H9N2 Influenza Virus Infections in Human Cells Require a Balance between Neuraminidase Sialidase Activity and Hemagglutinin Receptor Affinity

Arai, Yasuha; Elgendy, Emad Mohamed; Daidoji, Tomo; Ibrahim, Madiha S.; Ono, Tetsuya; Sriwilaijaroen, Nongluk; Suzuki, Yasuo; Nakaya, Takaaki; Matsumoto, Kazuhiko; Watanabe, Yohei

doi:10.1128/jvi.01210-20

Cited by 17 publications

(14 citation statements)

References 61 publications

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“…To explore the molecular basis of the preference of many contemporary H9N2 strains for sulfated avian receptors, a property not shared with non-H9N2 avian influenza viruses, we investigated amino acid differences between UDL1/08 and Em/R66, which do and do not show this preference, respectively ( 17 , 18 , 20 ). Generally, these viruses had few differences near the RBS, though they did differ at the positions 190, 226, and 227, to which substitutions were introduced singly and in combination ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, for avian influenza viruses to be able to efficiently infect and transmit between humans they must gain the ability to bind to α2,6-linked SA. Furthermore, contemporary chicken-adapted H9N2 and H6N1 (Taiwanese lineage) viruses have specifically been identified as having a receptor preference for α2,3-linked SA, sulphated on the antepenultimate sugar, while highly pathogenic H5, H7 as well as low pathogenicity avian influenzas viruses from waterfowl appear to bind sulphated and non-sulphated α2,3-linked SA equally well (17)(18)(19)(20)(21)(22)(23)(24)(25).…”

Section: Downloaded Frommentioning

confidence: 99%

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Genetic Determinants of Receptor-Binding Preference and Zoonotic Potential of H9N2 Avian Influenza Viruses

Peacock

Sealy

Harvey

et al. 2021

J Virol

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Receptor recognition and binding is the first step of viral infection and a key determinant of host specificity. The inability of avian influenza viruses to effectively bind human-like sialylated receptors is a major impediment to their efficient transmission in humans and pandemic capacity. Influenza H9N2 viruses are endemic in poultry across Asia and parts of Africa where they occasionally infect humans and are therefore considered viruses with zoonotic potential. We previously described H9N2 viruses, including several isolated from human zoonotic cases, showing a preference for human-like receptors. Here we take a mutagenesis approach, making viruses with single or multiple substitutions in H9 haemagglutinin and test binding to avian and human receptor analogues using biolayer interferometry. We determine the genetic basis of preferences for alternative avian receptors and for human-like receptors, describing amino acid motifs at positions 190, 226 and 227 that play a major role in determining receptor specificity, and several other residues such as 159, 188, 193, 196, 198 and 225 that play a smaller role. Furthermore, we show changes at residues 135, 137, 147, 157, 158, 184, 188, and 192 can also modulate virus receptor avidity and that substitutions that increased or decreased the net positive charge around the haemagglutinin receptor-binding site show increases and decreases in avidity, respectively. The motifs we identify as increasing preference for the human-receptor will help guide future H9N2 surveillance efforts and facilitate our understanding of the emergence of influenza viruses with increased zoonotic potential. IMPORTANCE As of 2020, over 60 infections of humans by H9N2 influenza viruses have been recorded in countries where the virus is endemic. Avian-like cellular receptors are the primary target for these viruses. However, given that human infections have been detected on an almost monthly basis since 2015, there may be a capacity for H9N2 viruses to evolve and gain the ability to target human-like cellular receptors. Here we identify molecular signatures that can cause viruses to bind human-like receptors, and we identify the molecular basis for the distinctive preference for sulphated receptors displayed by the majority of recent H9N2 viruses. This work will help guide future surveillance by providing markers that signify the emergence of viruses with enhanced zoonotic potential as well as improving understanding of the basis of influenza virus receptor-binding.

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Section: Resultsmentioning

confidence: 99%

Section: Downloaded Frommentioning

confidence: 99%

Genetic Determinants of Receptor-Binding Preference and Zoonotic Potential of H9N2 Avian Influenza Viruses

Peacock

Sealy

Harvey

et al. 2021

J Virol

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“…In addition, an NA stalk deletion and mutations in other genes (i.e. PA and PB1) have been reported to be involved in the human adaptation of AI viruses [28][29][30][31][32][33].…”

Section: Introductionmentioning

confidence: 99%

Double mutations in the H9N2 avian influenza virus PB2 gene act cooperatively to increase viral host adaptation and replication for human infections

