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1105 Data Byte COVID host factors
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Targets & Mechanisms

Data Byte: newly identified host factors that regulate ACE2 expression

Nov 6, 2020 | 1:29 AM GMT

Several recent publications highlighting host factors that modulate ACE2 expression point to possible new targets for COVID-19 therapies. 

ACE2 and TMPRSS2 are the most common host targets of COVID-19 therapies in development aimed at decreasing SARS-CoV-2 cell entry, according to BioCentury’s COVID-19 Resource Center

Over the last few months, three teams performed genome-scale CRISPR screens and identified additional host factors that affect SARS-CoV-2 cell entry — some by regulating ACE2 expression.

Yale School of Medicine and Broad Institute of MIT and Harvard scientists published data in Cell last month showing that HMGB1, a DNA binding protein that regulates chromatin, intrinsically regulates ACE2 expression. Disrupting HMGB1 protected SARS-CoV-2-induced cell death and diminished chromatin accessibility, decreased acetylation immediately downstream of the ACE2 transcription start site and reduced ACE2 mRNA transcripts.

Researchers from New York University and Icahn School of Medicine at Mount Sinai showed, also in Cell last monththat loss of RAB7A reduces viral entry by sequestering the ACE2 receptor inside cells.

In an August BioRxiv preprint, a team led by Shanghai Medical College researchers identified five genes that regulate cell surface expression of ACE2. While the mechanisms by which they regulate ACE2 are unknown, all five genes are known to be involved in retrieval and recycling complexes. 

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The groups identified many additional gene clusters affecting SARS-CoV-2 entry via pathways including cholesterol biosynthesis, though the precise mechanism by which changes in cholesterol disrupted viral infection has yet to be elucidated. 

Separately, a pair of Science studies published in October showed NRP1 facilitates SARS-CoV-2 cell entry.

A team led by German Center for Neurodegenerative Diseases and University of Helsinki scientists found that an NRP1-blocking antibody reduced virus infection of Caco-2 cells by ~40%. In autopsies from six COVID-19 patients, SARS-CoV-2-infected olfactory epithelial cells and olfactory neurons showed high NRP1 expression.

A University of Bristol group demonstrated that one of the cleaved SARS-CoV-2 S polypeptides binds directly to NRP1, and blocking the interaction using RNAi or selective inhibitors reduced SARS-CoV-2 entry and infectivity in cell culture.

TARGETS
CCDC22 – Coiled-coil domain containing 22 
COMMD3 – COMM domain containing 3 
HMGB1 – High mobility group box 1 
NRP1 – Neuropilin 1
RAB7A – RAB7A member RAS oncogene family
SARS-CoV-2 S – SARS-CoV-2 spike protein 
VPS29 – Vacuolar protein sorting 29 homolog 
VPS35 – Vacuolar protein sorting 35 homolog 
WASHC3 (CCDC53) – WASH complex subunit 3 

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