Risk assessment on potential disease severity and tissue tropism of influenza virus using in vitro and ex vivo models of human respiratory tract

Abstract

Active surveillance and risk assessment of influenza viruses are crucial in preparing for potential zoonotic and pandemic risks. The ability of currently circulating influenza viruses to develop efficient transmission among humans could cause high pandemic threats and increasing deaths. The recent emergence of avian-origin H7N9 and H5N6 outbreaks in the human population demands risk assessment of currently circulating influenza viruses for possible public health impact. A panel of influenza viruses of various subtypes and the wild bird surveillance isolates were assessed for their ability to induce acute lung injury (ALI) and their tissue tropism using our well-established in vitro lung injury model and ex vivo explant culture of human respiratory tract. While the ex vivo explant culture has been listed as one of the CDC’s Influenza Risk Assessment Tool (IRAT), we further proposed the in vitro human lung injury model as another IRAT. The rate of alveolar fluid clearance (AFC) and protein permeability (APP) of influenza virus in primary human alveolar epithelial cells indicated their ability to cause ALI, whereas the virus infectivity on human lung and bronchus explants provided information on the tissue tropism and possible transmissibility of virus. Our data reported that avian-origin influenza H5N1, H7N9 and H5N6 viruses impaired AFC and increased APP more significantly than the 2009 pandemic and seasonal H1N1 viruses. Furthermore, these H7N9 and H5N6 viruses had similar infectivity in human lungs but greater infectivity in human bronchi than the highly pathogenic avian H5N1 virus. In conclusion, influenza viruses with greater AFC impairment and higher infectivity of human respiratory tract might cause a more severe lung disease and higher transmissibility, and thus a greater potential of human pandemic risk. This risk assessment study aims to generate information on the risk of emergence and impact on the public health.