Elgendy

Arai

Kawashita

et al. 2021

Journal of General Virology

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Avian H9N2 influenza viruses in East Asia are genetically diversified and multiple genotypes (A-W) have been established in poultry. Genotype S strains are currently the most prevalent strains, have caused many human infections and pose a public health threat. In this study, human adaptation mutations in the PB2 polymerase in genotype S strains were identified by database screening. Several PB2 double mutations were identified that acted cooperatively to produce higher genotype S virus polymerase activity and replication in human cells than in avian cells and to increase viral growth and virulence in mice. These mutations were chronologically and phylogenetically clustered in a new group within genotype S viruses. Most of the relevant human virus isolates carry the PB2-A588V mutation together with another PB2 mutation (i.e. K526R, E627V or E627K), indicating a host adaptation advantage for these double mutations. The prevalence of PB2 double mutations in human H9N2 virus isolates has also been found in genetically related human H7N9 and H10N8 viruses. These results suggested that PB2 double mutations in viruses in the field acted cooperatively to increase human adaptation of the currently prevalent H9N2 genotype S strains. This may have contributed to the recent surge of H9N2 infections and may be applicable to the human adaptation of several other avian influenza viruses. Our study provides a better understanding of the human adaptation pathways of genetically related H9N2, H7N9 and H10N8 viruses in nature.

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“…In addition, H9N2 and H5N8 AI viruses have been cocirculating in Egypt and have become endemic in poultry since 2011 and 2017, respectively, with four human H9N2 infection cases reported ( 3 , 4 ). The continuous dissemination of these AI viruses raises concern for public health and animal health in the Middle East (and also worldwide), with the potential risk of the emergence of novel AI viruses ( 5 , 6 ).…”

Section: Introductionmentioning

confidence: 99%

PA Mutations Inherited during Viral Evolution Act Cooperatively To Increase Replication of Contemporary H5N1 Influenza Virus with an Expanded Host Range

Arai

Kawashita

Elgendy

et al. 2020

J Virol

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Adaptive mutations and/or reassortments in avian influenza virus polymerase subunits PA, PB1 and PB2 are one of the major factors enabling the virus to overcome the species barrier to infect humans. The majority of human-adaptation polymerase mutations have been identified in PB2: fewer adaptation mutations have been characterized in PA and PB1. Clade 2.2.1 avian influenza viruses (H5N1) are unique to Egypt and generally carry the human-adaptation PB2-E627K substitution during their dissemination in nature. In this study, we identified other human-adaptation polymerase mutations by analyzing phylogeny-associated PA mutations that H5N1 clade 2.2.1 viruses have accumulated during their evolution in the field. This analysis identified several PA mutations that produced increased replication by contemporary clade 2.2.1.2 viruses in vitro in human cells and in vivo in mice compared to ancestral clade 2.2.1 viruses. The PA mutations acted cooperatively to increase viral polymerase activity and replication both in avian and human cells, with the effect more prominent in human cells at 33°C than at 37°C. These results indicated that PA mutations have a role in establishing contemporary clade 2.2.1.2 virus infections in poultry and in adaptation to infect mammals. Our study provided data on the mechanism for PA mutations to accumulate during avian influenza virus evolution and extend the viral host range. IMPORTANCE Clade 2.2.1 avian influenza viruses (H5N1) are unique to Egypt and have caused the highest number of human H5N1 influenza cases worldwide, presenting a serious global public health threat. These viruses may have the greatest evolutionary potential for adaptation from avian hosts to human hosts. Using a comprehensive phylogenetic approach, we identified several novel clade 2.2.1 virus polymerase mutations that increased viral replication in vitro in human cells and in vivo in mice. These mutations were in the polymerase PA subunit and acted cooperatively with the E627K mutation in the PB2 polymerase subunit to provide higher replication in contemporary clade 2.2.1.2 viruses than in ancestral clade 2.2.1 viruses. These data indicated that ongoing clade 2.2.1 dissemination in the field has driven PA mutations to modify viral replication to enable host range expansion, with higher public health risk for humans.

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H9N2 Influenza Virus Infections in Human Cells Require a Balance between Neuraminidase Sialidase Activity and Hemagglutinin Receptor Affinity

Cited by 17 publications

References 61 publications

Genetic Determinants of Receptor-Binding Preference and Zoonotic Potential of H9N2 Avian Influenza Viruses

Genetic Determinants of Receptor-Binding Preference and Zoonotic Potential of H9N2 Avian Influenza Viruses

Double mutations in the H9N2 avian influenza virus PB2 gene act cooperatively to increase viral host adaptation and replication for human infections

PA Mutations Inherited during Viral Evolution Act Cooperatively To Increase Replication of Contemporary H5N1 Influenza Virus with an Expanded Host Range

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