.edu. 9 Sealy Institute for Vaccine Science, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. trbrasel@utmb.edu. 10 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. tljuelic@utmb.edu. 11 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. jeksmith@UTMB.EDU. 12 Office of Regulated Nonclinical Studies, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. jensmit1@utmb.edu. 13 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. bkkalver@utmb.edu. 14 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. dadperez@tamu.edu. 15 Office of Regulated Nonclinical Studies, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. chmassey@utmb.edu. 16 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. lihzhang@utmb.edu. 17 Sealy Institute for Vaccine Science, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. anfreibe@utmb.edu. 18 The Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. anfreibe@utmb.edu. 19 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. anfreibe@utmb.edu. 20 Institute for Human Infections and Immunity, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. anfreibe@utmb.edu.

 

Abstract

The 2014 Ebolavirus outbreak in West Africa highlighted the need for vaccines and therapeutics to prevent and treat filovirus infections. A well-characterized small animal model that is susceptible to wild-type filoviruses would facilitate the screening of anti-filovirus agents. To that end, we characterized knockout mice lacking α/β and γ interferon receptors (IFNAGR KO) as a model for wild-type filovirus infection. Intraperitoneal challenge of IFNAGR KO mice with several known human pathogenic species from the genus Ebolavirus and Marburgvirus, except Bundibugyo ebolavirus and Taï Forest ebolavirus, caused variable mortality rate. Further characterization of the prototype Ebola virus Kikwit isolate infection in this KO mouse model showed 100% lethality down to a dilution equivalent to 1.0 × 10-1 pfu with all deaths occurring between 7 and 9 days post-challenge. Viral RNA was detectable in serum after challenge with 1.0 × 10² pfu as early as one day after infection. Changes in hematology and serum chemistry became pronounced as the disease progressed and mirrored the histological changes in the spleen and liver that were also consistent with those described for patients with Ebola virus disease. In a proof-of-principle study, treatment of Ebola virus infected IFNAGR KO mice with favipiravir resulted in 83% protection. Taken together, the data suggest that IFNAGR KO mice may be a useful model for early screening of anti-filovirus medical countermeasures.

KEYWORDS: Ebola virus; filovirus; interferon receptor knockout; mouse

PMID: 30717492 DOI: 10.3390/v11020137 Free full text

Keywords: Filovirus; Ebola; Marburg; Ebola Bundibugyo; Tai Forest Virus; Favipiravir; Antivirals; Animal models.

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#Viral #Infections of the #CNS in #Africa (Brain Res Bull., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Brain Res Bull. 2019 Jan 15. pii: S0361-9230(18)30341-1. doi: 10.1016/j.brainresbull.2018.12.019. [Epub ahead of print]

Viral Infections of the Central Nervous System in Africa.

Kakooza-Mwesige A1, Tshala-Katumbay D2, Juliano SL3.

Author information: 1 Department of Paediatrics & Child Health, Makerere University College of Health Sciences and Mulago Hospital, Kampala, Uganda; Astrid Lindgren Children’s Hospital, Neuropediatric Research Unit, Karolinska Institutet, Sweden. Electronic address: akakooza246@gmail.com. 2 Department of Neurology and School of Public Health, Oregon Health & Science University, Portland, OR, USA; Department of Neurology, University of Kinshasa, Democratic Republic of the Congo; Institut National de Recherches Biomedicales, University of Kinshasa, Democratic Republic of the Congo. Electronic address: tshalad@ohsu.edu. 3 Neuroscience, USUHS, Bethesda, MD, 20814, USA. Electronic address: sharon.juliano@usuhs.edu.

 

Abstract

Viral infections are a major cause of human central nervous system infection, and may be associated with significant mortality, and long-term sequelae. In Africa, the lack of effective therapies, limited diagnostic and human resource facilities are especially in dire need. Most viruses that affect the central nervous system are opportunistic or accidental pathogens. Some of these viruses were initially considered harmless, however they have now evolved to penetrate the nervous system efficiently and exploit neuronal cell biology thus resulting in severe illness. A number of potentially lethal neurotropic viruses have been discovered in Africa and over the course of time shown their ability to spread wider afield involving other continents leaving a devastating impact in their trail. In this review we discuss key viruses involved in central nervous system disease and of major public health concern with respect to Africa. These arise from the families of Flaviviridae, Filoviridae, Retroviridae, Bunyaviridae, Rhabdoviridae and Herpesviridae. In terms of the number of cases affected by these viruses, HIV (Retroviridae) tops the list for morbidity, mortality and long term disability, while the Rift Valley Fever virus (Bunyaviridae) is at the bottom of the list. The most deadly are the Ebola and Marburg viruses (Filoviridae). This review describes their epidemiology and key neurological manifestations as regards the central nervous system such as meningoencephalitis and Guillain-Barré syndrome. The potential pathogenic mechanisms adopted by these viruses are debated and research perspectives suggested.

Copyright © 2019. Published by Elsevier Inc.

