A recent ground-breaking publication in Nature Communications, a peer-reviewed, Open Access journal, from the Molecular Virology Laboratory shows that a very early response to cellular stress synergises with innate immunity for a more efficient antiviral action.
Viruses like Dengue, Zika, Yellow fever are sadly famous in the tropical areas of the world. Tick-borne encephalitis, west Nile virus, Usutu virus are established in Europe and spreading. All these pathogens are delivered by mosquitoes or ticks and share similar replication strategies. Infected individuals may respond with mild symptoms or progress to debilitating or even fatal consequences. Key to the outcome of the infection is the early response of the cell to the virus. This first line of defence is called innate immunity, which could be the only defence in the absence of a vaccine or of antiviral drugs.
Recent findings from the Laboratory of Molecular Virology of the ICGEB show that a very early response to cellular stress synergises with innate immunity for a more efficient antiviral action (link to article in PubMed). The innate response to a pathogen is critical in determining the outcome of the infection. However, the interplay of different cellular responses that are activated following viral infection and their contribution to innate antiviral signalling has not been clearly established. This work shows that flaviviruses activate the unfolded protein response before transcription of interferon regulatory factor 3 induced genes. Infection in conditions of unfolded protein response priming leads to early activation of innate antiviral responses and cell intrinsic inhibition of viral replication, which is interferon regulatory factor 3 dependent. These results demonstrate that the unfolded protein response is not only a physiological reaction of the cell to viral infection, but also synergizes with pattern recognition sensing to mount a potent antiviral response.
The cell harbours several membrane organelles in their cytoplasm, which serve to fold and secrete essential proteins. Any insult to this delicate pathway, including viruses, triggers a block of protein synthesis, the arrest of cell growth and may lead either to recovery of the damage, or cell death as the extrema ratio. Previous work of the lab showed that tick-borne encephalitis virus, their model virus endemic of the area of Trieste, targets cytoplasmic membranes for replication but delay translation arrest and innate responses enough to allow robust viral replication . However, induction of the response before infection leads to a strong inhibition of viral replication and increased innate signalling not only for the tick virus, but also in the other viruses of the family.
Although antiviral pathways are activated by the classical innate sensing route, early membrane stress promotes a more robust and immediate antiviral response. Therefore, this early response works as a ‘danger’ signal for the cell. Molecular details of this pathway, described in the paper published in Nature Communications this week, provide a first understanding of the basic biology of the cell response to infection and could be therefore used to design innovative antiviral drugs.
Infrastructure and ICGEB intramural funding, as well as essential external funding from the Regione Autonoma FVG, the Beneficientia Stiftung and the Fondo Trieste, has been instrumental to explore unconventional routes of research and to translate research into diagnostics and therapeutics.
Link to the Article: Nature Communications