Human infections with the H7N9 avian flu virus were first reported in China in March 2013. As of October 5th, a total of 1,562 laboratory-confirmed cases have been reported to the World Health Organization, with more people getting infected each year. In a study published October 19 in the journal Cell Host & Microbe, researchers found that highly pathogenic avian influenza (HPAI) H7N9 viruses replicated efficiently in human airway cells and the lungs of animal models, spread among ferrets via respiratory droplets, and were minimally responsive to commonly used antiviral drugs.
"To date, no sustained transmission of H7N9 or H5N1 viruses among humans has been documented. However, further adaptation of these avian viruses to humans may result in transmissible viruses with pandemic potential," says senior author Yoshihiro Kawaoka of the University of Tokyo and University of Wisconsin-Madison. "Collectively, these data suggest that HPAI H7N9 viruses may be closer to acquiring efficient transmission in humans and, therefore, have greater pandemic potential than the HPAI H5N1 viruses."
Most human infections with H7N9 virus have occurred after exposure to poultry, and most patients have had severe respiratory illness such as pneumonia. Even though low pathogenic avian influenza (LPAI) viruses were circulating during the first four epidemics, approximately 40% of people confirmed with Asian H7N9 virus infection died.
In the new study, Kawaoka and his team set out to characterize the replication capacity, pathogenicity, and transmissibility of human HPAI H7N9 isolates in mammals to evaluate their pandemic potential. Specifically, they examined an HPAI H7N9 virus isolated from a fatal human case and created two variants by introducing mutations that conferred either sensitivity or resistance to neuraminidase inhibitors. They compared the three HPAI H7N9 viruses with a LPAI H7N9 virus they previously characterized.
They found that HPAI H7N9 viruses replicated efficiently in human airway epithelial cells and in mice, ferrets, and nonhuman primates. The HPAI H7N9 viruses were also more pathogenic in mice and ferrets than the LPAI H7N9 virus. In contrast to the LPAI H7N9 virus, the three HPAI viruses exhibited more robust replication in the brain of ferrets and caused lethal infections. All viruses tested transmitted among ferrets via respiratory droplets.
"Given that the amount of virus needed to initiate infection of exposed ferrets via respiratory droplets is small, these findings suggest that the HPAI H7N9 virus requires only a limited amount of virus to cause lethal infection, at least in this animal model," Kawaoka says. "The fact that respiratory droplet-exposed ferrets succumbed to their infections clearly suggests a substantial increase in the pathogenicity of HPAI H7N9 viruses in mammals compared with their progenitor LPAI H7N9 viruses, requiring close monitoring of HPAI H7N9 viruses in the field."
Because antiviral compounds are currently the only option for the treatment and prevention of H7N9 human infections, Kawaoka and his team assessed the efficacy of anti-influenza drugs. They found that neuraminidase inhibitors showed limited effectiveness against these viruses in the animal models. However, all viruses tested were susceptible to an experimental viral RNA polymerase inhibitor called favipiravir, suggesting that this drug may be an effective treatment option against neuraminidase inhibitor-resistant HPAI H7N9 viruses. The next step for Kawaoka and his team is to test whether H7N9 vaccine candidate strains provide protection in animal models against HPAI H7N9 viruses.
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The authors received grant support from Daiichi Sankyo Co., Ltd; Daiichi Sankyo Pharmaceutical; Chugai Pharmaceuticals; Toyama Chemical; and Ttsumura Co., Ltd. Some co-authors are founders or receive royalties from companies interested in flu vaccine development.
Cell Host & Microbe, Imai, Watanabe, Kiso, Nakajima, Yamayoshi, Iwatsuki-Horimoto, and Hatta et al.: "A Highly Pathogenic Avian H7N9 Influenza Virus Isolated from A Human Is Lethal in Some Ferrets Infected via Respiratory Droplets," http://www.cell.com/cell-host-microbe/fulltext/S1931-3128(17)30396-7
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