VPS29 Exerts Opposing Effects on Endocytic Viral Entry.

Area of Science:

• Virology
• Cell Biology
• Genetics

Background:

• Emerging zoonotic viruses pose significant global health risks, necessitating identification of host and viral factors influencing infection.
• Understanding host determinants is critical for developing antiviral strategies against pandemic threats like coronaviruses and ebolaviruses.

Purpose of the Study:

• To identify host genes essential for coronavirus infection using a genome-wide CRISPR screen.
• To investigate the role of VPS29 and the retromer complex in viral entry and replication.
• To explore the potential of targeting host pathways for broad-spectrum antiviral therapies.

Main Methods:

• Conducted a genome-wide CRISPR loss-of-function screen in a human lung cell line with HCoV-OC43.
• Validated candidate genes, including VPS29, using various coronaviruses (HCoV-OC43, SARS-CoV-2 variants) and ebolavirus.
• Assessed the impact of VPS29 deficiency on endosome morphology, acidity, protease activity, and viral entrapment.

Main Results:

• VPS29 is essential for infection by multiple coronaviruses, including SARS-CoV-2 (Omicron variant showing heightened dependence), and ebolavirus.
• VPS29 deficiency alters endosome properties, leading to viral entrapment for coronaviruses but enhancing influenza A virus infection.
• Retromer complex components influence endosomal environment, affecting susceptibility to different viral pathogens.

Conclusions:

• Host factor VPS29 and the retromer complex regulate endosomal characteristics critical for coronavirus and ebolavirus susceptibility.
• Targeting the VPS29-mediated pathway offers a potential therapeutic strategy for zoonotic viral diseases.
• Host-pathogen interactions involving endosomal trafficking can be modulated to control viral infections.