KEYWORDS: CNS viral infections; Ebola; HIV; Herpes; Rabies; Zika

PMID: 30658129 DOI: 10.1016/j.brainresbull.2018.12.019

Keywords: Emerging Diseases; Neurology; Flavivirus; Filovirus; Rhabdovirus; Herpesvirus; HIV/AIDS; Bunyavirus; Retrovirus.

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#Host and Viral #Proteins Modulating #Ebola and #Marburg Virus #Egress (Viruses, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Viruses. 2019 Jan 3;11(1). pii: E25. doi: 10.3390/v11010025.

Host and Viral Proteins Modulating Ebola and Marburg Virus Egress.

Gordon TB1,2, Hayward JA3,4, Marsh GA5,6, Baker ML7, Tachedjian G8,9,10,11.

Author information: 1 Health Security Program, Life Sciences Discipline, Burnet Institute, Melbourne, VIC 3004, Australia. tamsin.gordon@burnet.edu.au. 2 Department of Microbiology, Monash University, Clayton, VIC 3168, Australia. tamsin.gordon@burnet.edu.au. 3 Health Security Program, Life Sciences Discipline, Burnet Institute, Melbourne, VIC 3004, Australia. joshua.hayward@burnet.edu.au. 4 Department of Microbiology, Monash University, Clayton, VIC 3168, Australia. joshua.hayward@burnet.edu.au. 5 Department of Microbiology, Monash University, Clayton, VIC 3168, Australia. Glenn.marsh@csiro.au. 6 CSIRO Australian Animal Health Laboratory, Health and Biosecurity Business Unit, Geelong, VIC 3220, Australia. Glenn.marsh@csiro.au. 7 CSIRO Australian Animal Health Laboratory, Health and Biosecurity Business Unit, Geelong, VIC 3220, Australia. Michelle.Baker@csiro.au. 8 Health Security Program, Life Sciences Discipline, Burnet Institute, Melbourne, VIC 3004, Australia. gilda.tachedjian@burnet.edu.au. 9 Department of Microbiology, Monash University, Clayton, VIC 3168, Australia. gilda.tachedjian@burnet.edu.au. 10 Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne VIC 3010, Australia. gilda.tachedjian@burnet.edu.au. 11 School of Science, College of Science, Engineering and Health, RMIT University, Melbourne, VIC 3000, Australia. gilda.tachedjian@burnet.edu.au.

 

Abstract

The filoviruses Ebolavirus and Marburgvirus are among the deadliest viral pathogens known to infect humans, causing emerging diseases with fatality rates of up to 90% during some outbreaks. The replication cycles of these viruses are comprised of numerous complex molecular processes and interactions with their human host, with one key feature being the means by which nascent virions exit host cells to spread to new cells and ultimately to a new host. This review focuses on our current knowledge of filovirus egress and the viral and host factors and processes that are involved. Within the virus, these factors consist of the major matrix protein, viral protein 40 (VP40), which is necessary and sufficient for viral particle release, and nucleocapsid and glycoprotein that interact with VP40 to promote egress. In the host cell, some proteins are hijacked by filoviruses in order to enhance virion budding capacity that include members of the family of E3 ubiquitin ligase and the endosomal sorting complexes required for transport (ESCRT) pathway, while others such as tetherin inhibit viral egress. An understanding of these molecular interactions that modulate viral particle egress provides an important opportunity to identify new targets for the development of antivirals to prevent and treat filovirus infections.

KEYWORDS: ESCRT; Ebola virus; Marburg virus; VP40; budding; egress; filovirus; ubiquitination; viral inhibition

PMID: 30609802 DOI: 10.3390/v11010025

Keywords: Filovirus; Ebola; Marburg; Viral pathogenesis.

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A Recombinant #Rabies Virus Expressing the #Marburg Virus Glycoprotein is Dependent Upon ADCC for Protection Against Marburg Virus Disease in a Murine Model (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

A Recombinant Rabies Virus Expressing the Marburg Virus Glycoprotein is Dependent Upon ADCC for Protection Against Marburg Virus Disease in a Murine Model

Rohan Keshwara, Katie R. Hagen, Tiago Abreu-Mota, Amy B. Papaneri, David Liu, Christoph Wirblich, Reed F. Johnson, Matthias J. Schnell

DOI: 10.1128/JVI.01865-18

 

ABSTRACT

Marburg virus (MARV) is a filovirus related to Ebola virus (EBOV) associated with human hemorrhagic disease. Outbreaks are sporadic and severe with a reported case mortality rate upward of 88%. There is currently no antiviral or vaccine available. Given the sporadic nature of outbreaks, vaccines provide the best approach for long-term control of MARV in endemic regions. We have developed an inactivated rabies virus-vectored MARV vaccine (FILORAB3) to protect against Marburg virus disease. Immunogenicity studies in our lab have shown that a Th1-biased seroconversion to both RABV and MARV glycoproteins is beneficial for protection in a preclinical murine model. As such, we adjuvanted FILORAB3 with GLA-SE, a TLR-4 agonist. Across two different BALB/c mouse challenge models, we achieved 92% protection against murine-adapted Marburg virus (ma-MARV). Although our vaccine elicited strong MARV GP antibodies, it did not strongly induce neutralizing antibodies. Through both in vitro and in vivo approaches, we elucidated a critical role for NK cell-dependent antibody-mediated cellular cytotoxicity (ADCC) in vaccine-induced protection. Overall, these findings demonstrated that FILORAB3 is a promising vaccine candidate for Marburg virus disease.

