H9N2 influenza virus in China: a cause of concern

Sun, Yipeng; Liu, Jinhua

doi:10.1007/s13238-014-0111-7

Cited by 198 publications

(192 citation statements)

References 48 publications

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“…They have also been detected in multiple other species [16]. In mammalian hosts, the H9N2 influenza viruses have been shown to provide internal genes to other influenza subtypes to create novel genotypes, such as H7N9 and H5N1 [17, 18].…”

Section: Introductionmentioning

confidence: 99%

Effects of calcitriol (1, 25-dihydroxy-vitamin D3) on the inflammatory response induced by H9N2 influenza virus infection in human lung A549 epithelial cells and in mice

Gui

Chen

et al. 2017

Virol J

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BackgroundH9N2 influenza viruses circulate globally and are considered to have pandemic potential. The hyper-inflammatory response elicited by these viruses is thought to contribute to disease severity. Calcitriol plays an important role in modulating the immune response to viral infections. However, its unknown whether calcitriol can attenuate the inflammatory response elicited by H9N2 influenza virus infection.MethodsHuman lung A549 epithelial cells were treated with calcitriol (100 nM) and then infected with an H9N2 influenza virus, or infected and then treated with calcitriol (30 nM). Culture supernatants were collected every 24 h post infection and the viral growth kinetics and inflammatory response were evaluated. Calcitriol (5 mg/kg) was administered daily by intraperitoneal injection to BABL/c mice for 15 days following H9N2 influenza virus infection. Mice were monitored for clinical signs of disease, lung pathology and inflammatory responses.ResultsCalcitriol treatment prior to and post infection with H9N2 influenza significantly decreased expression of the influenza M gene, IL-6, and IFN-β in A549 cells, but did not affect virus replication. In vivo, we found that calcitriol treatment significantly downregulated pulmonary inflammation in mice 2 days post-infection, but increased the inflammatory response 4 to 6 days post-infection. In contrast, the antiviral cytokine IFN-β was significantly higher in calcitriol-treated mice than in the untreated infected mice at 2 days post-infection, but lower than in untreated infected mice on days 4 and 8 post-infection. The elevated levels of pro-inflammatory cytokines and the decreased levels of antiviral cytokine are consistent with the period of maximum body weight loss and the lung damage in calcitriol-treated mice.ConclusionsThese results suggest that calcitriol treatment might have a negative impact on the innate immune response elicited by H9N2 infection in mice, especially at the later stage of influenza virus infection. This study will provide some novel insights into the use of calcitriol to modulate the inflammatory response elicited by influenza virus infection in humans.

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Section: Introductionmentioning

confidence: 99%

Effects of calcitriol (1, 25-dihydroxy-vitamin D3) on the inflammatory response induced by H9N2 influenza virus infection in human lung A549 epithelial cells and in mice

Gui

Chen

et al. 2017

Virol J

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“…During the same period, a newly emergent avian H10N8 virus, also with six H9N2-like internal genes, was reported to cause fatal human infections in China (4). In the meantime, H9N2 viruses continued to cause human infections in China and other countries based on etiological and serological evidence (5)(6)(7)(8)(9)(10)(11)(12). We recently found that avian H9N2 viruses have undergone significant genetic evolution, especially in their internal genes, to form a predominant genotype (G57), which in turn provided the internal genes to multiple new subtypes, including H7N9 and H10N8 viruses (13).…”

mentioning

confidence: 99%

Prevailing PA Mutation K356R in Avian Influenza H9N2 Virus Increases Mammalian Replication and Pathogenicity

