Scientists at McMaster University report that they have found that it is the immune system response, and not acute viral infections like Zika or COVID-19, that is directly responsive for neurological damage. They published their study “Bystander activated CD8+ T cells mediate neuropathology during viral infection via antigen-independent cytotoxicity” in Nature Communications.

“Although many viral infections are linked to the development of neurological disorders, the mechanism governing virus-induced neuropathology remains poorly understood, particularly when the virus is not directly neuropathic. Using a mouse model of Zika virus (ZIKV) infection, we found that the severity of neurological disease did not correlate with brain ZIKV titers, but rather with infiltration of bystander activated NKG2D+CD8⁺ T cells,” wrote the investigators.

“Antibody depletion of CD8 or blockade of NKG2D prevented ZIKV-associated paralysis, suggesting that CD8⁺ T cells induce neurological disease independent of TCR signaling. Furthermore, spleen and brain CD8⁺ T cells exhibited antigen-independent cytotoxicity that correlated with NKG2D expression. Finally, viral infection and inflammation in the brain was necessary but not sufficient to induce neurological damage.

“We demonstrate that CD8⁺T cells mediate virus-induced neuropathology via antigen-independent, NKG2D-mediated cytotoxicity, which may serve as a therapeutic target for treatment of virus-induced neurological disease.”

“We were interested in trying to understand why so many viral infections are associated with neurological diseases,” said Elizabeth Balint, a PhD student at McMaster. “Our evidence suggests that it’s not the virus itself that causes the damage, but a unique population of T cells, which are part of the immune system, that are actually responsible for the damage.”

A team focused on Zika

To come to this conclusion, the McMaster team focused on Zika virus. During laboratory testing, researchers, as expected, found T cells that were specific for Zika and designed to eliminate infected cells. They found something else, too.

“What was interesting in our study is that although we did find some T cells specific for Zika, we identified cells that weren’t functioning like a normal T cell and were killing cells that weren’t infected with Zika,” added Balint.

According to the researchers, this aggressive behavior of these NKG2D+CD8+ T cells is responsible for neurological damage suffered from infections beyond just Zika, like COVID-19 and even septic shock. The response is the result of the body producing large amounts of cytokines, which in moderation help to coordinate the body’s response in battling an infection or injury by telling immune cells where to go and what to do when they arrive.

“If our body’s immune cells overreact and over produce inflammatory cytokines, this condition will lead to non-specific activation of our immune cells which in turn leads to collateral damage. This can have severe consequences if it happens in the brain,” explained, Ali Ashkar, PhD, DVM, a professor with the department of medicine and the Canada Research Chair in Natural Immunity and NK Cell Function.

The discovery offers scientists a new target for treatments of neurological diseases sparked by acute viral infections. In fact, Balint has already found a treatment that holds promise.

“Elizabeth has experimented with an antibody that can completely block and treat devastating neurotoxicity in the animal model, which is already in clinical trials for different uses in humans,” pointed out Ashkar.

Balint hopes to continue her work towards finding a treatment that would be effective in humans.

“There are a few different other viruses we’re interested in studying, which will aid us in creating the best treatment options,” Balint said.

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Also published by Genengnews.com

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