#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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Natural History and #Pathogenesis of Wild-Type #Marburg Virus #Infection in STAT2 Knockout Hamsters (J Infect Dis., abstract)

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

Natural History and Pathogenesis of Wild-Type Marburg Virus Infection in STAT2 Knockout Hamsters

Colm Atkins, Jinxin Miao, Birte Kalveram, Terry Juelich, Jennifer K Smith, David Perez, Lihong Zhang, Jonna L B Westover, Arnaud J Van Wettere, Brian B Gowen, Zhongde Wang, Alexander N Freiberg

The Journal of Infectious Diseases, jiy457, https://doi.org/10.1093/infdis/jiy457

Published: 06 September 2018

 

Abstract

Marburg virus (MARV; family Filoviridae) causes sporadic outbreaks of Marburg hemorrhagic fever in sub-Saharan Africa with case fatality rates reaching 90%. Wild-type filoviruses, including MARV and the closely related Ebola virus, are unable to suppress the type I interferon response in rodents, and therefore require adaptation of the viruses to cause disease in immunocompetent animals. In the current study, we demonstrate that STAT2knockout Syrian hamsters are susceptible to infection with different wild-type MARV variants. MARV Musoke causes a robust and systemic infection resulting in lethal disease. Histopathological findings share features similar to those observed in human patients and other animal models of filovirus infection. Reverse-transcription polymerase chain reaction analysis of host transcripts shows a dysregulation of the innate immune response. Our results demonstrate that the STAT2 knockout hamster represents a novel small animal model of severe MARV infection and disease without the requirement for virus adaptation.

Marburg virus, STAT2 KO hamster, Filovirus, animal model

Topic:  filovirus – cricetinae – marburg virus disease – animal model – infection – marburg virus

Issue Section: Supplement Article

© 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; Marburg; Animal Models.

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Persistent #Marburg Virus #Infection in the #Testes of Nonhuman #Primate #Survivors (Cell Host Microbe, abstract)

[Source: Cell, Host & Microbe, full page: (LINK). Abstract, edited.]

Persistent Marburg Virus Infection in the Testes of Nonhuman Primate Survivors

Kayla M. Coffin, Jun Liu, Travis K. Warren, Jens H. Kuhn, Sina Bavari, Xiankun Zeng

Published: August 30, 2018 / DOI: https://doi.org/10.1016/j.chom.2018.08.003

 

Highlights

  • Marburg virus (MARV) persists in the testes of macaque survivors after treatment
  • MARV infiltrates macaque testes late in infection
  • MARV persists in testicular Sertoli cells, thereby disrupting tissue barrier integrity
  • Local immunosuppressive Treg cell infiltration may sustain persistent infection

 

Summary

Sexual transmission of filoviruses was first reported in 1968 after an outbreak of Marburg virus (MARV) disease and recently caused flare-ups of Ebola virus disease in the 2013–2016 outbreak. How filoviruses establish testicular persistence and are shed in semen remain unknown. We discovered that persistent MARV infection of seminiferous tubules, an immune-privileged site that harbors sperm production, is a relatively common event in crab-eating macaques that survived infection after antiviral treatment. Persistence triggers severe testicular damage, including spermatogenic cell depletion and inflammatory cell invasion. MARV mainly persists in Sertoli cells, leading to breakdown of the blood-testis barrier formed by inter-Sertoli cell tight junctions. This disruption is accompanied by local infiltration of immunosuppressive CD4 +Foxp3 + regulatory T cells. Our study elucidates cellular events associated with testicular persistence that may promote sexual transmission of filoviruses and suggests that targeting immunosuppression may be warranted to clear filovirus persistence in damaged immune-privileged sites.

Keywords: Ebola virus – EBOV – filovirus – immunosuppression – Marburg virus – MARV – persistent infection – testis – Treg – viral persistence

Keywords: Filovirus; Marburg; Animal Models.

