Two Outbreak Sources of Influenza A (H7N9) Viruses Have Been Established in China
TL;DR: Both sources in the Yangtze River Delta region and the Pearl RiverDelta region have been established and found to be responsible for the H7N9 outbreaks in mainland China, posing a long-term threat of H7n9 infection in humans.
Abstract: Due to enzootic infections in poultry and persistent human infections in China, influenza A (H7N9) virus has remained a public health threat. The Yangtze River Delta region, which is located in eastern China, is well recognized as the original source for H7N9 outbreaks. Based on the evolutionary analysis of H7N9 viruses from all three outbreak waves since 2013, we identified the Pearl River Delta region as an additional H7N9 outbreak source. H7N9 viruses are repeatedly introduced from these two sources to the other areas, and the persistent circulation of H7N9 viruses occurs in poultry, causing continuous outbreak waves. Poultry movements may contribute to the geographic expansion of the virus. In addition, the AnH1 genotype, which was predominant during wave 1, was replaced by JS537, JS18828, and AnH1887 genotypes during waves 2 and 3. The establishment of a new source and the continuous evolution of the virus hamper the elimination of H7N9 viruses, thus posing a long-term threat of H7N9 infection in humans. Therefore, both surveillance of H7N9 viruses in humans and poultry and supervision of poultry movements should be strengthened.
IMPORTANCE Since its occurrence in humans in eastern China in spring 2013, the avian H7N9 viruses have been demonstrating the continuing pandemic threat posed by the current influenza ecosystem in China. As the viruses are silently circulated in poultry, with potentially severe outcomes in humans, H7N9 virus activity in humans in China is very important to understand. In this study, we identified a newly emerged H7N9 outbreak source in the Pearl River Delta region. Both sources in the Yangtze River Delta region and the Pearl River Delta region have been established and found to be responsible for the H7N9 outbreaks in mainland China.
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TL;DR: The different waves of H7N9 regarding their epidemiology, pathogenesis, evolution, and characteristic features are summarized and compared, and factors behind the recent increase in the number of human cases and sudden outbreaks in chickens are speculated on.
180 citations
TL;DR: This study comprehensively analyzed the sequences of HPAI H7N9 viruses from 28 human and 21 environmental samples covering eight provinces in China that were taken from November 2016 to June 2017 and showed that the ancestor virus of the HPAi H7n9 viruses originated in the Yangtze River Delta region.
Abstract: The novel low-pathogenic avian influenza A H7N9 viruses (LPAI H7N9 viruses) have been a threat to public health since their emergence in 2013 because of the high rates of mortality and morbidity that they cause. Recently, highly pathogenic variants of these avian influenza A H7N9 viruses (HPAI H7N9 viruses) have emerged and caused human infections and outbreaks among poultry in mainland China. However, it is still unclear how the HPAI H7N9 virus was generated and how it evolved and spread in China. Here, we show that the ancestor virus of the HPAI H7N9 viruses originated in the Yangtze River Delta region and spread southward to the Pearl River Delta region, possibly through live poultry trade. After introduction into the Pearl River Delta region, the origin LPAI H7N9 virus acquired four amino acid insertions in the hemagglutinin (HA) protein cleavage site and mutated into the HPAI H7N9 virus in late May 2016. Afterward, the HPAI H7N9 viruses further reassorted with LPAI H7N9 or H9N2 viruses locally and generated multiple different genotypes. As of 14 July 2017, the HPAI H7N9 viruses had spread from Guangdong Province to at least 12 other provinces. The rapid geographical expansion and genetic evolution of the HPAI H7N9 viruses pose a great challenge not only to public health but also to poultry production. Effective control measures, including enhanced surveillance, are therefore urgently needed.IMPORTANCE The LPAI H7N9 virus has caused five outbreak waves in humans and was recently reported to have mutated into highly pathogenic variants. It is unknown how the HPAI H7N9 virus originated, evolved, and disseminated in China. In this study, we comprehensively analyzed the sequences of HPAI H7N9 viruses from 28 human and 21 environmental samples covering eight provinces in China that were taken from November 2016 to June 2017. The results show that the ancestor virus of the HPAI H7N9 viruses originated in the Yangtze River Delta region. However, the insertion of four amino acids into the HA protein cleavage site of an LPAI H7N9 virus occurred in late May 2016 in the Pearl River Delta region. The mutated HPAI H7N9 virus further reassorted with LPAI H7N9 or H9N2 viruses that were cocirculating in poultry. Considering the rapid geographical expansion of the HPAI H7N9 viruses, effective control measures are urgently needed.
