Viruses are microscopic (non-living) infectious agents with a some-what terrifying potential to invade our nervous system. In fact, there are likely thousands of latent viral particles lying dormant in your body as you read this blog post, but don’t worry! Fortuitously, viruses such as John Cunningham virus, which infects 70 -90% of the human population, only becomes pathological when it is reactivated during immunodeficiency of immunosuppression. At some point or another, we have all likely been infected with a virus via inhalation, ingestion, an insect bite, or by other means. Evolutionarily, our bodies have developed many protective methods to keep these foreign invaders out of our delicate nervous system. Primarily, the blood brain and blood cerebrospinal fluid barriers, prevent large molecules from invading the brain. Unfortunately, viruses have developed several ways to circumvent these CNS barriers. Viruses can infect vascular endothelial cells and directly cross the blood brain barrier. They also enter the brain through the choroid plexus or circumventricular organs, which lack blood brain barriers. Viruses, such as polio and rabies virus, even migrate from infected peripheral nerves or infect exposed olfactory dendrites to enter the brain. Sadly, infants are the most susceptible to viral infections of the nervous system due to greater proliferation of viral particles as cells differentiate and migrate across the parenchyma during development.

So what do viruses do? CNS viruses can infect neurons in the spinal cord (myelitis), meninges (meningitis), parenchyma (encephalitis) or both (meningoencephalitis). Once inside, viruses hijack the molecular machinery of infected cells, replicating and assembling new viral particles. This process inevitably destroys the host cell but not before the virus has self-assembled enough new particles to infect more living tissue and continue its path of destruction1.1-s2.0-S1879625715000115-gr3

If CNS barriers fail to keep viruses out of the brain, the body mounts a rapid inflammatory response to combat the infection.

 

 

hiv_03_infected1_full

Microglia, macrophages, lymphocytes (as seen here) and dendritic cells are recruited to the site of injury to clear away dead tissue and remove viral particles.

 

 

lymphocytic

However, some viruses, such as lymphocytic choriomeningitis virus (LCMV), have found ways to become invisible to the body’s innate immune response system.

 

In a recent paper from the McGavern lab at the National Institutes of Health, genetically modified mice were infected with noncytopathic LCMV in order to elucidate innate immune activity in response to CNS viral infection. They utilized microarray analysis of gene regulation and 2-phton imaging to investigate the progression and effects of LCMV. Surprisingly, they found that the production of type 1 interferons (IFN-1) are an essential element in combating viral infection. IFN-1s are part of a non-redundant signaling pathway that induces a protective inflammatory response including activation of microglia and recruitment to the vasculature to clear viral agents2.

Microglia (green) surrounding blood vessel (blue) and astrocytes (red).

IFN-1 signaling is an incredibly important process in fighting viral infection. It is the single orchestrator of innate immune gene expression and there is no redundant mechanism to mount an alternative counter-response. Without the activity of IFN-1, viruses such as LCMV can run rampant in the nervous system, spreading from the meninges to parenchymal astrocytes and oligodendrocytes. Current research is uncovering what neurotropic viruses are affected by IFN-1 signaling. This research has the potential to facilitate the development of therapeutics to modulate anti-viral immunity in the CNS.

To learn more about the nature of viruses and their effect on the global community, come hear Axel Nimmerjahn speak at the CNBC, Tuesday, May 19th at 4:00 pm.

 

  1. Swanson, P. A. 2nd and McGavern D. B. (2015). Viral Diseases of the Central Nervous SystemCurrent Opinion Virology,11;11C:44-45
  2. Nayak, D., Johnson, K. R., Heydari, S., Roth, T. L., Zinselmeyer, B. H., & McGavern, D. B. (2013). Type I Interferon Programs Innate Myeloid Dynamics and Gene Expression in the Virally Infected Nervous System. PLoS Pathogens, 9(5), e1003395.

 

Bankole Aladesuyi is a first-year Neurosciences student currently rotating with Dr. Tom Hnasko. Although a little less worried about common viruses like LCMV, in his spare time he tirelessly labors to find a vaccine for the rare zombies virus.

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