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#Vaccine-Mediated Induction of an #Ebolavirus Cross-Species #Antibody Binding to Conserved Epitopes on the Glycoprotein Heptad Repeat 2/Membrane-Proximal External Junction (J Infect Dis., abstract)

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

Vaccine-Mediated Induction of an Ebolavirus Cross-Species Antibody Binding to Conserved Epitopes on the Glycoprotein Heptad Repeat 2/Membrane-Proximal External Junction

Alberto Cagigi, Aurélie Ploquin, Thomas Niezold, Yan Zhou, Yaroslav Tsybovsky, John Misasi, Nancy J Sullivan

The Journal of Infectious Diseases, jiy450, https://doi.org/10.1093/infdis/jiy450

Published: 22 August 2018

 

Abstract

The membrane-proximal external regions (MPER) of the human immunodeficiency virus envelope glycoprotein (GP) generate broadly reactive antibody responses and are the focus of vaccine development efforts. The conservation of amino acids within filovirus GP heptad repeat region (HR)2/MPER suggests that it may also represent a target for a pan-filovirus vaccine. We immunized a cynomolgus macaque against Ebola virus (EBOV) using a deoxyribonucleic acid/adenovirus 5 prime/boost strategy, sequenced memory B-cell receptors, and tested the antibodies for functional activity against EBOV GP. Antibody ma-C10 bound to GP with an affinity of 48 nM and was capable of inducing antibody-dependent cellular cytotoxicity. Three-dimensional reconstruction of single-particle, negative-stained, electron microscopy showed that ma-C10 bound to the HR2/MPER, and enzyme-linked immunosorbent assay reveals it binds to residues 621–631. More importantly, ma-C10 was found to bind to the GP of the 3 most clinically relevant Ebolavirus species, suggesting that a cross-species immunogen strategy targeting the residues in this region may be a feasible approach for producing a pan-filovirus vaccine.

Ad5 immunization, cynomolgus macaques, Ebolavirus, MPER

Issue Section: Supplement Article

Keywords: Ebolavirus; Filovirus; Vaccines.

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DNA-launched RNA #replicon #vaccines induce potent anti- #Ebolavirus immune responses that can be further improved by a recombinant MVA boost (Sci Rep., abstract)

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

Sci Rep. 2018 Aug 20;8(1):12459. doi: 10.1038/s41598-018-31003-6.

DNA-launched RNA replicon vaccines induce potent anti-Ebolavirus immune responses that can be further improved by a recombinant MVA boost.

Öhlund P1,2, García-Arriaza J3, Zusinaite E4, Szurgot I1, Männik A5, Kraus A6, Ustav M5, Merits A4, Esteban M3, Liljeström P1, Ljungberg K7.

Author information: 1 Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden. 2 Department of Biomedical Science and Veterinary Public Health, Virology Unit, Swedish University of Agricultural Sciences, Uppsala, Sweden. 3 Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CNB-CSIC), Madrid, Spain. 4 Institute of Technology, University of Tartu, Tartu, Estonia. 5 Icosagen Cell Factory OÜ, Ülenurme vald, Tartumaa, Estonia. 6 Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden. 7 Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden. Karl.Ljungberg@ki.se.

 

Abstract

There are currently no licensed therapeutic treatment or preventive vaccines against Ebolavirus disease, and the 2013-2016 West African outbreak of Ebolavirus disease spread rapidly and resulted in almost 30,000 cases and more than 11,000 deaths. However, the devastating outbreak has spurred the development of novel Ebolavirus vaccines. Here, we demonstrate that alphavirus-based DNA-launched self-replicating RNA replicon vaccines (DREP) encoding either the glycoprotein (GP) gene or co-expressing the GP and VP40 genes of Sudan or Zaire Ebolavirus are immunogenic in mice inducing both binding and neutralizing antibodies as well as CD8 T cell responses. In addition, antibodies were cross-reactive against another Ebolavirus, although the specificity was higher for the vaccination antigen. DREP vaccines were more immunogenic than recombinant MVA vaccines expressing the same Ebolavirus antigens. However, a DREP prime followed by an MVA boost immunization regimen improved vaccine immunogenicity as compared to DREP and MVA homologous prime-boost immunizations. Moreover, we show that a bivalent approach targeting both Sudan and Zaire Ebolavirus can be employed without significant loss of immunity. This opens for further investigation of a pan-Ebolavirus or even a pan-filovirus vaccine.

PMID: 30127450 DOI: 10.1038/s41598-018-31003-6

Keywords: Ebola; Filovirus; Vaccines; Animal Models.

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