A mosquito bite is usually little more than an annoyance. Mosquitoes can carry pathogens that cause serious disease. A single mosquito bite can transmit neurotropic viruses, including West Nile virus (WNV). In a fraction of people, this virus reaches the brain and can cause potentially fatal viral encephalitis, leaving many survivors with post-infection sequelae. A new study in Immunity, led by HFSP Long-Term fellow Alexander Lercher and PhD student Tyler Lewy in the laboratory of Charles M. Rice at The Rockefeller University, explores the mechanisms by which the body protects itself against viral neuroinvasion. Using mouse models, the researchers found that detecting virus in the skin rapidly induces an antiviral gene expression program in the brain, priming its defense before a potential neuroinvasive event.
To uncouple local viral sensing in the skin from pathogen replication and systemic immune responses, the researchers injected a molecule mimicking a virus into the footpad of mice and then modeled a neuroinvasive event by intracranial injection of WNV. Strikingly, virus sensing via the skin dramatically improved survival following WNV infection. This observation was accompanied by reduced viral loads in the brain and a reduced hyperinflammatory response, known as a “cytokine storm” – a hallmark of severe encephalitis.
Through complementary experiments, they found that this observation hinged on a single antiviral signaling molecule: type I interferon. Type I interferon is rapidly induced in the bloodstream following detection of virus in the footpad. Under homeostatic conditions, the brain is quarantined behind the blood-brain, a protective layer of cells that limits the entry of immune cells and inflammatory signals, helping to prevent unwanted inflammation. Excitingly, the researchers found that endothelial cells of the blood-brain-barrier are highly responsive to circulating type I interferon and thereby facilitate the rapid induction of a potent antiviral state within the brain. Tellingly, this response was not only beneficial in WNV infection, but also protected mice from fatal encephalitis caused by a range of neurotropic viruses.
As mosquito-borne neurotropic viruses continue to spread, driven in part by climate change, urbanization, and population growth, a better understanding of how the body prepares the brain to fend off neurotropic viruses is becoming increasingly important. This study reveals a novel cross-organ antiviral communication circuit that connects viral detection in the periphery with antiviral defenses in the brain, potently counteracting severe encephalitis. These findings point towards new ways to protect people at risk of severe encephalitis caused by neurotropic viruses.