ATG9A is an essential host factor for parechovirus RNA replication

Area of Science:

• Virology
• Molecular Biology
• Genetics

Background:

• Parechoviruses (PeVs), particularly PeV-A3, cause severe neonatal sepsis and meningoencephalitis.
• The viral life cycle and pathogenesis of PeV-A3 are not well understood.
• Identifying host factors is crucial for understanding PeV-A3 infection and developing treatments.

Purpose of the Study:

• To identify host factors essential for PeV-A3 replication using a genome-wide CRISPR screen.
• To elucidate the role of identified host factors in the PeV-A3 life cycle.
• To explore potential therapeutic targets for PeV-A3 infection.

Main Methods:

• Genome-wide CRISPR screening to identify host factors for PeV-A3 replication.
• Assays to determine the necessity of host factors for viral entry, translation, and RNA replication.
• Co-localization studies using double-stranded RNA (dsRNA) as a marker for viral replication organelles (ROs).

Main Results:

• A set of Golgi-localized proteins, including the lipid scramblase ATG9A, were found to be essential for PeV infection across genotypes.
• ATG9A is critical for PeV-A3 viral RNA replication, independent of canonical autophagy.
• ATG9A co-localizes with dsRNA within ROs, and the ATG2-ATG9A complex is required for optimal viral replication.

Conclusions:

• The ATG2-ATG9A complex plays a vital role in PeV-A3 replication by potentially delivering lipids to ROs.
• ATG9A's function in viral RNA replication offers a novel target for antiviral drug development against PeV-A3.
• This study provides critical insights into the molecular mechanisms underlying PeV pathogenesis.