AVIAN INFLUENZA H5N1 VIRUS INDUCES CYTOPATHY AND PROINFLAMMATORY CYTOKINE RESPONSES IN HUMAN ASTROCYTIC AND NEURONAL CELL LINES

It has previously been reported that the avian H5N1 type of influenza A virus can be detected in neurons and astrocytes of human brains in autopsy cases. However, the underlying neuropathogenicity remains unexplored. In this study, we used differentiated human astrocytic and neuronal cell lines as models to examine the effect of H5N1 influenza A viral infection on the viral growth kinetics and immune responses of the infected cells. We found that the influenza virus receptors, sialic acid-alpha 2,3-galactose and sialic acid-alpha 2,6-galactose, were expressed on differentiated human astrocytic and neuronal cells. Both types of cells could be infected with H5N1 influenza A viruses, but progeny viruses were only produced from infected astrocytic cells but not neuronal cells. Moreover, increased expression of interleukin (IL)-6 and/or tumor necrosis factor a (TNF-alpha) mRNA was detected in both astrocytic and neuronal cells at 6 and 24 h post-infection. To examine the biological consequences of such enhanced cytokine expression, differentiated astrocytic and neuronal cells were directly treated with these two cytokines. TNF-alpha treatment induced apoptosis, as well as proinflammatory cytokine, chemokine and inflammatory responses in differentiated astrocytic and neuronal cells. Taken together, our findings reveal that avian influenza H5N1 viruses can infect human astrocytic and neuronal cells, resulting in the induction of direct cellular damage and proinflammatory cytokine cascades. Our observations suggest that avian influenza H5N1 infection can trigger profound CNS injury, which may play an important role in the influenza viral pathogenesis. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.