Neurologic Alterations Due to Respiratory Virus Infections

Abstract

Central Nervous System (CNS) infections are one of the most critical problems in public health, as frequently patients exhibit neurologic sequelae. Usually, CNS pathologies are caused by known neurotropic viruses such as measles virus (MV), herpes virus and human immunodeficiency virus (HIV), among others. However, nowadays respiratory viruses have placed themselves as relevant agents responsible for CNS pathologies. Among these neuropathological viruses are the human respiratory syncytial virus (hRSV), the influenza virus (IV), the coronavirus (CoV) and the human metapneumovirus (hMPV). These viral agents are leading causes of acute respiratory infections every year affecting mainly children under 5 years old and also the elderly. Up to date, several reports have described the association between respiratory viral infections with neurological symptoms. The most frequent clinical manifestations described in these patients are febrile or afebrile seizures, status epilepticus, encephalopathies and encephalitis. All these viruses have been found in cerebrospinal fluid (CSF), which suggests that all these pathogens, once in the lungs, can spread throughout the body and eventually reach the CNS. The current knowledge about the mechanisms and routes used by these neuro-invasive viruses remains scarce. In this review article, we describe the most recent findings associated to neurologic complications, along with data about the possible invasion routes of these viruses in humans and their various effects on the CNS, as studied in animal models.

Keywords: CNS pathologies; HCoV; Influenza virus; hMPV; hRSV; respiratory virus.

Figure 1

Human respiratory syncytial virus (hRSV) spreads from lungs to the central nervous system (CNS) through hematogenous route altering the local homeostasis. Upon hRSV infection, the virus spreads from the lungs to the brain by hematogenous route. Elevated levels of IL-6, IL8, CCL2, CCL4 and brain-derived neurotrophic factor (BDNF) have been found in cerebrospinal fluid (CSF) from infected patients, along with the detection of antibodies against the virus and viral RNA. It has been suggested that hRSV could infect neurons; however, this was only reported in vitro cultures.

Figure 2

Influenza virus (IV) spreads from the lungs to the CNS through the vagus nerve promoting an inflammatory state. Upon infection of IV, the virus reaches the lungs and, from there, it can spread into the CNS by transneural route, through the vagus nerve. Once set on the brain, it induces the secretion of several pro-inflammatory cytokines such as IL-1, IL-6, IL-8 and G-CSF. Viral RNA has been detected in CSF of infected patients, and also microglial apoptosis has been described.

Figure 3

Human coronavirus (HCoV) enters the CNS through the olfactory bulb, causing inflammation and demyelination. Upon nasal infection, HCoV can reach the CNS through the olfactory bulb, as ablation of this part of the brain restricts its neurotropic capacities in mice. Once the infection is set, the virus can reach the whole brain and CSF in less than 7 days. Accordingly, it has been described that this virus can induce demyelination. Likewise, primary glial cultures have been described to secrete IL-6, IL-12p40, IL-15, TNF-α, CXCL9 and CXCL10 upon viral infection.