Proteolytic Processing of the Ebola Virus Glycoprotein Is Not Critical for Ebola Virus Replication in Nonhuman Primates

Neumann, Gabriele; Geisbert, Thomas W.; Ebihara, Hideki; Daddario-DiCaprio, Kathleen M.; Feldmann, Heinz; Kawaoka, Yoshihiro

doi:10.1128/jvi.02486-06

Cited by 59 publications

(61 citation statements)

References 12 publications

(9 reference statements)

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“…Interestingly, a variant of EBOV that is resistant to furin cleavage (the same variant noted as being more cytopathic in vivo) was recently reported to be similar to wild-type EBOV in its virulence to non-human primates 37 .…”

Section: Box 1 | Filovirus-disease Basicsmentioning

confidence: 97%

How Ebola and Marburg viruses battle the immune system

2007

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PantropicTending towards the capacity to infect a wide range of cells and organs. CoagulopathyRefers to a group of conditions of the blood-clotting system in which bleeding is prolonged and excessive. Cell tropismA virus's affinity for or tendency towards preferential infection of certain cells. How Ebola and Marburg viruses battle the immune systemMansour Mohamadzadeh* ‡ , Lieping Chen ‡ , and Alan L. Schmaljohn* Abstract | The filoviruses Ebola and Marburg have emerged in the past decade from relative obscurity to serve now as archetypes for some of the more intriguing and daunting challenges posed by such agents. Public imagination is captured by deadly outbreaks of these viruses and reinforced by the specter of bioterrorism. As research on these agents has accelerated, it has been found increasingly that filoviruses use a combination of familiar and apparently new ways to baffle and battle the immune system. Filoviruses have provided thereby a new lens through which to examine the immune system itself. R E V I E W S Report Documentation PageForm Public reporting burden for the collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden, to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to a penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number.

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Section: Box 1 | Filovirus-disease Basicsmentioning

confidence: 97%

How Ebola and Marburg viruses battle the immune system

2007

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“…However, lack of endoproteolysis of viral glycoproteins does not necessarily correlate with reduced infectivity. For instance, Ebola viruses displaying on their surface a mutant glycoprotein defective for furin cleavage replicate in cell culture (16) and in a nonhuman primate model (17) identically to virions displaying the wildtype cleaved glycoprotein. Here the biological significance of CCHFV PreGn conversion to Gn by SKI-1/S1P and its importance for virus infectivity were examined.…”

mentioning

confidence: 99%

Crimean-Congo Hemorrhagic Fever Virus Glycoprotein Processing by the Endoprotease SKI-1/S1P Is Critical for Virus Infectivity

Bergeron

Vincent

Nichol

2007

J Virol

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Crimean-Congo hemorrhagic fever virus (CCHFV) causes severe human disease. The CCHFV medium RNA encodes a polyprotein which is proteolytically processed to yield the glycoprotein precursors PreGn and PreGc, followed by structural glycoproteins Gn and Gc. Subtilisin kexin isozyme-1/site-1 protease (SKI-1/S1P) plays a central role in Gn processing. Here we show that CCHFV-infected cells deficient in SKI-1/S1P produce no infectious virus, although PreGn and PreGc accumulated normally in the Golgi apparatus, the site of virus assembly. Only nucleoprotein-containing particles which lacked virus glycoproteins (Gn/Gc or PreGn/PreGc) were secreted. Complementation of SKI-1/S1P-deficient cells with a SKI-1/S1P expression vector restored release of infectious virus (>10 6 PFU/ml), confirming that SKI-1/S1P processing is required for incorporation of viral glycoproteins. SKI-1/S1P may represent a promising antiviral target.

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“…This knowledge raises the question of the biological relevance of a 10-fold titer reduction, as seen in vitro with MARV and EBOV in the present study. The question was very recently answered by showing that the EBOV mutant lacking the furin recognition site was lethal for nonhuman primates, with no appreciable differences in disease progression noted for infection with the EBOV mutant, compared with infection with wild-type EBOV [17].…”

Section: Discussionmentioning

confidence: 98%

Blockage of Filoviral Glycoprotein Processing by Use of a Protein‐Based Inhibitor

et al. 2007

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Cleavage of the glycoproteins of many virus species by furin and other host cell proteases is required for virus infectivity and, hence, determines viral pathogenicity. Proteolytic processing of Marburg virus and Ebola virus glycoproteins is also mediated by furin; however, for Ebola virus, in contrast to other viruses, glycoprotein cleavage is dispensable for replication in vitro, as has been shown in previous studies. In the present study, by use of a highly potent and selective furin inhibitor, we demonstrate that glycoprotein cleavage inhibition results in a minimal reduction in the virus titer that is insufficient to block filoviral replication. Thus, furin inhibitors are unlikely to be effective in the treatment of filoviral infections.

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Proteolytic Processing of the Ebola Virus Glycoprotein Is Not Critical for Ebola Virus Replication in Nonhuman Primates

Cited by 59 publications

References 12 publications

How Ebola and Marburg viruses battle the immune system

How Ebola and Marburg viruses battle the immune system

Crimean-Congo Hemorrhagic Fever Virus Glycoprotein Processing by the Endoprotease SKI-1/S1P Is Critical for Virus Infectivity

Blockage of Filoviral Glycoprotein Processing by Use of a Protein‐Based Inhibitor

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