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ARF6 is a host factor for SARS-CoV-2 infection in vitro
C Mirabelli1,2, J Bragazzi Cunha3, J W Wotring4
1Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
The Journal of General Virology
|June 21, 2023
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into cells relies on cholesterol, not dynamin. ADP-ribosylation factor 6 (ARF6) inhibition reduces viral infection, suggesting ARF6 as a potential antiviral target.
Area of Science:
- Virology
- Cell Biology
- Molecular Medicine
Background:
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes ACE2 and other factors for cell entry, primarily through plasma membrane fusion or endocytosis.
- Viral entry via the endocytic pathway remains less understood compared to direct fusion.
- Host factors like ADP-ribosylation factor 6 (ARF6) are implicated in viral replication and infection.
Purpose of the Study:
- To investigate the mechanisms of SARS-CoV-2 entry through the endocytic pathway.
- To evaluate the role of dynamin and cholesterol in SARS-CoV-2 endocytosis.
- To assess ADP-ribosylation factor 6 (ARF6) as a potential host factor and therapeutic target for SARS-CoV-2 infection.
Main Methods:
- Utilized Huh-7 cells, resistant to camostat, to study SARS-CoV-2 entry independent of TMPRSS2.
- Employed CRISPR/Cas9 genetic deletion to assess the impact of ARF6 on viral uptake and infection.
- Administered pharmacological inhibition of ARF6 using NAV-2729 in cell lines and organoid models.
Main Results:
- SARS-CoV-2 entry in Huh-7 cells was found to be cholesterol-dependent, not dynamin-dependent.
- CRISPR/Cas9-mediated deletion of ARF6 resulted in a modest reduction in SARS-CoV-2 uptake and infection.
- Pharmacological inhibition of ARF6 with NAV-2729 demonstrated a dose-dependent decrease in viral infection across cell lines and kidney organoids.
Conclusions:
- Cholesterol plays a significant role in SARS-CoV-2 endocytic entry.
- ADP-ribosylation factor 6 (ARF6) is a crucial host factor for SARS-CoV-2 replication and infection in various cellular contexts.
- Targeting ARF6 with inhibitors like NAV-2729 presents a promising antiviral strategy against SARS-CoV-2.
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