H5N1, not seasonal flu, targeted human pulmonary endothelial cells

Zeng H. J Virol. 2012;86:667-678.

The H5N1 virus — but not seasonal influenza viruses — targets human pulmonary endothelium cells, where it induces inflammation often associated with H5N1-induced acute respiratory distress syndrome, according to study results published in the Journal of Virology.

Using an in vitro model to assess the tolerance of pulmonary endothelial cells to virus infection, researchers compared replication of selected seasonal, pandemic and potentially pandemic influenza virus strains. They also examined the differences in infection rate and varying host responses to the subtype influenza viruses, including four H5N1 strains, four H7N7 strains, two H7N3 strains, five H1N1 strains, two H3N2 strains and one H7N2 strain.

According to the study data, pulmonary endothelial cells support productive replication only of highly pathogenic avian influenza H5N1 viruses, which favor entry through and are released from the apical surface of polarized human endothelial monolayers.

Among the various subtype influenza viruses, two H5N1 virus strains — A/Thailand/16/2004 and A/Vietnam/1203/2004 (VN/1203) — exhibited heightened virulence in mammalian models and were observed to replicate to higher titers than less virulent H5N1 strains. In particular, infection from the VN/1203 strain caused a significant decrease in endothelial cell proliferation compared with other subtype viruses and was observed to be a potent inducer of cytokines and adhesion molecules that regulate inflammation during acute lung injury.

Responding to previous theories that the polybasic amino acids at the hemagglutinin precursor molecule cleavage site are crucial to H5N1 virus replication, researchers found that the deletion of the H5 hemagglutinin multi-basic cleavage site did not affect virus infectivity; however, deletion of hemagglutinin decreased virus replication in endothelial cells.

“Although the mechanism of H5N1 pathogenesis is not entirely known, our research identified one virulent factor, the cleavage site of the viral surface glycoprotein hemagglutinin, which we found to be critical for the production of infectious progeny H5N1 virus in pulmonary endothelial cells,” Terrence Tumpey, PhD, of the CDC, said in a press release.

“Treatment with anti-inflammatory drugs has been proposed as a therapeutic option for patients infected with H5N1 viruses,” Tumpey said. “The development of new, more targeted therapies for H5N1 disease along with combination antiviral drug treatment could be an effective approach in reducing acute lung injury and mortality caused by H5N1 virus.”

Disclosure: The researchers report funding from the NIH grant HL-60024 and HL-66299.

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