Identify Host Factors for SARS-CoV-2 and Common Cold Coronaviruses

Authors:
Wang R, Simoneau CR, Kulsuptrakul J, Bouhaddou M, Travisano KA, Hayashi JM, Carlson-Stevermer J, Zengel JR, Richards CM, Fozouni P, Oki J, Rodriguez L, Joehnk B, Walcott K, Holden K, Sil A, Carette JE, Krogan NJ, Ott M, Puschnik AS
In:
Source: Cell
Publication Date: (2021)
Issue: Jan 7;184(1): 106-119.e14.
Research Area:
Basic Research
Cells used in publication:
HuH7
Species: human
Tissue Origin: liver
A549
Species: human
Tissue Origin: lung
Platform:
4D-Nucleofector® 96-well Systems
384-well HT Nucleofector® System
Experiment

Generation of RNP edited A549-ACE2 and Huh7.5.1-ACE2/TMPRSS2 cells

All cells were dissociated into single cells using TrypLE Express (GIBCO), as described above, resuspended in culture media and counted. For A549-ACE2 transfections, 100,000 cells per reaction were used while for Huh7.5.1-ACE2/TMPRSS2 200,000 cells per reaction were used. Cells were pelleted by centrifugation at 200 xg for 5 min. Following centrifugation, cells were resuspended in transfection buffer according to cell type. 5 mL of cell solution was added to preformed RNP solution and gently mixed. Nucleofections were performed on a Lonza HT 96-well nucleofector system using program CM-120 and CM-104 for A549-ACE2 and Huh7.5.1-ACE2/TMPRSS2, respectively. All transfections were performed in Lonza SE buffer. Immediately following nucleofection, each reaction was divided evenly between two wells of a tissue-culture treated 96-well plate containing 100mL normal culture media.


Abstract

The Coronaviridae are a family of viruses that cause disease in humans ranging from mild respiratory infection to potentially lethal acute respiratory distress syndrome. Finding host factors common to multiple coronaviruses could facilitate the development of therapies to combat current and future coronavirus pandemics.
Here,we conducted genome-wide CRISPRscreens in cells infected by SARS-CoV-2 as well as two seasonally circulating common cold coronaviruses, OC43 and 229E. This approach correctly identified the distinct viral entry factors ACE2 (forSARS-CoV-2), aminopeptidaseN(for 229E), and glycosaminoglycans (forOC43). Additionally,
we identified phosphatidylinositol phosphate biosynthesis and cholesterol homeostasis as critical host pathways supporting infection by all three coronaviruses.By contrast, the lysosomal protein TMEM106B appeared unique to SARS-CoV-2 infection. Pharmacological inhibition of phosphatidylinositol kinases and
cholesterol homeostasis reduced replication of all three coronaviruses. These findings offer important insights for the understanding of the coronavirus life cycle and the development of host-directed therapies.