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Here we report that the Low Density Lipoprotein Receptor (LDLR) is a\n                critical receptor for CCHFV cell entry, playing a vital role in CCHFV infection in\n                cell culture and blood vessel organoids. The interaction between CCHFV and LDLR is\n                highly specific, with other members of the LDLR protein family failing to bind to or\n                neutralize the virus. Biosensor experiments demonstrate that LDLR specifically binds\n                the surface glycoproteins of CCHFV. Importantly, mice lacking LDLR exhibit a delay\n                in CCHFV-induced disease. Furthermore, we identified the presence of Apolipoprotein\n                E (ApoE) on CCHFV particles. Our findings highlight the essential role of LDLR in\n                CCHFV infection, irrespective of ApoE presence, when the virus is produced in tick\n                cells. This discovery holds profound implications for the development of future\n                therapies against CCHFV.<\/jats:p>","DOI":"10.1038\/s41564-024-01672-3","type":"journal-article","created":{"date-parts":[[2024,3,28]],"date-time":"2024-03-28T13:03:08Z","timestamp":1711630988000},"page":"1499-1512","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Crimean\u2013Congo haemorrhagic fever virus uses LDLR to bind and\n            enter host cells"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2652-5695","authenticated-orcid":false,"given":"Vanessa M.","family":"Monteil","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7470-5068","authenticated-orcid":false,"given":"Shane 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W.","family":"Platzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Ibrahim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4637-4609","authenticated-orcid":false,"given":"Hyesoo","family":"Kwon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1510-487X","authenticated-orcid":false,"given":"Ioannis","family":"Pittarokoilis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattia","family":"Mirandola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3337-8291","authenticated-orcid":false,"given":"Georg","family":"Michlits","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0618-5611","authenticated-orcid":false,"given":"Stephanie","family":"Devignot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1615-2642","authenticated-orcid":false,"given":"Elizabeth","family":"Elder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samir","family":"Abdurahman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e1ndor","family":"Bereczky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binnur","family":"Bagci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Youhanna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teodor","family":"Aastrup","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1140-6204","authenticated-orcid":false,"given":"Volker M.","family":"Lauschke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5136-7406","authenticated-orcid":false,"given":"Cristiano","family":"Salata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9515-770X","authenticated-orcid":false,"given":"Nazif","family":"Elaldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9737-337X","authenticated-orcid":false,"given":"Friedemann","family":"Weber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1603-1755","authenticated-orcid":false,"given":"Nuria","family":"Monserrat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8233-8176","authenticated-orcid":false,"given":"David 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Crimean\u2013Congo Haemorrhagic Fever\n                        in the EU\/EEA, 2013\u2013Present\n                    (ECDC, 2024);\n                            https:\/\/www.ecdc.europa.eu\/en\/crimean-congo-haemorrhagic-fever\/surveillance\/cases-eu-since-2013"},{"key":"1672_CR2","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1089\/vbz.2011.0771","volume":"12","author":"A Estrada-Pe\u00f1a","year":"2012","unstructured":"Estrada-Pe\u00f1a, A., S\u00e1nchez, N. & Estrada-S\u00e1nchez, A. An\n                    assessment of the distribution and spread of the tick Hyalomma marginatum in the western Palearctic under different\n                    climate scenarios. Vector Borne Zoonotic Dis.\n                    12, 758\u2013768 (2012).","journal-title":"Vector Borne Zoonotic Dis."