Avian influenza virus infection in human innate immune cells

Influenza A viruses are one of the most significant pathogens to humans. These viruses cause recurrent epidemics and occasional devastating pandemics. Avian influenza viruses (AIVs) circulate constantly among birds and some of these viruses are able to infect humans. Most human cases have been caused by H7N9, H5N1, H7N7 and H9N2 subtypes of influenza A viruses. H9N2 virus infections have been generally mild in humans. H5N1 and H7N9 viruses have caused a severe acute respiratory distress syndrome (ARDS) in several patients, and among humans, mortality rates are around 50% and 40%, respectively. AIVs pose a major pandemic threat, because practically all humans lack pre-existing immunity against these viruses. Innate immune responses are the first barrier against AIV infections prior to adaptive immunity is being activated. In the present study, innate immune responses have been characterized in human primary innate immune cells induced by avian influenza viruses. H5N2, H7N3, H7N9 and H9N2 low pathogenic AIV strains were used, which had been isolated either from birds or humans and highly pathogenic AIV (H5N1) strains of human origin. Macrophages and dendritic cells are the central cells of innate immunity. The present study shows that avian isolates of H5N2, H7N3 and H9N2 viruses are able to infect and replicate in human dendritic cells. Also, human isolates of H5N1, H7N9 and H9N2 viruses infected and replicated in dendritic cells, but in their ability to spread in human immune cells there was remarkable difference between different virus subtypes. It was evident, that the H5N1 viruses were able to spread extremely efficiently and eventually infected the whole cell culture starting from very low virus dose. H5N1 virus infection was productive in human monocyte-derived macrophages and dendritic cells, indicating that the infection produced new infective virus particles. Seasonal influenza H3N2 virus and H7N9 AIV infections seemed to be productive only in macrophages but not in dendritic cells. It was also noted that H5N1 virus particles were more often propagation competent than H3N2 or H7N9 viruses. In addition, innate immune responses induced by the different influenza virus strains were investigated. The data shows that low pathogenic H5N2, H7N3 and H9N2 AIVs induced interferon and pro-inflammatory cytokine responses and antiviral protein expression in a similar fashion as the seasonal influenza H3N2 virus. Surprisingly, interferon and pro-inflammatory cytokine responses were impaired in the H7N9 virus infection. In contrast to the H7N9 virus-induced deficient responses, H5N1 virus triggered very strong cytokine responses, which is known as a "cytokine storm". In conclusion, the results of these studies show that currently circulating avian influenza viruses are able to infect human cells. The results also indicate that H5N1 and H7N9 viruses interfere with human innate immune signaling but by totally different mechanisms.