Low-density lipoprotein receptor–related protein 1 (LRP1) as an auxiliary host factor for RNA viruses

Abstract

Viruses with an RNA genome are often the cause 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 are resistant to Rift Valley fever virus (RVFV). This screen returned the low-density lipoprotein receptor–related protein 1 (LRP1) as a top hit, a plasma membrane protein involved in a wide variety of cell activities. Inactivation ofLRP1in human cells reduced RVFV RNA levels already at the attachment and entry stages of infection. Moreover, the role of LRP1 in promoting RVFV infection was dependent on physiological levels of cholesterol and on endocytosis. In the human cell line HuH-7, LRP1 also promoted early infection stages of sandfly fever Sicilian virus and La Crosse virus, but had a minor effect on late infection by vesicular stomatitis virus, whereas encephalomyocarditis virus was entirely LRP1-independent. Moreover, siRNA experiments in human Calu-3 cells demonstrated that also SARS-CoV-2 infection benefitted from LRP1. Thus, we identified LRP1 as a host factor that supports infection by a spectrum of RNA viruses.

Identification of host factors for Rift Valley Fever Phlebovirus

“…These results demonstrate that the knock-down of WDR7 and LRP1 significantly impaired RVFV replication. Given that the role of LPR1 gene in RVFV replication has been recently demonstrated [29,37], we focused our further analysis on the newly discovered putative RVFV host factor WDR7 .…”

“…To investigate the role of WDR7 in the RVFV and LACV replication cycle, we quantified intracellular viral RNA accumulation at 0 hour(s) post-infection (h pi; attachment phase), 2 h pi (entry phase), 5 h pi (replication phase) and 24 h pi (late phase of replication) using previously established protocols [37,47]. At 0, 2 and 5 h pi, there was no significant difference in RVFV RNA accumulation between the control and WDR7 KO cells ( Fig 4A ).…”

“…The viral RNA accumulation was determined at various time points (0, 2, 5 and 24 hours) post-infection (h pi) as previously described [37,47]. The CT and WDR7 KO 1 cells were plated in 6-well plates.…”

“…Like many other RNA viruses, RVFV depends on various host factors to complete its replication cycle [27][28][29]. Several groups have conducted exploratory studies aimed to find host factors or co-factors that might play a role in RVFV replication [27,[29][30][31][32][33][34][35][36][37]. Notably, other researchers have shown that LRP1 [29,37], heparin sulfate [33] play essential roles in cell entry of RVFV.…”

“…Several groups have conducted exploratory studies aimed to find host factors or co-factors that might play a role in RVFV replication [27,[29][30][31][32][33][34][35][36][37]. Notably, other researchers have shown that LRP1 [29,37], heparin sulfate [33] play essential roles in cell entry of RVFV. Furthermore, exogenous administration of the LRP1 inhibitor mRAPD3 protected mice from infection with a virulent strain of RVFV [29].…”