Viral infections can appear like a runaway train, careering through the human body without a brake in sight; however, the meandering journey taken for the development of antivirals has now discovered a new way to stop runaway SARS-CoV-2 infections in their tracks thanks to CRISPR technology and a trip through the chromatin landscape of infected cells.
A highly “trained” team of researchers led by Ruilin Tian and Martin Kampmann (University of California San Francisco) aimed to uncover druggable pathways that interrupt binding of the SARS-CoV-2 spike protein to the angiotensin-converting enzyme 2 (ACE2) cell surface receptor in human cells (which initiates infection) using a focused CRISPR interference (CRISPRi)-based screen. In contrast to previous studies that assayed cells overexpressing an ACE2 transgene or non-target/non-human cell types, the authors employed an ACE2-expressing lung epithelial cancer cell line (Calu-3) in their screens and other relevant cell/animal models to confirm regulators of ACE2 expression as potential therapeutic strategies for COVID-19.
All aboard! Let’s hear how Samelson and colleagues timetabled their research, mapped out their route, and revealed how disrupting chromatin interactions with the transcriptional machinery might stop SARS-CoV-2 in its tracks:
- A CRISPRi screen using a single guide RNA library (~16,000 RNAs) targeting the ‘druggable genome’ (~2,300 genes) in Calu-3 cells revealed a decrease in SARS-CoV-2 Spike protein binding after knockdown of two genes:
- BRD2 inhibition, using current clinically-evaluated small molecules, downregulates endogenous ACE2 expression in Calu-3 cells as well as in induced pluripotent stem cell (iPSC)-derived cardiomyocytes and primary human lung epithelial cells (which are both susceptible to SARS-CoV-2 infection)
- BRD2 inhibition also reduces ACE2/interferon-stimulated gene expression and stops SARS-CoV-2 infection in reconstructed primary human nasal epithelia and golden Syrian hamsters, which represent physiologically-relevant models
- The inhibition of BRD2 appears to directly regulate ACE2 transcription, alongside additional SARS-CoV-2 infection-induced genes such as those related to the interferon antiviral response
- BRD2 inhibition also blocks the interferon-stimulated expression of ACE2, which indicates a potential indirect effect on ACE2 expression
This exciting new research takes us one stage of the journey closer to the desired destination. Overall, the data supports BRD2 as a critical regulator of SARS-CoV-2 infection and highlights the disruption of chromatin interactions as a possible means to stop a viral runaway train in its tracks and prevent the development of severe COVID-19 cases.
Pack your bags, pick up a ticket, and take a journey over to Nature Cell Biology, January 2022.