 

IMPORTANCE

Marburg virus (MARV) is a virus similar to Ebola virus and also causes a hemorrhagic disease, which is highly lethal. In contrast to EBOV, only a few vaccines are developed against MARV and researcher do not understand what kind of immune responses are required to protect from MARV. Here we show that antibodies directed against MARV after application of our vaccine protect in an animal system but fail to neutralize the Virus in widely used virus neutralization assay against MARV. This newly discovered activity needs to be more considered when analyzing MARV vaccines or infections.

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Filovirus; Marburg; Vaccines.

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#Persistence and #Sexual #Transmission of #Filoviruses (Viruses, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Viruses. 2018 Dec 2;10(12). pii: E683. doi: 10.3390/v10120683.

Persistence and Sexual Transmission of Filoviruses.

Schindell BG1, Webb AL2, Kindrachuk J3.

Author information: 1 Laboratory of Emerging and Re-Emerging Viruses, Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9, Canada. schindeb@myumanitoba.ca. 2 Laboratory of Emerging and Re-Emerging Viruses, Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9, Canada. webba2@myumanitoba.ca. 3 Laboratory of Emerging and Re-Emerging Viruses, Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9, Canada. Jason.Kindrachuk@umanitoba.ca.

 

Abstract

There is an increasing frequency of reports regarding the persistence of the Ebola virus (EBOV) in Ebola virus disease (EVD) survivors. During the 2014⁻2016 West African EVD epidemic, sporadic transmission events resulted in the initiation of new chains of human-to-human transmission. Multiple reports strongly suggest that these re-emergences were linked to persistent EBOV infections and included sexual transmission from EVD survivors. Asymptomatic infection and long-term viral persistence in EVD survivors could result in incidental introductions of the Ebola virus in new geographic regions and raise important national and local public health concerns. Alarmingly, although the persistence of filoviruses and their potential for sexual transmission have been documented since the emergence of such viruses in 1967, there is limited knowledge regarding the events that result in filovirus transmission to, and persistence within, the male reproductive tract. Asymptomatic infection and long-term viral persistence in male EVD survivors could lead to incidental transfer of EBOV to new geographic regions, thereby generating widespread outbreaks that constitute a significant threat to national and global public health. Here, we review filovirus testicular persistence and discuss the current state of knowledge regarding the rates of persistence in male survivors, and mechanisms underlying reproductive tract localization and sexual transmission.

KEYWORDS: Ebola virus; blood-testis barrier; emerging virus; filovirus; outbreak; persistence; public health; sexual transmission; testis

PMID: 30513823 DOI: 10.3390/v10120683 Free full text

Keywords: Filovirus; Ebola; Marburg.

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#Marburg and #Ebola Viruses – Marking 50 Years Since Their #Discovery (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Summary, edited.]

Marburg and Ebola Viruses – Marking 50 Years Since Their Discovery

Stephan Becker, Heinz Feldmann, Tom Geisbert, Yoshihiro Kawaoka

The Journal of Infectious Diseases, Volume 218, Issue suppl_5, 22 November 2018, Pages Si, https://doi.org/10.1093/infdis/jiy674

Published:22 November 2018

Citation: Stephan Becker, Heinz Feldmann, Tom Geisbert, Yoshihiro Kawaoka; Marburg and Ebola Viruses – Marking 50 Years Since Their Discovery, The Journal of Infectious Diseases, Volume 218, Issue suppl_5, 22 November 2018, Pages Si, https://doi.org/10.1093/infdis/jiy674

© 2018 Oxford University Press

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In 1967, a mysterious infectious disease was described in patients at the University Hospital in Marburg, Germany. Most patients had come into contact with a shipment of African green monkeys from Uganda. Additional patients were noted in Frankfurt, Germany and Belgrade, now Serbia. The etiological agent was identified as a virus and named after the city of Marburg – Marburg virus. Nine years later, a similar clinical infectious syndrome was described in patients in rural areas in southern Sudan (now South Sudan) and northern Zaire (now the Democratic Republic of Congo, DRC). The pathogen was identified as a virus similar to Marburg virus and named Ebola…

(…)

Issue Section: Preface

© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Filovirus; Ebola; Marburg.

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Structural Basis of Pan- #Ebolavirus #Neutralization by a #Human #Antibody against a Conserved, yet Cryptic Epitope (mBio, abstract)

[Source: mBio, full page: (LINK). Abstract, edited.]

Structural Basis of Pan-Ebolavirus Neutralization by a Human Antibody against a Conserved, yet Cryptic Epitope

Brandyn R. West, Crystal L. Moyer, Liam B. King, Marnie L. Fusco, Jacob C. Milligan, Sean Hui, Erica Ollmann Saphire

Peter Palese, Editor

DOI: 10.1128/mBio.01674-18

 

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.

Keywords: Ebolavirus; Filovirus; Neutralizing Antibodies; Monoclonal Antibodies.

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