Nerve tissue damage in viral infection explained by T-lymphocyte infiltration

Canadian immunologists conducted a series of experiments on mice and found that the severity of neurological symptoms in the Zika fever model depended not on the virus titer in the brain, but on the degree of infiltration of activated NKG2D+CD8+ T-lymphocytes. Reduction in CD8-lymphocyte numbers or blockade of NKG2D receptors prevented virus-associated paralysis, and CD8-lymphocytes in the spleen and brain exhibited antigen-independent cytotoxicity that correlated with NKG2D expression. The study is published in the journal Nature Communications.

Many viral infections, whose causative agents have a poor affinity for nervous tissue, are associated with the development of debilitating neurological disorders, many of which can be fatal. To date, however, physicians and scientists know little about the mechanism by which viruses cause neuropathology. One hypothesis claims direct damage to nerve cells by the virus, while others find no correlation between viral load and the severity of neurological symptoms.

Meanwhile, the increasingly widespread infections caused by Zika virus and SARS-CoV-2 have been associated with neurological complications, including encephalitis and Guillain-Barré Syndrome. In these cases, the mechanism also remains unknown. In addition, scientists have an inadequate understanding of the interactions between the virus, immune cells, nerve cells and glia in the development of virus-mediated neurological disorders.

Ali Ashkar (Ali Ashkar) and colleagues from McMaster University investigated the molecular mechanism of the development of disorders in the nervous tissue of mice when infected with Zika virus. The scientists noted that at the time of the highest viral load, cell death and infiltration of immune cells into the brain, the mice showed clinical symptoms of neurological disease - weakness or paralysis of the hind limbs. Administration of the drug with interleukins-12 and -18, which have a synergistic effect on NK-cell activation and interferon-gamma production, significantly reduced Zika virus titers, but hind limb paralysis in mice only progressed. Thus, the scientists concluded that viral load did not directly correlate with the severity of neuropathology.

Because the interleukins studied are inflammatory cytokines that can activate innate and adaptive immune cells, the scientists hypothesized that their administration exacerbates neural tissue pathology. By tracing several pathways that are activated by these interleukins, the researchers concluded that they enhance Zika virus-induced neuropathology through the pathogenic response of CD8 lymphocytes, despite lower titers of the virus in the brain.

Activated T cells are known to express high levels of the NK cell receptor NKG2D and exhibit NKG2D-mediated cytotoxicity. Using these findings, immunologists investigated the possibility of this effect in the brains of Zika virus-infected mice. Blockade of the NKG2D receptor and depletion of the CD8-lymphocyte pool in the brain and spleen prevented symptoms of paralysis during virus infection. Similarly, such interventions significantly reduced cell death in the cerebral cortex and cerebellum.

In addition, the scientists were able to find out that this effect is possible precisely because of the innate cytotoxicity of CD8-lymphocytes, mediated by antigen-dependent activation of NKG2D. Viral infection itself and the resulting inflammation in the brain were necessary but not sufficient to cause neurological damage.

This study explains for the first time the molecular mechanism of neurological disease development in viral infection. Since immune cells, rather than the virus itself, play a major role in it, it can be used as a universal therapeutic target for drug development. However, it is necessary to confirm the universality of this mechanism in models with other viruses.