Oropouche orthobunyavirus infection is mediated by the cellular host factor Lrp1

Abstract

Oropouche orthobunyavirus (OROV; Peribunyaviridae ) is a mosquito-transmitted virus that causes widespread human febrile illness in South America, with occasional progression to neurologic effects. Host factors mediating the cellular entry of OROV are undefined. Here, we show that OROV uses the host protein low-density lipoprotein–related protein 1 (Lrp1) for efficient cellular infection. Cells from evolutionarily distinct species lacking Lrp1 were less permissive to OROV infection than cells with Lrp1. Treatment of cells with either the high-affinity Lrp1 ligand receptor-associated protein (RAP) or recombinant ectodomain truncations of Lrp1 significantly reduced OROV infection. In addition, chimeric vesicular stomatitis virus (VSV) expressing OROV glycoproteins (VSV-OROV) bound to the Lrp1 ectodomain in vitro. Furthermore, we demonstrate the biological relevance of the OROV-Lrp1 interaction in a proof-of-concept mouse study in which treatment of mice with RAP at the time of infection reduced tissue viral load and promoted survival from an otherwise lethal infection. These results with OROV, along with the recent finding of Lrp1 as an entry factor for Rift Valley fever virus, highlight the broader significance of Lrp1 in cellular infection by diverse bunyaviruses. Shared strategies for entry, such as the critical function of Lrp1 defined here, provide a foundation for the development of pan-bunyaviral therapeutics.

Low Density Lipoprotein Receptor-Related Protein 1 (LRP1) as an auxiliary host factor for RNA viruses including SARS-CoV-2

“…Moreover, using RVFV as a model, we observe that cholesterol as well as endosomal acidification are involved in the positive influence of LRP1 on infection. In agreement with these findings, recent studies (published while our manuscript was in preparation) showed that LRP1 acts as a receptor for RVFV and the Oropouche orthobunyavirus (OROV) by binding to the viral envelope proteins and mediating their entry into the cytoplasm [33,34]. Strikingly, LRP1 is a transporter that can overcome the blood-brain barrier [35].…”

“…The results by us and others [33, 34] indicate that LRP1 is facilitating attachment and entry for a series of viruses. On the other hand we found that EMCV is not dependent on LRP1, and Schwarz et al reported the same for the Zika flavivirus (ZIKV) [34]. Thus, LRP1 appears to be a broad, but not entirely general host factor for viruses.…”

“…Our data as well as those of by Ganaie et al . and Schwarz et al .. [33, 34] clearly show that LRP1 is neither the only attachment factor for RVFV, nor for any of the other viruses tested. Indeed, heparan sulfates, C-type lectins like L-SIGN, and the intermediate filament vimentin were identified as auxiliary entry factors for RVFV, the LACV-related Schmallenberg virus, SARS-CoV-2 or many others [16, 42–49].…”

“…Indeed, also Ganaie et al . investigated the LRP1 dependency of VSV and observed that the effect of LRP1 on VSV attachment and entry is negligible [33], but nonetheless a reduction of VSV spread in cell culture was detectable later in the infection cycle [34]. It is therefore conceivable that for some viruses hard-to-measure minor effects on attachment can amplify in a manner they become statistically robust only late in infection.…”

LRP6 Is a Functional Receptor for Attenuated Canine Distemper Virus

“…Low-density lipoprotein (LDL) receptors belong to an evolutionarily ancient family of endocytic receptors that are known to be hijacked as docking sites by a group of viruses ( 51 , 52 ), bacterial toxins ( 53 , 54 ), and endogenous proteins that are associated with Alzheimer's disease ( 55 , 56 ). Recently, Rift Valley fever virus ( 57 ) and Oropouche orthobunyavirus ( 58 ) were shown to bind LRP1, and the low-density lipoprotein receptor class A domain-containing 3 (LDLRAD3) was discovered to act as a receptor for Venezuelan equine encephalitis virus ( 59 ). Furthermore, LRP1 was also found to be an important host factor for the different stages of RNA virus infection, including VSV, Sandfly fever Sicilian virus, encephalomyocarditis virus, as well as Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), and SARS-CoV-2 ( 60 ).…”