107 citations
Cites background from "Two Outbreak Sources of Influenza A..."
...The Yangtze River Delta region is well recognized as the original source of the H7N9 outbreaks (9, 18)....
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...Since the emergence of H7N9 avian influenza viruses, the influenza virus HA genes have evolutionarily diversified into two main lineages: the Yangtze River Delta lineage and the Pearl River Delta lineage (9)....
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...Multiple introductions of LPAI H7N9 viruses from the Yangtze River Delta region to the Pearl River Delta region have been previously observed, and these have caused the establishment of an additional outbreak source (9)....
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TL;DR: The results suggested that most cases in the fifth epidemic were still highly sporadically distributed without any epidemiology links; the main characteristics remained unchanged and the genetic characteristics of virus strains that were isolated in this epidemic remained similar to earlier epidemics.
Abstract: Since the first outbreak of avian influenza A(H7N9) virus in humans was identified in 2013, there have been five seasonal epidemics observed in China. An earlier start and a steep increase in the number of humans infected with H7N9 virus was observed between September and December 2016, raising great public concern in domestic and international societies. The epidemiological characteristics of the recently reported confirmed H7N9 cases were analysed. The results suggested that although more cases were reported recently, most cases in the fifth epidemic were still highly sporadically distributed without any epidemiology links; the main characteristics remained unchanged and the genetic characteristics of virus strains that were isolated in this epidemic remained similar to earlier epidemics. Interventions included live poultry market closures in several cities that reported more H7N9 cases recently.
102 citations
TL;DR: The presence of three different amino acid motifs at the cleavage sites of these novel H7N9 highly pathogenic avian influenza virus (HPAIV) variants which were isolated from chickens and humans and likely evolved from the preexisting LPAIVs highlights the high degree of pathogenicity and the valid transmissibility of this new H7n9 variant in chickens.
Abstract: Since its emergence in 2013, the H7N9 low-pathogenic avian influenza virus (LPAIV) has been circulating in domestic poultry in China, causing five waves of human infections. A novel H7N9 highly pathogenic avian influenza virus (HPAIV) variant possessing multiple basic amino acids at the cleavage site of the hemagglutinin (HA) protein was first reported in two cases of human infection in January 2017. More seriously, those novel H7N9 HPAIV variants have been transmitted and caused outbreaks on poultry farms in eight provinces in China. Herein, we demonstrate the presence of three different amino acid motifs at the cleavage sites of these HPAIV variants which were isolated from chickens and humans and likely evolved from the preexisting LPAIVs. Animal experiments showed that these novel H7N9 HPAIV variants are both highly pathogenic in chickens and lethal to mice. Notably, human-origin viruses were more pathogenic in mice than avian viruses, and the mutations in the PB2 gene associated with adaptation to mammals (E627K, A588V, and D701N) were identified by next-generation sequencing (NGS) and Sanger sequencing of the isolates from infected mice. No polymorphisms in the key amino acid substitutions of PB2 and HA in isolates from infected chicken lungs were detected by NGS. In sum, these results highlight the high degree of pathogenicity and the valid transmissibility of this new H7N9 variant in chickens and the quick adaptation of this new H7N9 variant to mammals, so the risk should be evaluated and more attention should be paid to this variant.IMPORTANCE Due to the recent increased numbers of zoonotic infections in poultry and persistent human infections in China, influenza A(H7N9) virus has remained a public health threat. Most of the influenza A(H7N9) viruses reported previously have been of low pathogenicity. Now, these novel H7N9 HPAIV variants have caused human infections in three provinces and outbreaks on poultry farms in eight provinces in China. We analyzed the molecular features and compared the relative characteristics of one H7N9 LPAIV and two H7N9 HPAIVs isolated from chickens and two human-origin H7N9 HPAIVs in chicken and mouse models. We found that all HPAIVs both are highly pathogenic and have valid transmissibility in chickens. Strikingly, the human-origin viruses were more highly pathogenic than the avian-origin viruses in mice, and dynamic mutations were confirmed by NGS and Sanger sequencing. Our findings offer important insight into the origin, adaptation, pathogenicity, and transmissibility of these viruses to both poultry and mammals.
97 citations
Cites background from "Two Outbreak Sources of Influenza A..."
...and the Pearl River Delta lineage of H7N9 cocirculated through waves 2 to 5 (4), with...
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TL;DR: The enhanced prevalence and diverse genetic characteristics that occurred with mammalian-adapted and NAI-resistant mutations may have contributed to increased numbers of human infections in wave 5 of H7N9.
