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LRRC15 inhibits SARS-CoV-2 cellular entry in trans
Jaewon Song1, Ryan D Chow2, Mario A Peña-Hernández3,4
1Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, Rhode Island, United States of America.
Plos Biology
|October 13, 2022
Summary
Researchers discovered LRRC15 as a novel protein that inhibits SARS-CoV-2 entry. This finding offers new insights into controlling viral infections by identifying a key factor that blocks virus attachment and entry into cells.
Area of Science:
- Virology
- Cell Biology
- Immunology
Background:
- Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) utilizes the angiotensin-converting enzyme 2 (ACE2) receptor for cellular entry.
- While viral entry facilitators are well-studied, cellular factors that inhibit viral entry remain largely unknown.
Purpose of the Study:
- To identify novel cellular factors that inhibit SARS-CoV-2 entry.
- To characterize the mechanism and physiological role of identified inhibitory factors.
Main Methods:
- A surfaceome CRISPR activation screen was employed to identify inhibitory factors.
- Direct binding assays were performed to assess the interaction between LRRC15 and the SARS-CoV-2 spike protein receptor-binding domain (RBD).
- Analysis of human lung single-cell RNA sequencing data was conducted to determine LRRC15 expression patterns.
Main Results:
- Human LRRC15 was identified as an inhibitory attachment factor for SARS-CoV-2.
- LRRC15 directly binds to the SARS-CoV-2 spike protein RBD, inhibiting viral entry.
- LRRC15 is expressed in lung fibroblasts, particularly pathological fibroblasts in COVID-19 patients, and is not coexpressed with ACE2.
- LRRC15 in ACE2-negative cells can inhibit viral entry into ACE2-positive cells in trans.
Conclusions:
- LRRC15 acts as a SARS-CoV-2 inhibitory attachment factor, directly blocking viral entry.
- The non-coexpression of ACE2 and LRRC15, along with LRRC15's trans-inhibitory function, suggests a protective role in lung physiology.
- LRRC15 represents a potential therapeutic target for modulating SARS-CoV-2 infection.
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