When viruses invade our bodies, they can sometimes do more than just cause typical flu-like symptoms. In some cases, they infiltrate our nervous system, leading to debilitating neurological diseases that are challenging to treat.
Traditionally, scientists believed that the severity of neurological disease caused by viral infections correlated with the amount of the virus present in the central nervous system (CNS). However, this assumption has been challenged by studies showing that viruses like influenza, Ebola, dengue, and measles can induce neurological symptoms even with limited evidence of CNS infection or uncontrolled viral replication.
Understanding how viruses trigger these neurological diseases has been a puzzle for scientists, but recent research from McMaster University led by Dr. Ali Ashkar — a professor in the Department of Medicine — has revealed that it is not the virus, but the immune response that is responsible for neurological damage. The findings of the study were published in Nature Communications.
How do viruses trigger neurological diseases?
The Zika virus (ZIKV), a mosquito-borne virus, has been particularly concerning due to its association with various neurological conditions. In a mouse model of ZIKV infection, researchers discovered that while the virus does invade the CNS, the severity of neurological symptoms cannot be solely attributed to the amount of virus present in the CNS. Instead, they found that an uncontrolled immune response — particularly involving a type of cells known as CD8+ T cells — played a key role in mediating brain damage.
CD8+ T cells are the subset of immune cells that are responsible for killing infected cells during an infection. These cells also release inflammatory proteins, called cytokines, that cause inflammation and signal other immune cells to go to the site of the infection.
Yet recent studies have revealed that in inflammatory diseases, there can be a non-specific overproduction of cytokines — that is, a production of cytokines in the absence of a trigger. This can lead to severe side effects, in a phenomenon known as bystander activation.
Using mouse models of ZIKV-induced neurological disease, Ashkar’s team revealed that while viral infection is necessary to induce neurological symptoms, the amount of virus present does not correlate with clinical symptoms. A population of bystander activated CD8+ T cells were found to target and kill stressed cells in the CNS, independent of viral infection of the cells, leading to tissue damage and neurological symptoms.
The team also used antibodies to deplete CD8 T cells in the CNS, which led to a reduction in the incidence of neurological symptoms. However, they did not notice changes in viral load, indicating that these cells do not play a role in infection clearance.
New avenues for treatment
The phenomenon of bystander activation of CD8+ T cells may not be unique to ZIKV infection, but could also play a role in other virus-induced neurological diseases, such as multiple sclerosis and COVID-19-associated neuropathology. This discovery challenges the traditional understanding of virus-induced neurological diseases and opens up new avenues for treatment. Instead of focusing solely on controlling viral replication, researchers are now exploring ways to modulate the immune response to prevent excessive tissue damage in the CNS.
While viruses like ZIKV can invade the CNS and cause neurological damage, the severity of neurological disease is not solely determined by viral replication. Instead, an uncontrolled immune response — particularly involving bystander activated CD8+ T cells — plays a critical role.
By unraveling the mysteries of virus-induced neurological diseases, researchers are moving closer to developing effective treatments to prevent and treat these debilitating conditions.
