Immune Response May Cause Virus-Induced Neurologic Damage

Neurologic damage following acute viral infections may be attributed to an excessive immune response to the infection, according to a new study.

Many viral infections that don’t directly infect the central nervous system (CNS) have been associated with severe neurologic disease. For these viruses, including newer viruses such as SARS-CoV-2 and Zika, the mechanism behind the association is poorly understood. To gain a better picture of how viruses may cause neurologic disease, researchers used a mouse model of Zika virus infection and identified a population of T cells that may be responsible for the damage.

“Our study ultimately finds that it isn’t the virus itself alone that causes the damage. Instead, we find that it’s a very excessive immune response to the virus,” study author Elizabeth Balint, a PhD student at McMaster University in Hamilton, Ontario, Canada, told Medscape Medical News. Balint’s research could serve as the first step toward eventually developing targeted therapies to prevent neurologic damage.

The study was published on February 5, 2024, in Nature Communications.

Cytotoxic T Cells

Traditionally, experts have thought that a high viral load results in more severe damage to the CNS. But surprisingly, the investigators found that the viral load did not correspond with the severity of neurologic damage. This finding suggests that a dysregulated immune response is likely at fault.

The researchers then identified a specific population of cytotoxic T cells called CD8⁺ T cells that became overactivated during the infection and likely caused the damage. T cells are generally thought to be antigen-specific immune cells that only attack certain pathogens. “What we found, which was quite surprising, was that there were a number of T cells that seem to be nonspecifically activated,” said Balint. The T cells appeared to be activated by a nonspecific receptor during a cytokine storm. “Lots of inflammation leads to excessive T cell activation, and then those T cells are what we’re calling ‘bystander activated’ and able to kill nonspecifically,” explained Balint.

The investigators chose to model Zika because of its status as an emerging virus that was linked to severe neurologic outcomes during the 2015-2016 epidemic. The disease is still circulating, and the mechanism for this association is poorly understood, said Balint. While the findings have yet to be tested in other models, Balint believes they may apply to viruses beyond Zika. She hopes to test other models in the future.

Specific Treatments

With a better understanding of the basic science behind how viral infections cause neurologic damage, researchers may be able to begin developing therapies to prevent and treat disease. “We’re really hoping that the more that we know about these T cells, the more specific treatments we can develop,” said Balint.

In the study, for example, the investigators experimented with an antibody that blocked a particular receptor called NKG2D to avoid activating the cytotoxic T cells. The antibody reduced cell death and prevented Zika-associated paralysis in the mice that received treatment. This antibody has been tested in clinical trials for other uses, such as for the treatment of Crohn’s disease, according to Balint.

She acknowledged that the research is in the early stages for such clinical implications but added that “it does show some promise for developing more targeted therapies.”

Difficult to Isolate

Commenting on the study for Medscape Medical News, Karl Weiss, MD, a professor of medicine at McGill University and chief of infectious diseases at Jewish General Hospital, Montreal, Quebec, Canada, said that the study advances basic science but may or may not produce applications for treatment in future research.

“In the past, whenever we tried to isolate one single element of a very complex immune system,” said Weiss, “we never were able to isolate the culprits very effectively.” That’s because the immune system includes many connected pathways and redundancies in case of failure. “If we find a way of blocking this pathway, we will prevent neurologic problems. The problem with this is that you might block this pathway, but there is probably an alternative.”

Preventing neurologic damage is an important goal, Weiss said. But because of these complexities, the research is still far from the development of any drug. Applying the science in clinical trials is a crucial next step and often the sticking point where potential treatments fail. Weiss also noted that further research using other viruses and models is needed before the findings can be generalized beyond Zika.

When considering clinical implications, Weiss said, “I think we have to be very prudent.”

The study was supported by grants from the Canadian Institutes of Health Research. Balint and Weiss reported no relevant financial relationships.

Gwendolyn Rak is a health reporter for Medscape Medical News based in Brooklyn, New York.