Viral and autoimmune diseases of the central nervous system – or ‘CNS’ – are often characterized by the onset of inflammation leading to neurological dysfunction, including impairments in memory and cognition. Dr. Robyn Klein at Western University in London, Ontario leads a team that specializes in neuroinflammatory diseases of the CNS. In recent years, her laboratory has been focusing on the molecular mechanisms behind inflammation and how they regulate blood-brain barrier permeability in viral and autoimmune diseases. Read More
Viruses may cross the blood-brain barrier due to increased permeability. Such increased permeability of the blood-brain barrier can be a consequence of viral attack mechanisms or the overexpression of inflammatory cytokines, such as tumor necrosis factor alpha and interleukin-1.
In a 2014 study, Dr. Klein’s team highlighted how West Nile Virus triggers the expression of tumor necrosis factor alpha and interleukin-1 to cause a cascade of reactions that limit viral replication, and facilitate recognition by immune cells.
In the same study, they showed that despite limiting viral replication in the CNS, tumor necrosis factor alpha and interleukin-1 signaling can also contribute to disease by increasing the permeability of the blood-brain barrier, allowing West Nile Virus to get through.
Although inflammation is necessary for clearing infections in the CNS, immune molecules can trigger a cascade of events that lead to neurological dysfunction. As such, patients surviving West Nile Virus encephalitis show high rates of memory and cognitive impairment.
In 2016, Dr. Klein’s team published an effective model of spatial memory impairment induced by West Nile Virus. This allowed them to identify that the virus induces the elimination of presynaptic terminals, which is a potential mechanism underlying impairments in patients recovering from West Nile Virus.
In 2017 they confirmed that interleukin-1 alters the proliferation and differentiation of neural progenitor cells, which cause an increase in the production of astrocytes and a decrease in the production of neurons. Astrocytes have an important role in maintaining the blood-brain barrier.
The recently emerged Zika Virus can also cause neurological complications in adults. Activation of microglia and astrocytes in the brain during acute infection promotes the recruitment of antiviral T cells.
Dr. Klein and her team reported that antiviral T cells persist within the hippocampus after recovery from infection in two animal models of West Nile Virus and Zika Virus. The presence of T cells is associated with the development of specific learning defects through microglial activation and loss of synapse formation.
In their most recent study, the researchers demonstrated that COVID-19 infection increases interleukin-1 levels in the brain due to microglial activation, leading to cognitive impairment. However, they also showed that this cognitive impairment can be prevented through vaccination.
The work by Dr. Klein’s team has helped to confirm the important role of astrocytes in neurological diseases. They are continuing to investigate the roles played by cytokine signaling and astrocytes in CNS autoimmunity with the aim of providing new insights for the development of targeted therapies.