Abstract: H7N9 virus has caused five infection waves since it emerged in 2013. The highest number of human cases was seen in wave 5; however, the underlying reasons have not been thoroughly elucidated. In this study, the geographical distribution, phylogeny, and genetic evolution of 240 H7N9 viruses in wave 5, including 35 new isolates from patients and poultry in nine provinces, were comprehensively analyzed together with strains from first four waves. Geographical distribution analysis indicated that the newly emerging highly pathogenic (HP) and low-pathogenicity (LP) H7N9 viruses were cocirculating, causing human and poultry infections across China. Genetic analysis indicated that dynamic reassortment of the internal genes among LP-H7N9/H9N2/H6Ny and HP-H7N9, as well as of the surface genes, between the Yangtze and Pearl River Delta lineages resulted in at least 36 genotypes, with three major genotypes (G1 [A/chicken/Jiangsu/SC537/2013-like], G3 [A/Chicken/Zhongshan/ZS/2017-like], and G11 [A/Anhui/40094/2015-like]). The HP-H7N9 genotype likely evolved from G1 LP-H7N9 by the insertion of a KRTA motif at the cleavage site (CS) and then evolved into 15 genotypes with four different CS motifs, including PKG KRTA R/G, PKG KRIA R/G, PKR KRAA R/G, and PKR KRTA R/G. Approximately 46% (28/61) of HP strains belonged to G3. Importantly, neuraminidase (NA) inhibitor (NAI) resistance (R292K in NA) and mammalian adaptation (e.g., E627K and A588V in PB2) mutations were found in a few non-human-derived HP-H7N9 strains. In summary, the enhanced prevalence and diverse genetic characteristics that occurred with mammalian-adapted and NAI-resistant mutations may have contributed to increased numbers of human infections in wave 5.IMPORTANCE The highest numbers of human H7N9 infections were observed during wave 5 from October 2016 to September 2017. Our results showed that HP-H7N9 and LP-H7N9 had spread virtually throughout China and underwent dynamic reassortment with different subtypes (H7N9/H9N2 and H6Ny) and lineages (Yangtze and Pearl River Delta lineages), resulting in totals of 36 and 3 major genotypes, respectively. Notably, the NAI drug-resistant (R292K in NA) and mammalian-adapted (e.g., E627K in PB2) mutations were found in HP-H7N9 not only from human isolates but also from poultry and environmental isolates, indicating increased risks for human infections. The broad dissemination of LP- and HP-H7N9 with high levels of genetic diversity and host adaptation and drug-resistant mutations likely accounted for the sharp increases in the number of human infections during wave 5. Therefore, more strategies are needed against the further spread and damage of H7N9 in the world.
82 citations
References
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TL;DR: This work presents some of the most notable new features and extensions of RAxML, such as a substantial extension of substitution models and supported data types, the introduction of SSE3, AVX and AVX2 vector intrinsics, techniques for reducing the memory requirements of the code and a plethora of operations for conducting post-analyses on sets of trees.
Abstract: Motivation: Phylogenies are increasingly used in all fields of medical and biological research. Moreover, because of the next-generation sequencing revolution, datasets used for conducting phylogenetic analyses grow at an unprecedented pace. RAxML (Randomized Axelerated Maximum Likelihood) is a popular program for phylogenetic analyses of large datasets under maximum likelihood. Since the last RAxML paper in 2006, it has been continuously maintained and extended to accommodate the increasingly growing input datasets and to serve the needs of the user community. Results: I present some of the most notable new features and extensions of RAxML, such as a substantial extension of substitution models and supported data types, the introduction of SSE3, AVX and AVX2 vector intrinsics, techniques for reducing the memory requirements of the code and a plethora of operations for conducting postanalyses on sets of trees. In addition, an up-to-date 50-page user manual covering all new RAxML options is available. Availability and implementation: The code is available under GNU
23,838 citations
23 Dec 2010
TL;DR: Development of the CIPRES Science Gateway is described, a web portal designed to provide researchers with transparent access to the fastest available community codes for inference of phylogenetic relationships, and implementation of these codes on scalable computational resources.
