Rockefeller University researchers, led by Charles M. Rice and published in Immunity, show that the brain mounts an anticipatory antiviral response within hours after an infection far from the head. In mouse models, WNV injected into footpads triggered activation of interferon-stimulated genes (ISGs) in the brain even when no virus was detectable there, indicating that virus-associated molecules in peripheral tissue are sufficient to start central responses. The authors note that although some insect-borne viruses can take days or weeks to cross the blood-brain barrier (BBB), the brain’s response can begin much sooner.
To trace the signaling network, the team tested several pathogen-associated molecular patterns (PAMPs) in the footpad and found that different PAMPs induced distinct transcriptomic programs in the brain. Administering the viral simulant poly(I:C) in the footpad provoked a systemic type I interferon response; these interferons induced ISGs in brain microvascular endothelial cells (BMECs) that form the BBB. Bioinformatic analyses suggest BMECs then relay the information into the central nervous system, prompting innate immune cells such as microglia to prepare for infection.
When mice were primed with poly(I:C) in the periphery and then infected directly in the brain, survival improved. This protective effect was seen for WNV and related Powassan virus, and for an unrelated herpes simplex infection in the experiments. The authors describe the BBB as a central immune signaling hub or sensor for the brain. Though basic research, these findings could guide preventive strategies for vector-borne neuroinflammation; Rice suggested that the right therapeutic—an adjuvant or an interferon-based therapy similar to those used previously for chronic hepatitis C—might prime the immune system early. The study received partial support from the Stavros Niarchos Foundation Institute for Global Infectious Disease Research at Rockefeller.
- Viruses tested: WNV
- Also tested: Powassan virus
- Also tested: herpes simplex
Difficult words
- anticipatory — happening before an expected event or threat
- interferon — a protein signal that cells release during infectioninterferons
- interferon-stimulated gene — a gene activated by interferon to fight virusesinterferon-stimulated genes
- blood-brain barrier — the physical barrier protecting brain blood vessels
- pathogen-associated molecular pattern — a molecule from microbes recognized by the immune systempathogen-associated molecular patterns
- microglia — immune cells in the brain that detect infection
- transcriptomic — related to the complete set of RNA transcripts
- adjuvant — a substance that increases an immune response
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Discussion questions
- How could the idea of the blood-brain barrier as an immune signaling hub change strategies for preventing neuroinflammation?
- What are possible benefits and risks of using an interferon-based therapy early after a peripheral infection? Give reasons from the article.
- The study used mouse models and several viruses. How might these findings apply to human vector-borne diseases, and what additional evidence would you want to see?
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