Respiratory Syncytial Virus Infects Peripheral and Spinal Nerves and Induces Chemokine-Mediated Neuropathy

Respiratory syncytial virus (RSV) primarily infects the respiratory epithelium, but growing evidence suggests that it may also be responsible for neurologic sequelae. In 3-dimensional microphysiologic peripheral nerve cultures, RSV infected neurons, macrophages, and dendritic cells along 2 distinct trajectories depending on the initial viral load. Low-level infection was transient, primarily involved macrophages, and induced moderate chemokine release with transient neural hypersensitivity. Infection with higher viral loads was persistent, infected neuronal cells in addition to monocytes, and induced robust chemokine release followed by progressive neurotoxicity. In spinal cord cultures, RSV infected microglia and dendritic cells but not neurons, producing a moderate chemokine expression pattern. The persistence of infection was variable but could be identified in dendritic cells as long as 30 days postinoculation. This study suggests that RSV can disrupt neuronal function directly through infection of peripheral neurons and indirectly through infection of resident monocytes and that inflammatory chemokines likely mediate both mechanisms. This study provides evidence that respiratory syncytial virus, a common respiratory virus, causes neurotoxic infection of dorsal root ganglia peripheral nerves innervating the lungs and spinal cord and could cause release of replicating virus into the central nervous system, triggering monocyte infection, chemokine-induced neuroinflammation, and neurologic dysfunction.