Abstract: Understanding the evolutionary history of living organisms is a central problem in biology. Until recently the ability to infer evolutionary relationships was limited by the amount of DNA sequence data available, but new DNA sequencing technologies have largely removed this limitation. As a result, DNA sequence data are readily available or obtainable for a wide spectrum of organisms, thus creating an unprecedented opportunity to explore evolutionary relationships broadly and deeply across the Tree of Life. Unfortunately, the algorithms used to infer evolutionary relationships are NP-hard, so the dramatic increase in available DNA sequence data has created a commensurate increase in the need for access to powerful computational resources. Local laptop or desktop machines are no longer viable for analysis of the larger data sets available today, and progress in the field relies upon access to large, scalable high-performance computing resources. This paper describes development of the CIPRES Science Gateway, a web portal designed to provide researchers with transparent access to the fastest available community codes for inference of phylogenetic relationships, and implementation of these codes on scalable computational resources. Meeting the needs of the community has included developing infrastructure to provide access, working with the community to improve existing community codes, developing infrastructure to insure the portal is scalable to the entire systematics community, and adopting strategies that make the project sustainable by the community. The CIPRES Science Gateway has allowed more than 1800 unique users to run jobs that required 2.5 million Service Units since its release in December 2009. (A Service Unit is a CPU-hour at unit priority).
9,117 citations
"Two Outbreak Sources of Influenza A..." refers methods in this paper
...A maximum likelihood phylogenetic tree for nucleotide sequences of each gene of selected influenza viruses was constructed under the GTRCAT model (a computational workaround for the general time-reversible model of nucleotide substitution under the Gamma model of rate heterogeneity) with 1,000 bootstrap replicates, using RAxML (9) via CIPRES Science Gateway (10)....
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...Creating the CIPRES Science Gateway for inference of large phylogenetic trees, p 1– 8....
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TL;DR: Novel reassortant H7N9 viruses were associated with severe and fatal respiratory disease in three patients, and all three patients died.
Abstract: Background Infection of poultry with influenza A subtype H7 viruses occurs worldwide, but the introduction of this subtype to humans in Asia has not been observed previously. In March 2013, three urban residents of Shanghai or Anhui, China, presented with rapidly progressing lower respiratory tract infections and were found to be infected with a novel reassortant avian-origin influenza A (H7N9) virus. Methods We obtained and analyzed clinical, epidemiologic, and virologic data from these patients. Respiratory specimens were tested for influenza and other respiratory viruses by means of real-time reverse-transcriptase–polymerase-chain-reaction assays, viral culturing, and sequence analyses. Results A novel reassortant avian-origin influenza A (H7N9) virus was isolated from respiratory specimens obtained from all three patients and was identified as H7N9. Sequencing analyses revealed that all the genes from these three viruses were of avian origin, with six internal genes from avian influenza A (H9N2) virus...
2,113 citations
"Two Outbreak Sources of Influenza A..." refers background in this paper
...All H7N9 viruses were resistant to adamantine due to the S31N mutation in M2 protein (1, 16, 22)....
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...Since the first emergence of influenza A (H7N9) virus in Eastern China (1), the novel virus has caused three outbreak waves in humans....
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TL;DR: Avian A/H5N1 influenza viruses can acquire the capacity for airborne transmission between mammals without recombination in an intermediate host and therefore constitute a risk for human pandemic influenza.
Abstract: Highly pathogenic avian influenza A/H5N1 virus can cause morbidity and mortality in humans but thus far has not acquired the ability to be transmitted by aerosol or respiratory droplet ("airborne transmission") between humans. To address the concern that the virus could acquire this ability under natural conditions, we genetically modified A/H5N1 virus by site-directed mutagenesis and subsequent serial passage in ferrets. The genetically modified A/H5N1 virus acquired mutations during passage in ferrets, ultimately becoming airborne transmissible in ferrets. None of the recipient ferrets died after airborne infection with the mutant A/H5N1 viruses. Four amino acid substitutions in the host receptor-binding protein hemagglutinin, and one in the polymerase complex protein basic polymerase 2, were consistently present in airborne-transmitted viruses. The transmissible viruses were sensitive to the antiviral drug oseltamivir and reacted well with antisera raised against H5 influenza vaccine strains. Thus, avian A/H5N1 influenza viruses can acquire the capacity for airborne transmission between mammals without recombination in an intermediate host and therefore constitute a risk for human pandemic influenza.
1,418 citations
"Two Outbreak Sources of Influenza A..." refers background in this paper
...Of note, almost all of the human- or avian-origin H7N9 viruses possessed the I368V mutation in PB1 protein, which would increase the H5N1 viral transmissibility in ferrets (20)....
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TL;DR: Cross species poultry-to-person transmission of this new reassortant H7N9 virus is associated with severe pneumonia and multiorgan dysfunction in human beings and monitoring of the viral evolution and further study of disease pathogenesis will improve disease management, epidemic control, and pandemic preparedness.
784 citations
"Two Outbreak Sources of Influenza A..." refers background in this paper
...All H7N9 viruses were resistant to adamantine due to the S31N mutation in M2 protein (1, 16, 22)....
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