ABSTRACT
The Crimean-Congo hemorrhagic fever virus (CCHFV) is an emerging pathogen of the Orthonairovirus genus that can cause severe and often lethal hemorrhagic diseases in humans. CCHFV has a broad tropism and can infect a variety of species and tissues. Here, by using gene silencing, blocking antibodies or soluble receptor fragments, we identify the low-density lipoprotein receptor (LDL-R) as a CCHFV entry factor. The LDL-R facilitates binding of CCHFV particles but does not allow entry of Hazara virus (HAZV), another member of the genus. In addition, we show that apolipoprotein E (apoE), an exchangeable protein that mediates LDL/LDL-R interaction, is incorporated on CCHFV particles, though not on HAZV particles, and enhances their specific infectivity by promoting an LDL-R dependent entry. Finally, we show that molecules that decrease LDL-R from the surface of target cells could inhibit CCHFV infection. Our study highlights that CCHFV takes advantage of a lipoprotein receptor and recruits its natural ligand to promote entry into cells.
Subject(s)
Apolipoproteins E , Hemorrhagic Fever Virus, Crimean-Congo , Receptors, LDL , Virus Internalization , Humans , Receptors, LDL/metabolism , Apolipoproteins E/metabolism , Apolipoproteins E/genetics , Hemorrhagic Fever Virus, Crimean-Congo/metabolism , Hemorrhagic Fever Virus, Crimean-Congo/physiology , Animals , HEK293 Cells , Chlorocebus aethiops , Hemorrhagic Fever, Crimean/virology , Hemorrhagic Fever, Crimean/metabolism , Virion/metabolism , Vero CellsABSTRACT
The Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne bunyavirus that causes high mortality in humans. This enveloped virus harbors two surface glycoproteins (GP), Gn and Gc, that are released by processing of a glycoprotein precursor complex whose maturation takes place in the ER and is completed through the secretion pathway. Here, we characterized the trafficking network exploited by CCHFV GPs during viral assembly, envelopment, and/or egress. We identified membrane trafficking motifs in the cytoplasmic domains (CD) of CCHFV GPs and addressed how they impact these late stages of the viral life cycle using infection and biochemical assays, and confocal microscopy in virus-producing cells. We found that several of the identified CD motifs modulate GP transport through the retrograde trafficking network, impacting envelopment and secretion of infectious particles. Finally, we identified PACS-2 as a crucial host factor contributing to CCHFV GPs trafficking required for assembly and release of viral particles.
Subject(s)
Hemorrhagic Fever Virus, Crimean-Congo , Protein Transport , Virus Assembly , Humans , Hemorrhagic Fever Virus, Crimean-Congo/physiology , Hemorrhagic Fever Virus, Crimean-Congo/genetics , Vesicular Transport Proteins/metabolism , Vesicular Transport Proteins/genetics , Animals , Viral Envelope Proteins/metabolism , Viral Envelope Proteins/genetics , Protein Domains , Amino Acid Motifs , Membrane Glycoproteins/metabolism , Membrane Glycoproteins/genetics , Chlorocebus aethiops , HEK293 Cells , Vero CellsABSTRACT
IMPORTANCE: Assessments of viral stability on surfaces or in body fluids under different environmental conditions and/or temperatures are often performed, as they are key to understanding the routes and parameters of viral transmission and to providing clues on the epidemiology of infections. However, for most viruses, the mechanisms of inactivation vs stability of viral particles remain poorly defined. Although they are structurally diverse, with different compositions, sizes, and shapes, enveloped viruses are generally less stable than non-enveloped viruses, pointing out the role of envelopes themselves in virus lability. In this report, we investigated the properties of hepatitis C virus (HCV) particles with regards to their stability. We found that, compared to alternative enveloped viruses such as Dengue virus (DENV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), hepatitis delta virus (HDV), and Crimean-Congo hemorrhagic fever virus (CCHFV) that infect the liver, HCV particles are intrinsically labile. We determined the mechanisms that drastically alter their specific infectivity through oxidation of their lipids, and we highlighted that they are protected from lipid oxidation by secreted cellular proteins, which can protect their membrane fusion capacity and overall infectivity.
Subject(s)
Hemorrhagic Fever Virus, Crimean-Congo , Hepatitis C , Humans , Hepacivirus , Hemorrhagic Fever Virus, Crimean-Congo/physiology , Hepatitis C/metabolismABSTRACT
The Crimean-Congo hemorrhagic fever virus (CCHFV) is the etiological agent of a severe hemorrhagic fever affecting Africa, Asia and southern Europe. Climate changes of recent decades have recently led to a rise in the distribution of this virus. Still few scientific data are available on the biology of its vector, the tick, or its own biology, but the proven presence of human infections observed in Spain and animals with positive serology in Corsica should focus our attention on this pathogen. This review takes stock of the epidemiologic evolution of CCHF in Europe, notably in France.
TITLE: La fièvre hémorragique de Crimée-Congo, une future problématique de santé en France ? ABSTRACT: Le virus de la fièvre hémorragique de Crimée-Congo (CCHFV) est l'agent étiologique d'une fièvre hémorragique grave affectant l'Afrique, l'Asie et le sud de l'Europe. Les modifications climatiques de ces dernières décennies induisent depuis peu une remontée de l'aire de distribution de ce virus. Encore peu de données scientifiques sont disponibles sur les interactions avec son vecteur, la tique, ou sur sa biologie propre. Cependant, la présence avérée d'infections humaines en Espagne et des sérologies positives dans le cheptel corse pourraient bien concentrer l'attention sur ce pathogène. Cette revue fait le point sur l'évolution des connaissances éco-épidémiologiques de ce virus, notamment en Europe et plus particulièrement en France.
