Within hours, they found interferon-stimulated antiviral genes (ISGs) in the brain had been activated even though there was no virus nearby.
“The virus was not detectable in the brain at this stage, and yet the CNS mounted a robust and distinct antiviral immune response,” says co-senior author Alexander Lercher.
Bioinformatic analyses suggests that these cells then pass the information along to the CNS, which prompted the brain’s immune cells – especially innate immune cells called microglia – to prepare for a potential viral invasion.
“In interpreting these immune signals, the blood-brain barrier is a bit like an infection sensor for the brain,” Lewy says.
“The right therapeutic could goose the immune system early, shifting the brain into this preventative state,” he says.
First they examined WNV, which causes tens of thousands of cases of encephalitis every year. It moves from the skin to the lymph nodes and spleen, causing fever and other symptoms. Most human immune systems conquer the virus at that stage, but for another 5% of people, some with inborn errors of immunity that render them vulnerable, WNV slips past the blood-brain barrier into the CNS, where it replicates in neurons, leading to severe inflammation and sometimes death.
To see whether the brain responds to any of the intermediary stages of infection, the researchers injected the footpads of mice with WNV and then examined their brains at different time intervals. Within hours, they found interferon-stimulated antiviral genes (ISGs) in the brain had been activated even though there was no virus nearby. “The virus was not detectable in the brain at this stage, and yet the CNS mounted a robust and distinct antiviral immune response,” says co-senior author Alexander Lercher. “That led us to hypothesize that the CNS was recognizing signals sent from the periphery.”
To characterize this signaling network, the team tested a battery of footpad-administered pathogen-associated molecular patterns (PAMPs) –conserved molecules found across pathogens that the immune system has evolved to readily recognize – and found the brain was highly specific in its response. “It’s finely tuned, depending on the PAMP,” Lercher adds. “We tried agonists that looked like bacteria or viruses, and, depending on the PAMP, the brain activated distinct transcriptomic programs.”
Intrigued, they challenged mice again with footpad PAMPs, then infected them with WNV directly in the brain, and let the virus run its course for several days. Only mice that had received poly(I:C), a potent viral simulant, had a robust rate of survival. They then repeated the experiments with other encephalitic viruses in the same viral family as WNV, including Powassan virus (which causes tick-borne encephalitis) as well as unrelated viruses such as herpes simplex. All benefitted from poly(I:C)-induced triggering of the early warning system. “It wasn’t very surprising that they got a boost in surviving Powassan virus, which is basically West Nile’s cousin, but the fact that it was effective against herpes virus is pretty notable, because genetically these viruses are as different as a sequoia and a house mouse,” Lewy says. “We didn’t exhaustively try every single encephalitic virus, but I think from this evidence we can conclude that it’s a pretty broad mechanism.”
Further experiments revealed that the viral PAMP poly(I:C) triggered a particularly robust systemic response of type I interferons, which activated ISGs in brain microvascular endothelial cells (BMECs) located in the blood-brain barrier. Bioinformatic analyses suggests that these cells then pass the information along to the CNS, which prompted the brain’s immune cells – especially innate immune cells called microglia – to prepare for a potential viral invasion. “In interpreting these immune signals, the blood-brain barrier is a bit like an infection sensor for the brain,” Lewy says. “Through the BBB’s early detection of infection signals in the periphery, the brain is able to mount a robust prophylactic response, ultimately preventing encephalitis in most cases.”
Rice says the basic science research, which was partly supported by the Stavros Niarchos Foundation (SNF) Institute for Global Infectious Disease Research at Rockefeller, could inform new approaches to preventing vector-borne neuroinflammation. “The right therapeutic could goose the immune system early, shifting the brain into this preventative state,” he says. “That might look like either some kind of adjuvant or even an interferon-based therapy like the ones that were used to treat chronic hepatitis C before the advent of more potent, curative regimens.”
Source: Rockefeller University
