Hemagglutinin Subtype Specificity and Mechanisms of Highly Pathogenic Avian Influenza Virus Genesis
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ABSTRACT:
SUBMITTER: de Bruin A
PROVIDER: S-EPMC9321182 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:To test the role of neutralizing antibodies (nAbs) and receptor adaptation in interspecies transmission of influenza virus, two H5N1 strains, isolated from human and avian hosts, with four amino acid differences in hemagglutinin (HA) and seven HA mutations were studied. We found that a mutation at amino acid position 90 in the H5N1 HA, outside the receptor-binding domain (RBD), could simultaneously induce changes in the RBD conformation to escape from nAb binding and alter the receptor preference through long-range regulation. This mutation was deemed a "key event" for interspecies transmission. It is likely a result of positive selection caused by antibodies, allowing the original invasion by new species-specific variants. A mutation at amino acid position 160 in the RBD only induced a change in receptor preference. This mutation was deemed a "maintaining adaptation", which ensured that influenza virus variants would be able to infect new organisms of a different species successfully. The mutation is the result of adaptation caused by the receptor. Our results suggest that continuing occurrence of these two types of mutations made the variants persist in the new host species.
| S-EPMC7086585 | biostudies-literature
Project description:UnlabelledThe novel H7N9 avian influenza virus (AIV) was demonstrated to cause severe human respiratory infections in China. Here, we examined poultry specimens from live bird markets linked to human H7N9 infection in Hangzhou, China. Metagenomic sequencing revealed mixed subtypes (H5, H7, H9, N1, N2, and N9). Subsequently, AIV subtypes H5N9, H7N9, and H9N2 were isolated. Evolutionary analysis showed that the hemagglutinin gene of the novel H5N9 virus originated from A/Muscovy duck/Vietnam/LBM227/2012 (H5N1), which belongs to clade 2.3.2.1. The neuraminidase gene of the novel H5N9 virus originated from human-infective A/Hangzhou/1/2013 (H7N9). The six internal genes were similar to those of other H5N1, H7N9, and H9N2 virus strains. The virus harbored the PQRERRRKR/GL motif characteristic of highly pathogenic AIVs at the HA cleavage site. Receptor-binding experiments demonstrated that the virus binds α-2,3 sialic acid but not α-2,6 sialic acid. Identically, pathogenicity experiments also showed that the virus caused low mortality rates in mice. This newly isolated H5N9 virus is a highly pathogenic reassortant virus originating from H5N1, H7N9, and H9N2 subtypes. Live bird markets represent a potential transmission risk to public health and the poultry industry.ImportanceThis investigation confirms that the novel H5N9 subtype avian influenza A virus is a reassortant strain originating from H5N1, H7N9, and H9N2 subtypes and is totally different from the H5N9 viruses reported before. The novel H5N9 virus acquired a highly pathogenic H5 gene and an N9 gene from human-infecting subtype H7N9 but caused low mortality rates in mice. Whether this novel H5N9 virus will cause human infections from its avian host and become a pandemic subtype is not known yet. It is therefore imperative to assess the risk of emergence of this novel reassortant virus with potential transmissibility to public health.
| S-EPMC4524050 | biostudies-literature
Project description:In 2014, novel highly pathogenic avian influenza A H5N2, H5N5, H5N6, and H5N8 viruses caused outbreaks in Asia, Europe, and North America. The H5 genes of these viruses form a monophyletic group that evolved from a clade 2.3.4 H5N1 variant. This rapid emergence of new H5Nx combinations is unprecedented in the H5N1 evolutionary history.
| S-EPMC4412238 | biostudies-literature
Project description:Clade 2.3.4.4 highly pathogenic avian influenza viruses (H5Nx) have spread from Asia to other parts of the world. Since 2014, human infections with clade 2.3.4.4 highly pathogenic avian influenza H5N6 viruses have been continuously reported in China. To investigate the genesis of the virus, we analyzed 123 H5 or N6 environmental viruses sampled from live-poultry markets or farms from 2012 to 2015 in Mainland China. Our results indicated that clade 2.3.4.4 H5N2/N6/N8 viruses shared the same hemagglutinin gene as originated in early 2009. From 2012 to 2015, the genesis of highly pathogenic avian influenza H5N6 viruses occurred via two independent pathways. Three major reassortant H5N6 viruses (reassortants A, B, and C) were generated. Internal genes of reassortant A and B viruses and reassortant C viruses derived from clade 2.3.2.1c H5N1 and H9N2 viruses, respectively. Many mammalian adaption mutations and antigenic variations were detected among the three reassortant viruses. Considering their wide circulation and dynamic reassortment in poultry, we highly recommend close monitoring of the viruses in poultry and humans. IMPORTANCE Since 2014, clade 2.3.4.4 highly pathogenic avian influenza (H5Nx) viruses have caused many outbreaks in both wild and domestic birds globally. Severe human cases with novel H5N6 viruses in this group were also reported in China in 2014 and 2015. To investigate the genesis of the genetic diversity of these H5N6 viruses, we sequenced 123 H5 or N6 environmental viruses sampled from 2012 to 2015 in China. Sequence analysis indicated that three major reassortants of these H5N6 viruses had been generated by two independent evolutionary pathways. The H5N6 reassortant viruses had been detected in most provinces of southern China and neighboring countries. Considering the mammalian adaption mutations and antigenic variation detected, the spread of these viruses should be monitored carefully due to their pandemic potential.
