scholarly journals Human MxA Protein Inhibits the Replication of Crimean-Congo Hemorrhagic Fever Virus

2004 ◽  
Vol 78 (8) ◽  
pp. 4323-4329 ◽  
Author(s):  
Ida Andersson ◽  
Linda Bladh ◽  
Mehrdad Mousavi-Jazi ◽  
Karl-Eric Magnusson ◽  
Åke Lundkvist ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Hemorrhagic Fever ◽  
Inhibitory Effect ◽  
Fever Virus ◽  
Progeny Virus ◽  
Crimean Congo Hemorrhagic Fever ◽  
Viral Genomes ◽  
Virus Particles ◽  
Hemorrhagic Fever Virus ◽  
Infected Cells

ABSTRACT Crimean-Congo hemorrhagic fever virus (CCHFV) belongs to the genus Nairovirus within the family Bunyaviridae and is the causative agent of severe hemorrhagic fever. Despite increasing knowledge about hemorrhagic fever viruses, the factors determining their pathogenicity are still poorly understood. The interferon-induced MxA protein has been shown to have an inhibitory effect on several members of the Bunyaviridae family, but the effect of MxA against CCHFV has not previously been studied. Here, we report that human MxA has antiviral activity against CCHFV. The yield of progeny virus in cells constitutively expressing MxA was reduced up to 1,000-fold compared with control cells, and accumulation of viral genomes was blocked. Confocal microscopy revealed that MxA colocalizes with the nucleocapsid protein (NP) of CCHFV in the perinuclear regions of infected cells. Furthermore, we found that MxA interacted with NP by using a coimmunoprecipitation assay. We also found that an amino acid substitution (E645R) within the C-terminal domain of MxA resulted in a loss of MxA antiviral activity and, concomitantly, in the capacity to interact with CCHFV NP. These results suggest that MxA, by interacting with a component of the nucleocapsid, prevents replication of CCHFV viral RNA and thereby inhibits the production of new infectious virus particles.

scholarly journals Antagonistic Antiviral Activity between IFN-Lambda and IFN-Alpha against Lethal Crimean-Congo Hemorrhagic Fever Virus In Vitro

PLoS ONE ◽  
2015 ◽  
Vol 10 (2) ◽  
pp. e0116816 ◽  
Author(s):  
Licia Bordi ◽  
Eleonora Lalle ◽  
Claudia Caglioti ◽  
Damiano Travaglini ◽  
Daniele Lapa ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Hemorrhagic Fever ◽  
Fever Virus ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus ◽  
Ifn Alpha ◽  
Ifn Lambda

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

2007 ◽  
Vol 81 (23) ◽  
pp. 13271-13276 ◽  
Author(s):  
Éric Bergeron ◽  
Martin J. Vincent ◽  
Stuart T. Nichol
Keyword(s):  
Infectious Virus ◽  
Virus Assembly ◽  
Hemorrhagic Fever ◽  
Fever Virus ◽  
Virus Infectivity ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus ◽  
Viral Glycoproteins ◽  
Infected Cells ◽  
Glycoprotein Processing

ABSTRACT 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 (>106 PFU/ml), confirming that SKI-1/S1P processing is required for incorporation of viral glycoproteins. SKI-1/S1P may represent a promising antiviral target.

scholarly journals Basolateral Entry and Release of Crimean-Congo Hemorrhagic Fever Virus in Polarized MDCK-1 Cells

2006 ◽  
Vol 81 (5) ◽  
pp. 2158-2164 ◽  
Author(s):  
Anne-Marie Connolly-Andersen ◽  
Karl-Erik Magnusson ◽  
Ali Mirazimi
Keyword(s):  
Epithelial Cells ◽  
Viral Entry ◽  
Hemorrhagic Fever ◽  
Fever Virus ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus ◽  
Infected Cells ◽  
Polarized Epithelial Cells ◽  
A Site ◽  
First Time

