Glial responses and synapse elimination in flavivirus neuroinfection: implications for motor and cognitive function

Identification: Maximova, Olga



Glial responses and synapse elimination in flavivirus neuroinfection: implications for motor and cognitive function
Olga A. Maximova1, Barbara Sampson2, John G. Bernbaum1, Jeffery K. Taubenberger1, Jeffrey I. Cohen1, Alexander G. Pletnev1
1National Institute of Allergy and Infectious Diseases; 2Office of Chief Medical Examiner, New York; United States of America
Neurons are the primary target cells of many flaviviral infections of the central nervous system (CNS). We recently showed that one of the neuropathogenic flaviviruses, West Nile virus (WNV), can spread within the CNS transsynaptically. WNV infection can result in the neuroinvasive disease, with manifestations across the spectrum of meningoencephalomyelitis. The clinical evidence, accumulating for the past 19 years since WNV introduction to the USA, suggests involvement of the cerebellum more often than previously recognized. Increasingly reported clinical signs include cerebellar dysmetria and ataxia, as well as dysphagia, tremor, and opsoclonus myoclonus syndrome. These complications motivated us to investigate the pathological substrate of cerebellar dysfunction in WNV neuroinfection (WNV-NI). We used cerebellar tissue from our nonhuman primate WNV-NI model and postmortem samples from the first US human cases of the WNV-NI and performed molecular pathology and electron microscopy studies. The topography of glial responses was indicative of the alterations in somatodendritic, axonal, and synaptic compartments of the major neuronal elements comprising the cerebellar microcircuitry (i.e., Purkinje and granule cells). Indeed, subsequent analysis with specific molecular markers revealed progressive degenerative changes in all these compartments. We propose a model in which a compensatory displacement and elimination of synapses occurs due to a coordinated effort of the reactive astrocytes and microglia to arrest the transsynaptic spread of virus at the expense of cerebellar motor and cognitive function. Whether this scenario employs the molecular mechanisms of synapse elimination known to play a role during the CNS development or neurodegenerative disease, warrants further investigation. A better understanding of neuronal network dysfunction during and after viral neuroinfection may provide innovative ideas and a hope to improve or restore the neuronal and synaptic function.
This work was supported by funds provided by the NIAID Intramural Research Program.



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