Low Density Lipoprotein Receptor-Related Protein 1 (LRP1) is a host factor for SARS-CoV-2

Researchers from the Institute for Virology at Liebig University-Germany together with scientists from Austrian Academy of Sciences (IMBA)-Austria, the Public Health Agency of Sweden, Karolinska Institutet-Sweden, University of British Columbia-Canada and the Centre for Infection Research (DZIF)-Germany have in a new study discovered that the Low Density Lipoprotein Receptor-Related Protein 1 (LRP1) is also host factor for RNA viruses including SARS-CoV-2 and this can also help explain certain aspects in the progression of the COVID-19 disease.

he study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2022.02.17.480904v1

Most pandemics, epidemics, and zoonotic spillover infections are caused by enveloped RNA viruses (1- 3). These pathogens contain an RNA genome of positive-sense or negative-sense polarity that is encapsidated by a viral nucleoprotein and surrounded by a lipid bilayer containing transmembrane glycoproteins. Although RNA viruses are phylogenetically very diverse, it is conceivable that all are depending on common basic factors of the cell.

Rift Valley fever virus (RVFV; family Phleboviridae, order Bunyavirales) is an emerging zoonotic negative-strand RNA virus (4) that is listed by the WHO among the pathogens posing the greatest public health risk (2). Using RVFV as a model, we aimed to identify host cell factors supporting the replication cycle of RNA viruses.

An insertion-mutagenized haploid cell library was screened for clones with resistance to the highly cytopathogenic RVFV as an indication that the deleted gene is essential for viral replication.

As top ranking hit emerged the Low Density Lipoprotein Receptor-Related protein 1 (LRP1), a large plasma membrane receptor that can bind and internalize more than 40 different ligands.

Indeed, a lack of LRP-1 reduced the ability of RVFV to attach to the cell surface and enter the cytoplasm, whereas RNA levels seemed not to be affected. Subsequent experiments using human HuH-7 knockout cells revealed that LRP1 is also a host cell factor for other, RVFV-related and –unrelated RNA viruses, most prominently human pathogenic coronaviruses SARS-CoV-1 and SARS-CoV-2.

Depending on the particular virus, however, LRP1 was important for different infection steps ranging from particle attachment to late-stage viral RNA synthesis.

Our study may thus establish LRP-1 as a broad-band host factor for many RNA viruses that acts not exclusively on attachment but in some cases at later stages of the replication cycle. Moreover, we show that SARS-coronaviruses are among the most LRP1- dependent viruses.