# FGFR signaling and neddylation facilitate SARS-CoV-2 infection by modulating interferon induction and viral entry, respectively

## TL;DR

This study identifies host factors NAE1 and FGFR1 that help SARS-CoV-2 infect cells and suggests targeting them as a potential treatment for COVID-19.

## Contribution

The study discovers NAE1 and FGFR1 as host dependency factors for SARS-CoV-2 and shows that their inhibition reduces viral replication and lung damage.

## Key findings

- Inhibitors of NAE1 and FGFR1 reduce replication of SARS-CoV-2 variants in human cells.
- NAE1 supports early stages of infection, likely viral entry, while FGFR1 suppresses interferon induction.
- Inhibiting NAE1 and FGFR1 decreases viral load and lung pathology in a murine model of severe COVID-19.

## Abstract

SARS-CoV-2 is the causative agent of COVID-19, and although vaccines have reduced disease severity, emerging variants remain a significant public health issue. Broadly effective therapeutics, particularly those targeting host pathways essential for coronavirus infection, are still needed. Here, we used a CRISPR knockout screen to identify druggable host factors required for SARS-CoV-2 infection. The screen revealed NAE1 and FGFR1 as key contributors to infection. Inhibitors, either FDA-approved or those in clinical trials, of these pathways reduced replication of both ancestral and contemporary viral variants. Mechanistic studies showed that FGFR1 promotes viral replication through downstream MEK/ERK signaling, while neddylation appears to support viral entry or infectivity rather than replication itself. In a murine model of severe COVID-19, inhibitors of NAE1 and FGFR1 significantly decreased viral load and lung pathology. These findings support the development of host-targeted antiviral strategies.

•NAE1 and FGFR1 are host dependency factors for SARS-CoV-2•NAE1 activity is important at early stages of infection, likely viral entry•FGFR1 and downstream signaling suppress interferon induction

NAE1 and FGFR1 are host dependency factors for SARS-CoV-2

NAE1 activity is important at early stages of infection, likely viral entry

FGFR1 and downstream signaling suppress interferon induction

Pharmacology; Natural sciences; Biological sciences; Microbiology; Virology