},{"key":"1672_CR3","doi-asserted-by":"crossref","unstructured":"Fern\u00e1ndez-Ruiz, N. & Estrada-Pe\u00f1a, A. Towards new horizons:\n                    climate trends in Europe increase the environmental suitability for permanent\n                    populations of Hyalomma marginatum\n                    (Ixodidae). Pathogens\n                    10, 95 (2021).","DOI":"10.3390\/pathogens10020095"},{"key":"1672_CR4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ttbdis.2022.102112","volume":"14","author":"EL Gillingham","year":"2023","unstructured":"Gillingham, E. L., Medlock, J. M., Macintyre, H. & Phalkey, R.\n                    Modelling the current and future temperature suitability of the UK for the\n                    vector Hyalomma marginatum (Acari: Ixodidae).\n                        Ticks Tick Borne Dis.\n                    14, 102112 (2023).","journal-title":"Ticks Tick Borne Dis."},{"key":"1672_CR5","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1099\/vir.0.006387-0","volume":"90","author":"M Simon","year":"2009","unstructured":"Simon, M., Johansson, C. & Mirazimi, A. Crimean-Congo\n                    hemorrhagic fever virus entry and replication is clathrin-, pH- and\n                    cholesterol-dependent. J. Gen. Virol.\n                    90, 210\u2013215 (2009).","journal-title":"J. Gen. Virol."},{"key":"1672_CR6","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.virol.2013.05.030","volume":"444","author":"AR Garrison","year":"2013","unstructured":"Garrison, A. R. et al. Crimean-Congo hemorrhagic fever virus\n                    utilizes a clathrin- and early endosome-dependent entry pathway. Virology\n                    444, 45\u201354 (2013).","journal-title":"Virology"},{"key":"1672_CR7","doi-asserted-by":"publisher","first-page":"e1004390","DOI":"10.1371\/journal.ppat.1004390","volume":"10","author":"O Shtanko","year":"2014","unstructured":"Shtanko, O., Nikitina, R. A., Altuntas, C. Z., Chepurnov, A. A.\n                    & Davey, R. A. Crimean-Congo hemorrhagic fever virus entry into host cells\n                    occurs through the multivesicular body and requires ESCRT regulators. PLoS Pathog.\n                    10, e1004390 (2014).","journal-title":"PLoS Pathog."},{"key":"1672_CR8","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.648077","volume":"11","author":"S Dai","year":"2021","unstructured":"Dai, S. et al. Differential cell line susceptibility to\n                    Crimean-Congo hemorrhagic fever virus. Front. Cell.\n                        Infect. Microbiol. 11, 648077\n                    (2021).","journal-title":"Front. Cell. Infect. Microbiol"},{"key":"1672_CR9","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/j.virol.2009.06.010","volume":"390","author":"AM Connolly-Andersen","year":"2009","unstructured":"Connolly-Andersen, A. M., Douagi, I., Kraus, A. A. & Mirazimi,\n                    A. Crimean Congo hemorrhagic fever virus infects human monocyte-derived\n                    dendritic cells. Virology\n                    390, 157\u2013162 (2009).","journal-title":"Virology"},{"key":"1672_CR10","doi-asserted-by":"crossref","unstructured":"F\u00f6ldes, K., Aligholipour Farzani, T., Erg\u00fcnay, K. & Ozkul, A.\n                    Differential growth characteristics of Crimean-Congo hemorrhagic fever virus in\n                    kidney cells of human and bovine origin. Viruses\n                    12, 685 (2020).","DOI":"10.3390\/v12060685"},{"key":"1672_CR11","doi-asserted-by":"publisher","first-page":"e29712","DOI":"10.1371\/journal.pone.0029712","volume":"7","author":"R Rodrigues","year":"2012","unstructured":"Rodrigues, R., Paranhos-Baccal\u00e0, G., Vernet, G. & Peyrefitte,\n                    C. N. Crimean-Congo hemorrhagic fever virus-infected hepatocytes induce\n                    ER-stress and apoptosis crosstalk. PLoS ONE\n                    7, e29712 (2012).","journal-title":"PLoS ONE"},{"key":"1672_CR12","doi-asserted-by":"publisher","first-page":"1386","DOI":"10.1093\/infdis\/jix215","volume":"216","author":"JR Spengler","year":"2017","unstructured":"Spengler, J. R. et al. Crimean-Congo hemorrhagic fever in humanized\n                    mice reveals glial cells as primary targets of neurological infection. J. Infect. Dis.\n                    216, 1386\u20131397 (2017).","journal-title":"J. Infect. Dis."},{"key":"1672_CR13","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/j.bbrc.2011.06.109","volume":"411","author":"X Xiao","year":"2011","unstructured":"Xiao, X., Feng, Y., Zhu, Z. & Dimitrov, D. S. Identification of\n                    a putative Crimean-Congo hemorrhagic fever virus entry factor. Biochem. Biophys. Res. Commun.