BREAKING! European And Canadian Study Discovers A New SARS-CoV-2 Human Host Receptor Called LRP1 Which Also Explains Certain Aspects Of Disease Progression

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.


 
Low density lipoprotein receptor-related protein 1 (LRP1), also known as alpha-2-macroglobulin receptor (A2MR), apolipoprotein E receptor (APOER) or cluster of differentiation 91 (CD91), is a protein forming a receptor found in the plasma membrane of cells involved in receptor-mediated endocytosis.
 
It is encoded by the LRP1 gene. LRP1 is also a key signaling protein and, thus, involved in various biological processes, such as lipoprotein metabolism and cell motility, and diseases, such as neurodegenerative diseases, atherosclerosis, and cancer.
 
LRP1 is also a scavenger-type receptor involved in a wide variety of cell activities like migration, proliferation, differentiation, but also regulation of cholesterol homeostasis, inflammation, or clearance of plasma proteins from the blood stream.
 
It is important for the integrity of blood-brain barrier and can bind and internalize more than 40 different ligands (including apoptotic bodies or the Alzheimer disease-associated tau protein).
 
Most importantly, LRP1 modulates signalling pathways like e.g. those by JAK/STAT, ERK1/2 or TGF-ß.
 
Besides the liver, LRP1 is also detectable in tissues like brain, respiratory system, kidney, sexual organs and connective and soft tissues. Cell types with highest LRP1 levels are hepatocytes, Leydig cells, brain cells like microglia and astrocytes, syncytiotrophoblasts, skeletal myocytes, fibroblasts, peritubular cells, and monocytes/macrophages.
 
Because of the abundance of LRP1 in these cells, tissues and organs, we suspect cell tropism of SARS-CoV-2 towards these and resulting disruption, dysfunction or damage in these cells, tissues and organs.
 
Already it is believed that neurodegenerative issues, liver and also male testicular issues arising in COVID-19 could have the LRP1 playing a key role.
 
The study team, in order to identify novel pro-viral host cell factors, 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).
 
Interestingly 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, f amily Picornaviridae), and the coronaviruses MERS-CoV, SARS-CoV-1, and SARS-CoV-2.
 
Although 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.
 
Significantly, 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.
 
Hence the study findings identified LRP1 as a host factor that supports various infection cycle stages of a broad spectrum of RNA viruses including the SARS-CoV-2.
 
The 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
 
The study 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.
 
Another study also showed that LRP1 acts as a receptor of RVFV by binding to the viral envelope protein and mediating its entry into the cytoplasm, hence collaborating this study. https://pubmed.ncbi.nlm.nih.gov/34559985/
 
Importantly, it was also found that some viruses including SARS-CoV-2 also require LRP1 for the later stages of infection. Like all positive-stranded RNA viruses, coronaviruses are known to intensively reorganize internal cell membranes in order to generate compartments that can serve as a safe space for transcription and replication of the genome RNA, and to assemble progeny particles.
 
As LPR1 is mostly cycling between the plasma membrane and the endosomes, it may transport factors critical for the RNA replication of SARS-coronaviruses, e.g. lipids required for the formation of virally-induced intracellular membrane compartments.
 
Interestingly, in HuH-7 cells the late-stage requirement for LRP1 was only present for SARS-CoV-1 and SARS-CoV-2 (subgenus Sarbecovirus, genus Betacoronavirus), but not for the related MERS-CoV (subgenus Merbecovirus, genus Betacoronavirus), while the early-stage requirement for LRP1 was observed for both these betacoronavirus subgenera.
 
Corresponding author, Dr Friedemann Weber, a professor at the Institute for Virology at Justus-Liebig University told Thailand Medical News, “It is hence possible that the SARS-coronaviruses engage LRP1 for two different viral activities, attachment and late-stage replication, whereas for MERS-CoV it may be only attachment or, alternatively, the requirement for the later infections stages is not as strict as for the SARS-coronaviruses.”
 
Also, it was noted that the SARS-CoV-2 exhibited the most profound LRP1-dependency in the hepatic HuH-7 cells, impacting both the early attachment step and the subsequent RNA synthesis. HuH-7 cells are of hepatic origin, and SARS-CoV-2 is capable of infecting and damaging organs including the liver. https://pubmed.ncbi.nlm.nih.gov/15780065/

https://pubmed.ncbi.nlm.nih.gov/33692570/
 
https://pubmed.ncbi.nlm.nih.gov/33332624/
 
https://pubmed.ncbi.nlm.nih.gov/32437830/
 
Aside from the liver, LRP1 is found extensively in tissues of the brain, respiratory system, kidney, sexual organs and connective and soft tissues.
 
The cell types with highest LRP1 levels are hepatocytes, Leydig cells, brain cells like microglia and astrocytes, syncytiotrophoblasts, skeletal myocytes, fibroblasts, peritubular cells, and monocytes/macrophages.
 
The study team suggest that more detailed studies may reveal whether in these and other cell types LRP1 is contributing to the cell tropism of SARS-CoV-2.
 
It was however found that in Calu-3 cells, LRP1 was neither required early in infection nor for virus yields, but exclusively for late-stage RNA synthesis. Like Calu-3, alveolar cells and other epithelial cells express much lower levels of LRP1 as hepatocytes, indicating that factors other than LRP1 are mainly supporting SARS-CoV-2 attachment and entry. Thus, apparently, early-stage LRP1 usage by SARS-CoV-2 is cell type-dependent, whereas the late-stage requirement for RNA synthesis is general.
 
The study team concluded, “Taken together, our study findings have identified LRP1 as a broadly active pro-viral factor that enables entry of RNA viruses. In some cases, most prominently SARS-CoV-1 and SARS-CoV-2, LRP1 is also facilitating the late stage of infection. It will be interesting to find out how SARS-coronaviruses are engaging LRP1 for their intracellular replication, and by which alternative mechanism MERS-CoV is circumventing LRP1 at the late stage of infection.”
 
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