Researchers from the University of California, San Diego and UC Riverside have further elucidated the molecular pathway used by the SARS-CoV-2 virus to infect human lung cells, identifying a key host cell player that may prove to be a new durable therapeutic target for the treatment of COVID -19.
The results are published in the January 23, 2023 issue of PNAS.
To enter and infect host cells, the SARS-CoV-2 virus deploys its signature spike proteins to bind to a cell surface receptor called angiotensin-converting enzyme (ACE2), triggering the expression of another enzyme called transmembrane serine protease 2 (TMPRSS2) that results in the generation of new virus particles that help advance COVID-19 disease.
Much research has been conducted to find ways to inhibit or disrupt the ACE2/TMPRSS2 pathway, in order to make it more difficult for the SARS-CoV-2 virus to replicate and spread. In the new study, Rana and colleagues highlight the role of another enzyme, which could provide a new therapeutic target and the possibility of broader and longer-lasting protection against current variants of COVID-19 and those that do not. haven’t emerged yet.
The enzyme is called phosphorylated CTD-interacting factor 1 or PCIF1, which regulates cellular entry through the mediation of the activity of N6,2-O-dimethyladenosine (m6Am), a conserved and abundant mRNA modification during evolution. The researchers found that PCIF1 promotes the stability of ACE2 and TMPRSS2 mRNAs, supporting two key entry factors for SARS-CoV-2 and other coronaviruses.
“Essentially, it’s like once SARS-CoV-2 opens the door to a cell, PCIF1 helps keep the door open,” said lead author Tariq Rana, PhD, professor emeritus of pediatrics at UC San Diego School of Medicine and a faculty member of the Institute of Genomic Medicine and Moores Cancer Center at UC San Diego Health.
Rana and her colleagues validated their findings using primary normal human bronchial cells, which line the passageways of the lungs and act as a defensive barrier against pathogens. They also found, not described in this publication, positive correlations between PCIF1 and ACE2/TMPRSS2 expression levels in human lung tissue.
Fundamentally, the researcher said, the results point to a novel approach to reducing or blocking SARS-CoV-2 infections. Currently, Paxlovid (a combination of two antiviral drugs) is being used to treat early cases of COVID-19. It works by directly targeting the virus itself, but may lose effectiveness as the virus mutates and new, concerning drug-resistant variants emerge.
Rana said the new findings argue for the development of drugs that target host cell factors, such as PCIF1 and TMPRSS2.
By doing so, there is less potential for drug resistance. And in combination with viral-targeting agents, there could be a synergistic effect that more broadly and effectively protects against the coronavirus, both current and emerging strains. »
Tariq Rana, PhD, lead author
University of California San Diego
Wang, L. et al. (2023) PCIF1-mediated deposition of 5′-cap N6,2′-O-dimethyladenosine in ACE2 and TMPRSS2 mRNA regulates susceptibility to SARS-CoV-2 infection. PNAS. doi.org/10.1073/pnas.2210361120.
. researchers identify key actor cell host in infections COVID19