Abstract

The human respiratory syncytial virus (hRSV) is the most common infectious agent that affects children before two years of age. hRSV outbreaks cause a significant increase in hospitalizations during the winter season associated with bronchiolitis and pneumonia. Recently, neurologic alterations have been associated with hRSV infection in children, which include seizures, central apnea, and encephalopathy. Also, hRSV RNA has been detected in cerebrospinal fluids (CSF) from patients with neurological symptoms after hRSV infection. Additionally, previous studies have shown that hRSV can be detected in the lungs and brains of mice exposed to the virus, yet the potential effects of hRSV infection within the central nervous system (CNS) remain unknown. Here, using a murine model for hRSV infection, we show a significant behavior alteration in these animals, up to two months after the virus exposure, as shown in marble-burying tests. hRSV infection also produced the expression of cytokines within the brain, such as IL-4, IL-10, and CCL2. We found that hRSV infection alters the permeability of the blood-brain barrier (BBB) in mice, allowing the trespassing of macromolecules and leading to increased infiltration of immune cells into the CNS together with an increased expression of pro-inflammatory cytokines in the brain. Finally, we show that hRSV infects murine astrocytes both, in vitro and in vivo. We identified the presence of hRSV in the brain cortex where it colocalizes with vWF, MAP-2, Iba-1, and GFAP, which are considered markers for endothelial cells, neurons, microglia, and astrocyte, respectively. hRSV-infected murine astrocytes displayed increased production of nitric oxide (NO) and TNF-alpha. Our results suggest that hRSV infection alters the BBB permeability to macromolecules and immune cells and induces CNS inflammation, which can contribute to the behavioral alterations shown by infected mice. A better understanding of the neuropathy caused by hRSV could help to reduce the potential detrimental effects on the CNS in hRSV-infected patients.