| S-EPMC5309950 | biostudies-literature
Project description:UnlabelledHighly pathogenic avian influenza viruses (HPAIVs) of hemagglutinin H5 and H7 subtypes emerge after introduction of low-pathogenic avian influenza viruses (LPAIVs) from wild birds into poultry flocks, followed by subsequent circulation and evolution. The acquisition of multiple basic amino acids at the endoproteolytical cleavage site of the hemagglutinin (HA) is a molecular indicator for high pathogenicity, at least for infections of gallinaceous poultry. Apart from the well-studied significance of the multibasic HA cleavage site, there is only limited knowledge on other alterations in the HA and neuraminidase (NA) molecules associated with changes in tropism during the emergence of HPAIVs from LPAIVs. We hypothesized that changes in tropism may require alterations of the sialyloligosaccharide specificities of HA and NA. To test this hypothesis, we compared a number of LPAIVs and HPAIVs for their HA-mediated binding and NA-mediated desialylation of a set of synthetic receptor analogs, namely, α2-3-sialylated oligosaccharides. NA substrate specificity correlated with structural groups of NAs and did not correlate with pathogenic potential of the virus. In contrast, all HPAIVs differed from LPAIVs by a higher HA receptor-binding affinity toward the trisaccharides Neu5Acα2-3Galβ1-4GlcNAcβ (3'SLN) and Neu5Acα2-3Galβ1-3GlcNAcβ (SiaLe(c)) and by the ability to discriminate between the nonfucosylated and fucosylated sialyloligosaccharides 3'SLN and Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAcβ (SiaLe(x)), respectively. These results suggest that alteration of the receptor-binding specificity accompanies emergence of the HPAIVs from their low-pathogenic precursors.ImportanceHere, we have found for the first time correlations of receptor-binding properties of the HA with a highly pathogenic phenotype of poultry viruses. Our study suggests that enhanced receptor-binding affinity of HPAIVs for a typical "poultry-like" receptor, 3'SLN, is provided by substitutions in the receptor-binding site of HA which appeared in HA of LPAIVs in the course of transmission of LPAIVs from wild waterfowl into poultry flocks, with subsequent adaptation in poultry. The identification of LPAIVs with receptor characteristics of HPAIVs argues that the sialic acid-binding specificity of the HA may be used as a novel phenotypic marker of HPAIVs.
| S-EPMC4442535 | biostudies-literature
Project description:First identified in May 2014 in China's Sichuan Province, initial cases of H5N6 avian influenza virus (AIV) infection in humans raised great concerns about the virus's prevalence, origin, and development. To evaluate both AIV contamination in live poultry markets (LPMs) and the risk of AIV infection in humans, we have conducted surveillance of LPMs in Guangdong Province since 2013 as part of environmental sampling programs. With environmental samples associated with these LPMs, we performed genetic and phylogenetic analyses of 10 H5N6 AIVs isolated from different cities of Guangdong Province from different years. Results revealed that the H5N6 viruses were reassortants with hemagglutinin (HA) genes derived from clade 2.3.4.4 of H5-subtype AIV, yet neuraminidase (NA) genes derived from H6N6 AIV. Unlike the other seven H5N6 viruses isolated in first 7 months of 2014, all of which shared remarkable sequence similarity with the H5N1 AIV in all internal genes, the PB2 genes of GZ693, GZ670, and ZS558 more closely related to H6N6 AIV and the PB1 gene of GZ693 to the H3-subtype AIV. Phylogenetic analyses revealed that the environmental H5N6 AIV related closely to human H5N6 AIVs isolated in Guangdong. These results thus suggest that continued reassortment has enabled the emergence of a novel H5N6 virus in Guangdong, as well as highlight the potential risk of highly pathogenic H5N6 AIVs in the province.
