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First Author:  Wei, Wan, Yan, Wang, Zhang et al.  

Journal/preprint name: BioRxiv 

Tags: Virology, Viral Entry, Lipid metabolism, cholesterol, in vitro 

Summary 

Viral entry of SARS-CoV-2 is mediated through receptor recognition of angiotensin-converting enzyme 2 (ACE2). However, eventual co-receptors which could promote viral uptake into cells remain largely unknown. In this preprint, Wei et al. demonstrate that in the presence of high-density lipoprotein (HDL) particles, SARS-CoV-2 shows increased uptake into cells which is dependent on the S1 subunit of the viral spike protein. This uptake is mediated by the HDL receptor SR-B1. Although S1 does not directly bind to SR-B1, the authors find evidence that S1 interacts with the cholesterol and thereby increasing the chances to find ACE2 for viral uptake. Overexpression of SR-B1 in the presence of HDL and ACE2 increases viral replication, conversely transitory inhibition of SR-B1 inhibits viral replication. Inhibition of SR-B1 pharmacologically inhibits viral production and viral entry. It remains to be seen if this pathway is exploited by the virus in vivo, especially since cholesterol is significantly lowered in more severe COVID19. 

Research Highlights 

  1. SARS-CoV-2 spike protein associates to HDL and cholesterol using cholesterol recognition motifs in the S1 subunit. 

  1. SR-B1 (HDL uptake receptor) overexpression increases uptake of SARS-CoV-2, while SR-B1 siRNA-mediated downregulation decreases viral infection. 

  1. SR-B1-enhanced viral uptake requires ACE2 expression since SR-B1 overexpression in the absence of ACE2 does not lead to viral infection. 

  1. SARS-CoV-2 spike protein does not bind to SR-B1 directly, but rather to cholesterols. 

  1. Pharmacological inhibition of SR-B1 using ITX5061 reduces SARS-CoV-2 viral entry and replication.  

Impact for COVID-19 research:  

  • This research outlines a potential mechanism through which specific patient groups may have increased risk of severe COVID19 pathology, such as atherosclerotic patients who have higher SR-B1 expression in arteries than non-atherosclerotic patients. 

  • These results provide an interesting new candidate for inhibiting viral entry in vivo (but further in vivo validation is required).  

Methodologies: 

  • Study Typein vitro 

  • Important cell lines/viral models used: various cell lines (293T, Vero E6, MDCK, Hepa1-6, Huh-7), SARS-CoV-2-pseudovirus (based on HIV backbone) and SARS-CoV-2 (clinical isolate) 

  • Key Techniques: Standard molecular, cellular and virological tools  

Limitations: 

  • Distinction of viral uptake and viral replication sometimes difficult. Since many viral uptake data is based on expression of luciferase vector which could also arise from differences in viral replication speed due to changed cellular cholesterol uptake. Non-replicating vector may be preferred to answer the question of sole effect on viral uptake. 

  • Relevance of this finding in the context of in vivo decrease of circulating cholesterol levels would be of interest.  

  • In vivo data of SR-B1 expression from post-mortem lung tissue as well from animal models are required for determination of biological relevance in disease pathology. 

  • Since the structure of S1 is known, it would help the manuscript to identify the structure position of the cholesterol binding sites and whether they are also crucial in the context of lipid raft recognition.