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.

The Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-born zoonotic virus, responsible for severe hemorrhagic fever outbreaks in humans, with a case fatality rate of 10-40%, while being asymptomatic in non-human hosts 1 . CCHFV is endemic in Asia, the Middle East, Eastern Europe, Africa, and more recently, Southern Europe 2,3 , which corresponds to the geographic distribution of its vector and/or reservoir, mainly Hyalomma ticks 4 .

CCHFV is an enveloped virus that belongs to the Nairoviridae family of the Bunyavirales order. The viral genome consists of three single-stranded RNA segments (L, M, and S) of negative or ambisense polarity. The RNA segments exclusively replicate in the cytosol and encode up to five non-structural proteins and four structural proteins, which are the RNA-dependent RNA polymerase L, the nucleoprotein NP, and two envelope glycoproteins (GP) Gc and Gn. The NP protein binds to genomic RNA to form, together with the viral polymerase, the pseudo-helical ribonucleoproteins (RNPs) inside the virions. Inserted on the viral envelope, the Gn and Gc GPs are responsible for the attachment of viral particles to the surface of host cells and their subsequent penetration into the cytosol (reviewed in 5 ).