\n                    411, 253\u2013258 (2011).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"1672_CR14","doi-asserted-by":"publisher","first-page":"1447","DOI":"10.1007\/s00705-016-2803-1","volume":"161","author":"Y Suda","year":"2016","unstructured":"Suda, Y. et al. Analysis of the entry mechanism of Crimean-Congo\n                    hemorrhagic fever virus, using a vesicular stomatitis virus pseudotyping system.\n                        Arch. Virol.\n                    161, 1447\u20131454 (2016).","journal-title":"Arch. Virol."},{"key":"1672_CR15","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-08135-4","volume":"10","author":"M Flint","year":"2019","unstructured":"Flint, M. et al. A genome-wide CRISPR screen identifies\n                    N-acetylglucosamine-1-phosphate transferase as a potential antiviral target for\n                    Ebola virus. Nat. Commun.\n                    10, 285 (2019).","journal-title":"Nat. Commun."},{"key":"1672_CR16","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-022-01013-1","volume":"14","author":"M Grodzki","year":"2022","unstructured":"Grodzki, M. et al. Genome-scale CRISPR screens identify host\n                    factors that promote human coronavirus infection. Genome\n                        Med.\n                    14, 10 (2022).","journal-title":"Genome Med."},{"key":"1672_CR17","doi-asserted-by":"publisher","first-page":"2415","DOI":"10.1016\/j.febslet.2014.06.032","volume":"588","author":"U Elling","year":"2014","unstructured":"Elling, U. & Penninger, J. M. Genome wide functional genetics\n                    in haploid cells. FEBS Lett.\n                    588, 2415\u20132421 (2014).","journal-title":"FEBS Lett."},{"key":"1672_CR18","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1016\/j.stem.2011.10.012","volume":"9","author":"U Elling","year":"2011","unstructured":"Elling, U. et al. Forward and reverse genetics through derivation\n                    of haploid mouse embryonic stem cells. Cell Stem\n                        Cell\n                    9, 563\u2013574 (2011).","journal-title":"Cell Stem Cell"},{"key":"1672_CR19","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1038\/nature10348","volume":"477","author":"JE Carette","year":"2011","unstructured":"Carette, J. E. et al. Ebola virus entry requires the cholesterol\n                    transporter Niemann\u2013Pick C1. Nature\n                    477, 340\u2013343 (2011).","journal-title":"Nature"},{"key":"1672_CR20","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1038\/nature10380","volume":"477","author":"M Cote","year":"2011","unstructured":"Cote, M. et al. Small molecule inhibitors reveal Niemann\u2013Pick C1 is\n                    essential for Ebola virus infection. 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Science\n                    344, 1506\u20131510 (2014).","journal-title":"Science"},{"key":"1672_CR23","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1126\/science.1233675","volume":"340","author":"LT Jae","year":"2013","unstructured":"Jae, L. T. et al. Deciphering the glycosylome of\n                    dystroglycanopathies using haploid screens for lassa virus entry. Science\n                    340, 479\u2013483 (2013).","journal-title":"Science"},{"key":"1672_CR24","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-15-1016","volume":"15","author":"M Tokunaga","year":"2014","unstructured":"Tokunaga, M. et al. Simulation and estimation of gene number in a\n                    biological pathway using almost complete saturation mutagenesis screening of\n                    haploid mouse cells. BMC Genomics\n                    15, 1016 (2014).","journal-title":"BMC Genomics"},{"key":"1672_CR25","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1038\/nchembio.2226","volume":"13","author":"JV Forment","year":"2017","unstructured":"Forment, J. V. et al. Genome-wide genetic screening with chemically\n                    mutagenized haploid embryonic stem cells. Nat. Chem.\n                        Biol.\n                    13, 12\u201314 (2017).","journal-title":"Nat. Chem. Biol."