Abstract
Influenza A (H7N9) is an emerging zoonotic pathogen with pandemic potential. To understand its adaptation capability, we examined the genetic changes and cellular responses following serial infections of A (H7N9) in primary human airway epithelial cells (hAECs). After 35 serial passages, six amino acid mutations were found, i.e. HA (R54G, T160A, Q226L, H3 numbering), NA (K289R, or K292R for N2 numbering), NP (V363V/I) and PB2 (L/R332R). The mutations in HA enabled A(H7N9) virus to bind with higher affinity (from 39.2% to 53.4%) to sialic acid α2,6-galactose (SAα2,6-Gal) linked receptors. A greater production of proinflammatory cytokines in hAECs was elicited at later passages together with earlier peaking at 24 hours post infection of IL-6, MIP-1α, and MCP-1 levels. Viral replication capacity in hAECs maintained at similar levels throughout the 35 passages. In conclusion, during the serial infections of hAECs by influenza A(H7N9) virus, enhanced binding of virion to cell receptors with subsequent stronger innate cell response were noted, but no enhancement of viral replication could be observed. This indicates the existence of possible evolutional hurdle for influenza A(H7N9) virus to transmit efficiently from human to human.
Highlights
In February 2013, avian influenza A(H7N9) virus crossed the species barrier in China and for the first time caused human infections[1]
Due to the limited subpassaging ability of the human airway epithelial cells (hAECs), three different hAECs series were used in the serial passages of H7N9
We hypothesized that after serial passages in hAECs, influenza A(H7N9) virus would gradually adapt to the environment and undergo mutation, thereby leading to increased viral replication
Summary
In February 2013, avian influenza A(H7N9) virus crossed the species barrier in China and for the first time caused human infections[1]. Amino acid substitutions in the hemagglutinin (HA) and polymerase basic protein 2 (PB2) viral proteins enable the virus to overcome the host restriction barrier and infect humans. By using ex vivo human respiratory organ cultures, Chan et al confirmed that PB2-E627K was the most important mutation on PB2 protein for efficient replication of influenza H7N911. These substitutions in PB2 were rapidly selected upon. Infection of humans with avian H5N1 or H7N9 influenza viruses, adapting the viral polymerase for the mammalian corresponding protein, such as ANP32A12. Despite the presence of a pressing need to gain a better understanding of the association between severe respiratory disease and A(H7N9) human infection, there are few studies examining the host responses in human airway epithelial cells (hAECs) following the virus infection[13,14,15]
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