| S-EPMC4829614 | biostudies-literature
Project description:The H7 subtype of avian influenza viruses (AIV) stands out among other AIV. The H7 viruses circulate in ducks, poultry and equines and have repeatedly caused outbreaks of disease in humans. The laboratory strain A/chicken/Rostock/R0p/1934 (H7N1) (R0p), which was previously derived from the highly pathogenic strain A/FPV/Rostock/1934 (H7N1), was studied in this work to ascertain its biological property, genome stability and virulent changing mechanism. Several virus variants were obtained by serial passages in the chicken lungs. After 10 passages of this virus through the chicken lungs we obtained a much more pathogenic variant than the starting R0p. The study of intermediate passages showed a sharp increase in pathogenicity between the fifth and sixth passage. By cloning these variants, a pair of strains (R5p and R6p) was obtained, and the complete genomes of these strains were sequenced. Single amino acid substitution was revealed, namely reversion Gly140Arg in HA1. This amino acid is located at the head part of the hemagglutinin, adjacent to the receptor-binding site. In addition to the increased pathogenicity in chicken and mice, R6p differs from R5p in the shape of foci in cell culture and an increased affinity for a negatively charged receptor analogue, while maintaining a pattern of receptor-binding specificity and the pH of conformational change of HA.
| S-EPMC8402889 | biostudies-literature
Project description:The outbreaks of the highly pathogenic avian influenza (HPAI) in 2016-2017 and 2017-2018, caused by novel reassortant clade 2.3.4.4 H5N6 viruses, resulted in the loss of one billion birds in South Korea. Here, we characterized the H5N6 viruses isolated from wild birds in South Korea from December 2017 to August 2019 by next-generation sequencing. The results indicated that clade 2.3.4.4 H5N6 viruses isolated in 2017 and 2019 shared almost identical nucleotide sequences with the HPAI H5N6 viruses from 2016 in South Korea. This repeated detection of evolutionarily identical H5N6 viruses in same region for more than three years may suggest indigenization of the HPAI H5N6 virus in South Korea. Phylogenetic analysis demonstrated that the clade 2.3.4.4 H5N6 viruses isolated in 2017 and 2019 were evolutionarily distinct from those isolated in 2018. Molecular analysis revealed that the H5N6 viruses isolated in 2017 and 2019 had features associated with an increased risk of human infection (e.g. a deletion at position 133 of HA and glutamic acid residue at position 92 of NS1). Overall, these genomic features of HPAI H5N6 viruses highlight the need for continuous monitoring of avian influenza viruses in wild migratory birds as well as in domestic birds.
| S-EPMC7190616 | biostudies-literature
Project description:BackgroundThe highly pathogenic H5N1 is a major avian pathogen that crosses species barriers and seriously affects humans as well as some mammals. It mutates in an intensified manner and is considered a potential candidate for the possible next pandemic with all the catastrophic consequences.MethodsNasal swabs were collected from donkeys suffered from respiratory distress. The virus was isolated from the pooled nasal swabs in specific pathogen free embryonated chicken eggs (SPF-ECE). Reverse transcriptase polymerase chain reaction (RT-PCR) and sequencing of both haemagglutingin and neuraminidase were performed. H5 seroconversion was screened using haemagglutination inhibition (HI) assay on 105 donkey serum samples.ResultsWe demonstrated that H5N1 jumped from poultry to another mammalian host; donkeys. Phylogenetic analysis showed that the virus clustered within the lineage of H5N1 from Egypt, closely related to 2009 isolates. It harboured few genetic changes compared to the closely related viruses from avian and humans. The neuraminidase lacks oseltamivir resistant mutations. Interestingly, HI screening for antibodies to H5 haemagglutinins in donkeys revealed high exposure rate.ConclusionsThese findings extend the host range of the H5N1 influenza virus, possess implications for influenza virus epidemiology and highlight the need for the systematic surveillance of H5N1 in animals in the vicinity of backyard poultry units especially in endemic areas.
| S-EPMC2867947 | biostudies-literature
Project description:Influenza A viruses are one of the major threats in modern health care. Novel viruses arise due to antigenic drift and antigenic shift, leading to escape from the immune system and resulting in a serious problem for disease control. In order to investigate the escape process and to enable predictions of escape, we serially passaged influenza A H5N1 virus in vitro 100 times under immune pressure. The generated escape viruses were characterized phenotypically and in detail by full-genome deep sequencing. Mutations already found in natural isolates were detected, evidencing the in vivo relevance of the in vitro-induced amino acid substitutions. Additionally, several novel alterations were triggered. Altogether, the results imply that our in vitro system is suitable to study influenza A virus evolution and that it might even be possible to predict antigenic changes of influenza A viruses circulating in vaccinated populations.
| S-EPMC3264362 | biostudies-literature