},{"key":"1672_CR26","doi-asserted-by":"publisher","first-page":"9838","DOI":"10.18632\/oncotarget.24305","volume":"9","author":"M Horn","year":"2018","unstructured":"Horn, M. et al. Unbiased compound-protein interface mapping and\n                    prediction of chemoresistance loci through forward genetics in haploid stem\n                    cells. Oncotarget\n                    9, 9838\u20139851 (2018).","journal-title":"Oncotarget"},{"key":"1672_CR27","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1038\/nature24027","volume":"550","author":"U Elling","year":"2017","unstructured":"Elling, U. et al. A reversible haploid mouse embryonic stem cell\n                    biobank resource for functional genomics. Nature\n                    550, 114\u2013118 (2017).","journal-title":"Nature"},{"key":"1672_CR28","doi-asserted-by":"publisher","first-page":"7306","DOI":"10.1073\/pnas.1214441110","volume":"110","author":"D Finkelshtein","year":"2013","unstructured":"Finkelshtein, D., Werman, A., Novick, D., Barak, S. &\n                    Rubinstein, M. LDL receptor and its family members serve as the cellular\n                    receptors for vesicular stomatitis virus. Proc. Natl\n                        Acad. Sci. USA\n                    110, 7306\u20137311 (2013).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1672_CR29","doi-asserted-by":"publisher","first-page":"5163","DOI":"10.1016\/j.cell.2021.09.001","volume":"184","author":"SS Ganaie","year":"2021","unstructured":"Ganaie, S. S. et al. Lrp1 is a host entry factor for Rift Valley\n                    fever virus. Cell\n                    184, 5163\u20135178.e24 (2021).","journal-title":"Cell"},{"key":"1672_CR30","doi-asserted-by":"crossref","unstructured":"Devignot, S. et al. Low-density lipoprotein receptor-related\n                    protein 1 (LRP1) as an auxiliary host factor for RNA viruses. Life Sci. Alliance\n                    6, e202302005 (2023).","DOI":"10.26508\/lsa.202302005"},{"key":"1672_CR31","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1038\/nmeth.3398","volume":"12","author":"LA Stoddart","year":"2015","unstructured":"Stoddart, L. A. et al. Application of BRET to monitor ligand\n                    binding to GPCRs. Nat. Methods\n                    12, 661\u2013663 (2015).","journal-title":"Nat. Methods"},{"key":"1672_CR32","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/0092-8674(84)90188-0","volume":"39","author":"T Yamamoto","year":"1984","unstructured":"Yamamoto, T. et al. The human LDL receptor: a cysteine-rich protein\n                    with multiple Alu sequences in its mRNA. Cell\n                    39, 27\u201338 (1984).","journal-title":"Cell"},{"key":"1672_CR33","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12178","volume":"7","author":"Y Namkung","year":"2016","unstructured":"Namkung, Y. et al. Monitoring G protein-coupled receptor and\n                    \u03b2-arrestin trafficking in live cells using enhanced bystander BRET. Nat. Commun.\n                    7, 12178 (2016).","journal-title":"Nat. Commun."},{"key":"1672_CR34","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202013426","volume":"13","author":"V Monteil","year":"2021","unstructured":"Monteil, V. et al. Human soluble ACE2 improves the effect of\n                    remdesivir in SARS-CoV-2 infection. EMBO Mol.\n                        Med.\n                    13, e13426 (2021).","journal-title":"EMBO Mol. Med."},{"key":"1672_CR35","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202115230","volume":"14","author":"V Monteil","year":"2022","unstructured":"Monteil, V. et al. Clinical grade ACE2 as a universal agent to\n                    block SARS-CoV-2 variants. EMBO Mol. Med.\n                    14, e15230 (2022).","journal-title":"EMBO Mol. Med."},{"key":"1672_CR36","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1016\/j.cell.2020.04.004","volume":"181","author":"V Monteil","year":"2020","unstructured":"Monteil, V. et al. Inhibition of SARS-CoV-2 infections in\n                    engineered human tissues using clinical-grade soluble human ACE2. Cell\n                    181, 905\u2013913.e7 (2020).","journal-title":"Cell"},{"key":"1672_CR37","doi-asserted-by":"crossref","unstructured":"Patel, M. R. & Kratzke, R. A. in Translating Gene Therapy to the Clinic (eds Laurence, J. &\n                    Franklin, M.) 261\u2013279 (Academic Press, 2015).","DOI":"10.1016\/B978-0-12-800563-7.00017-8"},{"key":"1672_CR38","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1038\/s41586-018-0858-8","volume":"565","author":"RA Wimmer","year":"2019","unstructured":"Wimmer, R. A. et al. Human blood vessel organoids as a model of\n                    diabetic vasculopathy. 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