Lrp1 is a host entry factor for Rift Valley fever virus

Ganaie, Safder S.; Schwarz, Madeline M.; McMillen, Cynthia M.; Price, David A.; Feng, Annie; Albe, Joseph R.; Wang, Wenjie; Miersch, Shane; Orvedahl, Anthony; Cole, Aidan R; Sentmanat, Monica F.; Mishra, Nawneet; Boyles, Devin A.; Koenig, Zachary T.; Kujawa, Michael R.; Demers, Matthew A.; Hoehl, Ryan M.; Moyle, Austin B.; Wagner, Nicole D.; Stubbs, Sarah H.; Cardarelli, Lia; Teyra, Joan; McElroy, Anita K.; Gross, Michael L.; Whelan, Sean P. J.; Doench, John G.; Cui, Xiaoxia; Brett, Tom J.; Sidhu, Sachdev S.; Virgin, Herbert W.; Egawa, Takeshi; Leung, Daisy W.; Amarasinghe, Gaya K.; Hartman, Amy L.

doi:10.1016/j.cell.2021.09.001

Cited by 84 publications

(99 citation statements)

References 52 publications

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“…Our findings indicate that many viruses are aided by LRP1 at their attachment and entry step, as might be expected from a membrane protein involved in constitutive endocytosis. In agreement with these findings, a recent study (published while our manuscript was in preparation) showed that LRP1 acts as a receptor of RVFV by binding to the viral envelope protein and mediating its entry into the cytoplasm (15). Interestingly however, some virusesincluding SARS-CoV-2 -also require LRP1 for the later stages of infection.…”

Section: Discussionsupporting

confidence: 80%

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

Devignot

Sha

Burkard

et al. 2022

Preprint

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Viruses with an RNA genome are the main causes of zoonotic infections. In order to identify novel pro-viral host cell factors, we screened a haploid insertion-mutagenized mouse embryonic cell library for clones that rendered them resistant to the zoonotic Rift Valley fever virus (RVFV; family Phleboviridae, order Bunyavirales). This screen returned the Low Density Lipoprotein Receptor-Related protein 1 (LRP1, or CD91) as top hit, a 600 kDa plasma membrane protein known to be involved in a wide variety of cell activities. Inactivation of LRP1 expression in human cells reduced RVFV infection at the early stages of infection, including the particle attachment to the cell. In the highly LRP1-positive human HuH-7 cell line, LRP1 was required for the early infection stages also of Sandfly fever Sicilian virus (SFSV; family Phleboviridae, order Bunyavirales), vesicular stomatitis (VSV; family Rhabdoviridae, order Mononegavirales), Encephalomyocarditis virus (EMCV, family Picornaviridae), and the coronaviruses MERS-CoV, SARS-CoV-1, and SARS-CoV-2. While for RVFV, EMCV, and MERS-CoV the replication cycle could eventually catch up, LRP1 requirement for the late infection stage in HuH-7 cells was observed for SFSV, La Crosse virus (LACV; family Peribunyaviridae, order Bunyavirales), VSV, SARS-CoV-1, and SARS-CoV-2. For SARS-CoV-2, the absence of LRP1 stably reduced viral RNA levels in human lung Calu-3 cells, and both RNA levels and particle production in the hepatic HuH-7 cells. Thus, we identified LRP1 as a host factor that supports various infection cycle stages of a broad spectrum of RNA viruses.

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Section: Discussionsupporting

