Scientists at the Francis Crick Institute have discovered how a cellular protein called DDX41 detects invading viruses and sparks an antiviral immune response. The detailed mechanism uncovered provides a potential target for new treatments for viral infections, such as influenza, herpes simplex virus and other respiratory infections.

The research, published in the journal Nature, reveals how DDX41 acts as a virus sensor, responding to the presence of viral RNA by triggering the production of antiviral proteins that are essential for the host's defence.

DDX41 is part of a group of proteins called RNA helicases, which play a crucial role in regulating RNA metabolism. Previous studies have shown that DDX41 is involved in the innate immune response, which is the body's first line of defence against infections. However, the exact mechanism by which DDX41 detects viruses was unknown.

Key findings:

To uncover how DDX41 detects viruses, the research team conducted a series of experiments using cells infected with different viruses, including influenza A virus and herpes simplex virus 1. They found that DDX41 specifically binds to a region of viral RNA called the 5' untranslated region (5'UTR).

The 5'UTR is a key regulatory region of viral RNA that is essential for viral replication and transcription. DDX41 binds to a specific sequence within the 5'UTR, and this binding triggers a conformational change in the protein that enables it to interact with other proteins involved in the antiviral response.

Binding of DDX41 to the viral RNA triggers the assembly of a complex of proteins called the DDX41-containing antiviral complex (DDX41-AC). This complex includes several proteins involved in the innate immune response, including the protein kinase R (PKR) and the transcription factor interferon regulatory factor 3 (IRF3).

DDX41-AC triggers antiviral response:

The assembly of the DDX41-AC leads to the activation of PKR and IRF3. PKR phosphorylates the translation initiation factor eIF2α, which inhibits protein synthesis and prevents viral replication. IRF3 is translocated to the nucleus, where it activates the transcription of antiviral genes, leading to the production of antiviral proteins that are essential for the host's defence.

The research team also found that DDX41 is essential for the antiviral response in vivo. Mice deficient in DDX41 were more susceptible to infection with influenza A virus, and they produced lower levels of antiviral proteins.

The findings of this study provide a detailed understanding of how DDX41 acts as a virus sensor and initiates the antiviral immune response. This knowledge could be exploited to develop new treatments for viral infections by targeting DDX41 or its interacting proteins.