Contribution of Pro-Inflammatory Molecules Induced by Respiratory Virus Infections to Neurological Disorders

Abstract

Neurobehavioral alterations and cognitive impairment are common phenomena that represent neuropsychiatric disorders and can be triggered by an exacerbated immune response against pathogens, brain injury, or autoimmune diseases. Pro-inflammatory molecules, such as cytokines and chemokines, are produced in the brain by resident cells, mainly by microglia and astrocytes. Brain infiltrating immune cells constitutes another source of these molecules, contributing to an impaired neurological synapse function, affecting typical neurobehavioral and cognitive performance. Currently, there is increasing evidence supporting the notion that behavioral alterations and cognitive impairment can be associated with respiratory viral infections, such as human respiratory syncytial virus, influenza, and SARS-COV-2, which are responsible for endemic, epidemic, or pandemic outbreak mainly in the winter season. This article will review the brain's pro-inflammatory response due to infection by three highly contagious respiratory viruses that are the leading cause of acute respiratory illness, morbidity, and mobility in infants, immunocompromised and elderly population. How these respiratory viral pathogens induce increased secretion of pro-inflammatory molecules and their relationship with the alterations at a behavioral and cognitive level will be discussed.

Keywords: brain; neuropsychiatric disorders; pro-inflammatory molecules; viral infection.

Figure 3

Infection with SARS-CoV-2 could cause neurologic consequences in patients. The respiratory infection with SARS-CoV-2 might lead to neuroinflammation as a consequence of a cytokine storm, which might increase the pro-inflammatory cytokines in the brain [74]. This increase might promote the development of neurologic disorders such as ageusia, anosmia, delirium, psychosis, encephalitis, mood disorders, Guillain-Barré Syndrome, and neurocognitive syndrome [75,76,159,164,165].

Figure 1

Infections with the influenza virus can cause neurologic consequences directly and indirectly. The respiratory infection with the Influenza virus can lead to neuroinflammation as a consequence of the elevated pro-inflammatory molecules, such as IL-6, TNF-α, IL-1β, CXCL8, CCL2, CXCL10 and CXCL9 [103,107,108]. An increase of these molecules can directly promote the development of neurologic symptoms such as schizophrenia (SCZ), autism spectrum disorder (ASD), myelitis, seizures, meningitis, encephalitis, mood disorders and Guillain-Barré syndrome. On the other hand, the respiratory infection with Influenza virus in pregnant women can increase maternal immune activation (MIA), which increases the secretion of pro-inflammatory cytokines, such as IL-6, TNF-α and IL-1β. An increase expression of these molecules might indirectly promote brain inflammation of the offspring in the uterus, impairing brain development [42,109]. A possible result of brain inflammation is SCZ and ASD [110].

Figure 2

Human respiratory syncytial virus infection can cause neurologic consequences in patients. The respiratory infection with the respiratory syncytial virus can lead to neuroinflammation as a consequence of the elevated pro-inflammatory molecules such as IL-6, IL-8, CCL2, and CCL4 [150]. This increase can promote the development of neurologic symptoms such as encephalitis and encephalopathies [144,145,146].

Figure 4

Possible treatments to prevent neurologic consequences in patients infected by respiratory viruses. Adults and infants that present diverse neuropsychiatric disorders can be decreased using antivirals drugs, which will prevent the brain′s local infection and therefore protect from further consequences. Additionally, the use of inhibitors of pro-inflammatory molecules and mild hypothermia can decrease the secretion of pro-inflammatory molecules, and as a result, decrease neuroinflammation. The use of vaccines might protect from developing neuropsychiatric disorders in adults, infants, and offspring due to the maternal vaccination.