Zhang

Gao

et al. 2016

J Virol

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Adaptation of the viral polymerase complex comprising PB1, PB2, and PA is necessary for efficient influenza A virus replication in new host species. We found that PA mutation K356R (PA-K356R) has become predominant since 2014 in avian H9N2 viruses in China as with seasonal human H1N1 viruses. The same mutation is also found in most human isolates of emergent avian H7N9 and H10N8 viruses whose six internal gene segments are derived from the H9N2 virus. We further demonstrated the mammalian adaptive functionality of the PA-K356R mutation. Avian H9N2 virus with the PA-K356R mutation in human A549 cells showed increased nuclear accumulation of PA and increased viral polymerase activity that resulted in elevated levels of viral transcription and virus output. The same mutant virus in mice also enhanced virus replication and caused lethal infection. In addition, combined mutation of PA-K356R and PB2-E627K, a well-known mammalian adaptive marker, in the H9N2 virus showed further cooperative increases in virus production and severity of infection in vitro and in vivo. In summary, PA-K356R behaves as a novel mammalian tropism mutation, which, along with other mutations such as PB2-E627K, might render avian H9N2 viruses adapted for human infection. IMPORTANCE Mutations of the polymerase complex (PB1, PB2, and PA) of influenza A virus are necessary for viral adaptation to new hosts.This study reports a novel and predominant mammalian adaptive mutation, PA-K356R, in avian H9N2 viruses and human isolates of emergent H7N9 and H10N8 viruses. We found that PA-356R in H9N2 viruses causes significant increases in virus replication and severity of infection in human cells and mice and that PA-K356R cooperates with the PB2-E627K mutation, a wellcharacterized human adaptive marker, to exacerbate mammalian infection in vitro and in vivo. Therefore, the PA-K356R mutation is a significant adaptation in H9N2 viruses and related H7N9 and H10N8 reassortants toward human infectivity. The emergence of new pandemic influenza A viruses requires overcoming barriers to cross-species transmission from animal reservoirs to human populations. Influenza viruses of the H9N2 subtype and their reassortants circulating in poultry are a potential source of pandemic viruses and hence represent a significant public health threat (1). Since spring 2013, a novel avian H7N9 reassortant with six internal genes of the H9N2 virus had caused three major outbreaks in humans throughout China (2, 3). During the same period, a newly emergent avian H10N8 virus, also with six H9N2-like internal genes, was reported to cause fatal human infections in China (4). In the meantime, H9N2 viruses continued to cause human infections in China and other countries based on etiological and serological evidence (5-12). We recently found that avian H9N2 viruses have undergone significant genetic evolution, especially in their internal genes, to form a predominant genotype (G57), which in turn provided the internal genes to multiple new subtypes, including H7N9 and H10N8 viru...

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“…Since then, different lineages of H9N2 viruses were sporadically detected in swine in Mainland China [9–11]. Although these infections of humans and pigs indicate that H9N2 viruses can overcome the species barrier without prior adaptation, no human-to-human or pig-to-pig transmission has been reported so far [12]. …”

Section: Introductionmentioning

confidence: 99%

Effect of serial pig passages on the adaptation of an avian H9N2 influenza virus to swine

et al. 2017

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H9N2 avian influenza viruses are endemic in poultry in Asia and the Middle East. These viruses sporadically cause dead-end infections in pigs and humans raising concerns about their potential to adapt to mammals or reassort with human or swine influenza viruses. We performed ten serial passages with an avian H9N2 virus (A/quail/Hong Kong/G1/1997) in influenza naïve pigs to assess the potential of this virus to adapt to swine. Virus replication in the entire respiratory tract and nasal virus excretion were examined after each passage and we deep sequenced viral genomic RNA of the parental and passage four H9N2 virus isolated from the nasal mucosa and lung. The parental H9N2 virus caused a productive infection in pigs with a predominant tropism for the nasal mucosa, whereas only 50% lung samples were virus-positive. In contrast, inoculation of pigs with passage four virus resulted in viral replication in the entire respiratory tract. Subsequent passages were associated with reduced virus replication in the lungs and infectious virus was no longer detectable in the upper and lower respiratory tract of inoculated pigs at passage ten. The broader tissue tropism after four passages was associated with an amino acid residue substitution at position 225, within the receptor-binding site of the hemagglutinin. We also compared the parental H9N2, passage four H9N2 and the 2009 pandemic H1N1 (pH1N1) virus in a direct contact transmission experiment. Whereas only one out of six contact pigs showed nasal virus excretion of the wild-type H9N2 for more than four days, all six contact animals shed the passage four H9N2 virus. Nevertheless, the amount of excreted virus was significantly lower when compared to that of the pH1N1, which readily transmitted and replicated in all six contact animals. Our data demonstrate that serial passaging of H9N2 virus in pigs enhances its replication and transmissibility. However, full adaptation of an avian H9N2 virus to pigs likely requires an extensive set of mutations.

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H9N2 influenza virus in China: a cause of concern

Cited by 198 publications

References 48 publications

Effects of calcitriol (1, 25-dihydroxy-vitamin D3) on the inflammatory response induced by H9N2 influenza virus infection in human lung A549 epithelial cells and in mice

Effects of calcitriol (1, 25-dihydroxy-vitamin D3) on the inflammatory response induced by H9N2 influenza virus infection in human lung A549 epithelial cells and in mice

Prevailing PA Mutation K356R in Avian Influenza H9N2 Virus Increases Mammalian Replication and Pathogenicity

Effect of serial pig passages on the adaptation of an avian H9N2 influenza virus to swine

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