Lipopolysaccharide treatment and inoculation of influenza A virus results in influenza virus–associated encephalopathy–like changes in neonatal mice

Influenza virus-associated encephalopathy (IAE) is a highly mortal neural complication of influenza A virus (IAV) infection, mostly affecting children younger than 5 years old, and the brain pathology of IAE is characterized by peracute brain edema with evidence of an impaired blood-brain barrier. The pathogenesis of IAE is unknown, but hypercytokinemia of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 is suspected of playing a central role in the development of IAE. Because the brain pathology of IAE is similar to that of septic encephalopathy due to endotoxemia, the effect of combined treatment of IAV and lipopolysaccharide (LPS) was tested using suckling mice. The results show that pulmonary infection with non-neurotropic IAV enhanced the neuropathogenicity of LPS and induced encephalopathy that was similar to IAE with respect to the occurrence of central nervous system (CNS) histopathology and the absence of direct infection of IAV in the brain. Influenza A virus also increased blood-brain barrier (BBB) permeability and induced inflammatory cytokines in the blood. These results suggested that the mice treated with IAV+LPS are possible animal models of IAE, and that hypercytokinemia and/or the involvement of endotoxemia in IAV infection are possible causes of IAE.