Neonatal influenza infection causes pathological changes in the mouse brain

Influenza A virus infections have been proposed to be associated with a broad spectrum of central nervous system complications that range from acute encephalitis/encephalopathy to neuropsychiatric disorders in humans. In order to study early influenza virus exposure in the brain, we created an influenza-infection model in neonatal mice to investigate infection route and resulting pathological changes in the brain. Real-time polymerase chain reaction and immunohistochemical analyses showed that influenza virus infection induced by an intraperitoneal injection was first detected as early as 1 day post infection (dpi), and the peak infection was observed at 5 dpi. The viral antigen was detected in a wide range of brain regions, including: the cerebral cortex, hippocampus, cerebellum, and brainstem. Apoptotic cell death and gliosis were detected in the areas of viral infection. Significant increases in proinflammatory cytokine expression were also observed at 5 dpi. Viral RNAs were detected in the cerebrospinal fluid of infected adult mice as early as 1 dpi. In addition, many infected cells were observed near the ventricles, indicating that the virus may enter the brain parenchyma through the ventricles. These results demonstrate that influenza virus may effectively infect broad regions of the brain through the hematogenous route, potentially through the cerebrospinal fluid along the ventricles, and subsequently induce neuropathological changes in the neonatal mouse brain.