ABSTRACT Crimean-Congo hemorrhagic fever virus (CCHFV) is an etiological agent of a disease with mortality rates in patients averaging 30%. The disease is characterized by fever, myalgia, and hemorrhage. Mechanisms underlying the hemorrhage have to our knowledge not been elucidated for CCHFV. Possibly, a direct or indirect viral effect on tight junctions (TJ) could cause the hemorrhage observed in patients, as TJ play a crucial role in vascular homeostasis and can cause leakage upon deregulation. Moreover, there is no knowledge regarding the site of entry and release of CCHFV in polarized epithelial cells. Such cells represent a barrier to virus dissemination within the host, and as a site of viral entry and release, they could play a key role in further spread. For the first time, we have shown preferential basolateral entry of CCHFV in Madin-Darby canine kidney 1 (MDCK-1) epithelial cells. Furthermore, we demonstrated basolateral release of CCHFV in polarized epithelial cells. Interestingly, by measuring transepithelial electrical resistance, we found no effect of CCHFV replication on the function of TJ in this study. Neither did we observe any difference in the localization of the TJ proteins ZO-1 and occludin in CCHFV-infected cells compared to mock-infected cells.

scholarly journals Heat Shock Protein 70 Family Members Interact with Crimean-Congo Hemorrhagic Fever Virus and Hazara Virus Nucleocapsid Proteins and Perform a Functional Role in the Nairovirus Replication Cycle

2016 ◽  
Vol 90 (20) ◽  
pp. 9305-9316 ◽  
Author(s):  
Rebecca Surtees ◽  
Stuart D. Dowall ◽  
Amelia Shaw ◽  
Stuart Armstrong ◽  
Roger Hewson ◽  
...  
Keyword(s):  
Life Cycle ◽  
Hemorrhagic Fever ◽  
Therapeutic Strategies ◽  
Fever Virus ◽  
Immunological Methods ◽  
Content Type ◽  
Crimean Congo Hemorrhagic Fever ◽  
Virus Particles ◽  
Hemorrhagic Fever Virus ◽  
Hsp70 Family

ABSTRACTTheNairovirusgenus of theBunyaviridaefamily contains serious human and animal pathogens classified within multiple serogroups and species. Of these serogroups, the Crimean-Congo hemorrhagic fever virus (CCHFV) serogroup comprises sole members CCHFV and Hazara virus (HAZV). CCHFV is an emerging zoonotic virus that causes often-fatal hemorrhagic fever in infected humans for which preventative or therapeutic strategies are not available. In contrast, HAZV is nonpathogenic to humans and thus represents an excellent model to study aspects of CCHFV biology under conditions of more-accessible biological containment. The three RNA segments that form the nairovirus genome are encapsidated by the viral nucleocapsid protein (N) to form ribonucleoprotein (RNP) complexes that are substrates for RNA synthesis and packaging into virus particles. We used quantitative proteomics to identify cellular interaction partners of CCHFV N and identified robust interactions with cellular chaperones. These interactions were validated using immunological methods, and the specific interaction between native CCHFV N and cellular chaperones of the HSP70 family was confirmed during live CCHFV infection. Using infectious HAZV, we showed for the first time that the nairovirus N-HSP70 association was maintained within both infected cells and virus particles, where N is assembled as RNPs. Reduction of active HSP70 levels in cells by the use of small-molecule inhibitors significantly reduced HAZV titers, and a model for chaperone function in the context of high genetic variability is proposed. These results suggest that chaperones of the HSP70 family are required for nairovirus replication and thus represent a genetically stable cellular therapeutic target for preventing nairovirus-mediated disease.IMPORTANCENairoviruses compose a group of human and animal viruses that are transmitted by ticks and associated with serious or fatal disease. One member is Crimean-Congo hemorrhagic fever virus (CCHFV), which is responsible for fatal human disease and is recognized as an emerging threat within Europe in response to climate change. No preventative or therapeutic strategies against nairovirus-mediated disease are currently available. Here we show that the N protein of CCHFV and the related Hazara virus interact with a cellular protein, HSP70, during both the intracellular and extracellular stages of the virus life cycle. The use of inhibitors that block HSP70 function reduces virus titers by up to 1,000-fold, suggesting that this interaction is important within the context of the nairovirus life cycle and may represent a potent target for antinairovirus therapies against which the virus cannot easily develop resistance.

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