Long-distance interferon signaling within the brain blocks virus spread

Area of Science:

• Neuroimmunology
• Virology
• Central Nervous System (CNS) Defense

Background:

• Virus infections of the CNS can cause severe neurological damage.
• Olfactory sensory neurons provide a direct route for viruses to enter the brain.
• The mechanisms protecting the brain from such infections are not fully understood.

Purpose of the Study:

• To investigate the protective mechanisms against viral entry into the brain via the olfactory nerve.
• To elucidate the signaling pathways involved in brain antiviral defense.

Main Methods:

• Intranasal inoculation of mice with RNA (vesicular stomatitis virus [VSV]) and DNA (cytomegalovirus [CMV]) viruses.
• Assessment of viral spread and interferon-stimulated gene (ISG) expression in different brain regions.
• Utilizing mice lacking interferon-alpha/beta receptors and chemical destruction of olfactory sensory neurons.

Main Results:

• Nasal viral inoculation triggered long-distance signaling, upregulating ISG expression in remote brain areas.
• This signaling, dependent on brain interferon-alpha/beta receptors, established a distant antiviral state.
• Mice lacking interferon receptors or with destroyed olfactory neurons showed increased viral spread and mortality.
• VSV replication was confined to the olfactory bulb in normal mice, which survived infection.

Conclusions:

• A unique long-distance interferon signaling pathway protects the brain from viruses entering through the olfactory nerve.
• This mechanism is critical for preventing widespread CNS infection and ensuring survival.
• The findings reveal a novel brain defense strategy against neurotropic viruses.