Abstract
Low pathogenic avian influenza (LPAI) H7N9 viruses have recently evolved to gain a polybasic cleavage site in the hemagglutinin (HA) protein, resulting in variants with increased lethality in poultry that meet the criteria for highly pathogenic avian influenza (HPAI) viruses. Both LPAI and HPAI variants can cause severe disease in humans (case fatality rate of ~40%). Here, we investigated the virulence of HPAI H7N9 viruses containing a polybasic HA cleavage site (H7N9-PBC) in mice. Inoculation of mice with H7N9-PBC did not result in observable disease; however, mice inoculated with a mouse-adapted version of this virus, generated by a single passage in mice, caused uniformly lethal disease. In addition to the PBC site, we identified three other mutations that are important for host-adaptation and virulence in mice: HA (A452T), PA (D347G), and PB2 (M483K). Using reverse genetics, we confirmed that the HA mutation was the most critical for increased virulence in mice. Our study identifies additional disease determinants in a mammalian model for HPAI H7N9 virus. Furthermore, the ease displayed by the virus to adapt to a new host highlights the potential for H7N9-PBC viruses to rapidly acquire mutations that may enhance their risk to humans or other animal species.
Highlights
The pandemic potential of avian influenza A (H7N9) viruses has risen substantially since its first emergence as a low pathogenic avian influenza (LPAI) virus in 2013
Since HA plays an important role in receptor binding and entry, we investigated whether the HA mutation changed the receptor specificity of H7N9-polybasic cleavage site (PBC) RG mP2
This study demonstrated the pathogenic potential of a H7N9 avian influenza virus containing a polybasic cleavage site in a mammalian animal model
Summary
The pandemic potential of avian influenza A (H7N9) viruses has risen substantially since its first emergence as a low pathogenic avian influenza (LPAI) virus in 2013. As of June 2019, avian influenza A (H7N9) viruses had caused six epidemic waves of human disease in China, totalling 1568 laboratory confirmed cases and 616 deaths (~40% case fatality rate) [3]. These HPAI H7N9 viruses demonstrated greater morbidity and mortality in poultry [6] This epidemic wave resulted in the greatest number of confirmed cases of human H7N9 infections (> 700 cases) with 28 of the cases caused by HPAI H7N9 infections [7,8], the overall disease severity was similar to previous patients infected with LPAI H7N9 [4,9,10]. The recent evolution of LPAI H7N9 to HPAI H7N9 viruses emphasizes the need to better understand the potential of these viruses to cause severe disease in humans, and what contributes to their pathogenicity. Sequencing of the passaged virus revealed critical mutations in addition to the PBC cleavage site that contributed to high pathogenicity of these viruses
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