Viral infections and their relationship to neurological disorders

Abstract

The chronic dysfunction of neuronal cells, both central and peripheral, a characteristic of neurological disorders, may be caused by irreversible damage and cell death. In 2016, more than 276 million cases of neurological disorders were reported worldwide. Moreover, neurological disorders are the second leading cause of death. Generally, the etiology of neurological diseases is not fully understood. Recent studies have related the onset of neurological disorders to viral infections, which may cause neurological symptoms or lead to immune responses that trigger these pathological signs. Currently, this relationship is mostly based on epidemiological data on infections and seroprevalence of patients who present with neurological disorders. The number of studies aiming to elucidate the mechanism of action by which viral infections may directly or indirectly contribute to the development of neurological disorders has been increasing over the years but these studies are still scarce. Comprehending the pathogenesis of these diseases and exploring novel theories may favor the development of new strategies for diagnosis and therapy in the future. Therefore, the objective of the present study was to review the main pieces of evidence for the relationship between viral infection and neurological disorders such as Alzheimer's disease, Parkinson's disease, Guillain-Barré syndrome, multiple sclerosis, and epilepsy. Viruses belonging to the families Herpesviridae, Orthomyxoviridae, Flaviviridae, and Retroviridae have been reported to be involved in one or more of these conditions. Also, neurological symptoms and the future impact of infection with SARS-CoV-2, a member of the family Coronaviridae that is responsible for the COVID-19 pandemic that started in late 2019, are reported and discussed.

Fig. 1

Pathological agents may infect the organism by different pathways, such as olfactory and gastric. These pathogens trigger a cascade of inflammatory responses (increased levels of cytokines, for example) that disrupt the BBB, activate microglia, and lead to a subsequent clustering around neuronal cells, resulting in neuronal damage. Source: adapted from Limphaibool et al. (2019) [71]

Fig. 2

Mechanisms used by pathological agents to cross the BBB. (a) A direct crossing may be possible when cells of monocyte-macrophage/microglia lineage are infected by the pathogens and carry them through the BBB, reaching the CNS. This mechanism is also called "Trojan horse" because the microorganism eludes the immune system defense by using these cells to move from the bloodstream to the brain. The transport of pathogens to CNS is favored by inflammation, which is typically observed in neurological disorders. During the inflammation process, inflammatory molecules are released, triggering the activation of infected leukocytes. The postcapillary venule is attacked by the infected leukocytes, which encircle the endothelial and parenchyma basement membranes. Next, these cells enter the CNS by crossing the BBB. Another mechanism used by pathological agents is to impair the BBB and reach the CNS directly, using the porous capillaries of the choroid plexus. In various neurological diseases, the BBB is damaged, which favors the entry of pathogens into the brain through the bloodstream. (b) Neurotropic viruses may enter the CNS through retrograde axonal transport. These pathogens infect the peripheral nerve that creates a link from the skin and the mucosa to the sensory, motor, and olfactory neurons. In neuronal cells, viruses can replicate and infect adjacent cells. Source: adapted from De Chiara et al. (2012) [16]