confidence: 80%

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

Devignot

Sha

Burkard

et al. 2022

Preprint

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“…Clonal BV2 knockout (KO) cell lines that are deleted for either Lrp1 or the Lrp1 chaperone protein RAP express significantly reduced levels of Lrp1, and this was visualized and quantified using immunofluorescence and western blot ( Fig. S1B-D ) (Ganaie et al ., 2021). Infection of both Lrp1 and RAP clonal KO cell lines with OROV resulted in significantly less infectious virus produced by 24 hpi when compared to infection of BV2 wt cells ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Recombinant Fc-fusions of the Lrp1 CL domains were shown to block RVFV infection (Ganaie et al ., 2021). We treated Vero E6 cells with soluble Fc-fused CL II and CL IV proteins (Ganaie et al ., 2021) and compared the relative infection to untreated cells and Fc-control treated cells. We observed that CL II and CL IV treatment significantly reduced OROV infection compared to the Fc-control treated cells ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Domain 3 of RAP specifically binds to two extracellular cluster domains of Lrp1 (CLII and CLIV) (Fig. 2A) and competes for attachment with other compatible ligands while chaperoning the protein through the ER to the cell surface (Bu, 2001;Ganaie et al, 2021). Here, we tested the ability of exogenous mouse RAPD3 (mRAPD3) to block OROV infection by adding it before infection, at the time of infection, or following infection (Fig.…”

Section: Rap (Receptor-associated Protein or Lrpap1mentioning

confidence: 99%

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Oropouche orthobunyavirus infection is mediated by the cellular host factor Lrp1

Schwarz

Price

Ganaie

et al. 2022

Preprint

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Oropouche orthobunyavirus (OROV; Peribunyaviridae) is a mosquito-transmitted virus that causes widespread cases of human febrile illness in South America, with occasional progression to neurologic effects. Host entry factors mediating cellular entry of OROV are undefined. Here, we show that OROV requires the host protein low density lipoprotein-related protein 1 (Lrp1) for 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. Thus, Lrp1 is an important host factor required for infection of cells by OROV. Taken together with our results showing that Lrp1 is a newly identified receptor for Rift Valley fever virus (RVFV), Lrp1 may play a broader role in cellular infection by bunyaviruses.

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“…The ability of some alphaviruses to bind LDLR family members probably accounts for their extensive tissue and species tropism. Many viruses, including vesicular stomatitis virus 34 , minor group rhinoviruses 39 , 40 , subgroup A Rous sarcoma virus 41 , several Flaviviridae family members 42 – 44 , VEEV 3 and Rift Valley fever virus 45 , have been reported to bind LDLR-repeat-containing receptors to enter cells. LDLR is also a receptor for Clostridium difficile toxin A 46 .…”

Section: Mainmentioning

confidence: 99%

VLDLR and ApoER2 are receptors for multiple alphaviruses

Clark

Lin

et al. 2021

Nature

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Alphaviruses, like many other arthropod-borne viruses, infect vertebrate species and insect vectors separated by hundreds of millions of years of evolutionary history. Entry into evolutionarily divergent host cells can be accomplished by recognition of different cellular receptors in different species, or by binding to receptors that are highly conserved across species. Although multiple alphavirus receptors have been described 1 – 3 , most are not shared among vertebrate and invertebrate hosts. Here we identify the very low-density lipoprotein receptor (VLDLR) as a receptor for the prototypic alphavirus Semliki forest virus. We show that the E2 and E1 glycoproteins (E2–E1) of Semliki forest virus, eastern equine encephalitis virus and Sindbis virus interact with the ligand-binding domains (LBDs) of VLDLR and apolipoprotein E receptor 2 (ApoER2), two closely related receptors. Ectopic expression of either protein facilitates cellular attachment, and internalization of virus-like particles, a VLDLR LBD–Fc fusion protein or a ligand-binding antagonist block Semliki forest virus E2–E1-mediated infection of human and mouse neurons in culture. The administration of a VLDLR LBD–Fc fusion protein has protective activity against rapidly fatal Semliki forest virus infection in mouse neonates. We further show that invertebrate receptor orthologues from mosquitoes and worms can serve as functional alphavirus receptors. We propose that the ability of some alphaviruses to infect a wide range of hosts is a result of their engagement of evolutionarily conserved lipoprotein receptors and contributes to their pathogenesis.

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Lrp1 is a host entry factor for Rift Valley fever virus

Cited by 84 publications

References 52 publications

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

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

Oropouche orthobunyavirus infection is mediated by the cellular host factor Lrp1

VLDLR and ApoER2 are receptors for multiple alphaviruses

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