Outbreak of Influenza A (H3N2) Variant Virus Infection among Attendees of an Agricultural Fair, Pennsylvania, USA, 2011

Wong, Karen K.; Greenbaum, Adena; Moll, Mària; Lando, James; Moore, Erin L.; Ganatra, Rahul B.; Biggerstaff, Matthew; Lam, Eugene; Smith, Erica E.; Storms, Aaron D.; Miller, Jeffrey R.; Dato, Virginia; Nalluswami, Kumar; Nambiar, Atmaram; Silvestri, Sharon A.; Lute, James R.; Ostroff, Stephen M.; Hancock, Kathy; Branch, Alicia; Trock, Susan C.; Klimov, Alexander; Shu, Bo; Brammer, Lynnette; Epperson, Scott; Finelli, Lyn; Jhung, Michael A.

doi:10.3201/eid1812.121097

Cited by 72 publications

(61 citation statements)

References 23 publications

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“…Finally, it is well understood that pigs often act as mixing vessels for human, swine, and avian influenza viruses (51), and our results provide evidence that the H7N9 virus and variants are able to productively infect pigs and suggest that the virus could readily become established in the swine population. If these H7N9 viruses or related viruses become enzootic in pigs, it will create new opportunities for the generation of novel reassortants with other swine influenza viruses circulating in Southeast Asia (e.g., swine, avian, and even human lineage viruses, introduced into pigs by reverse zoonosis), which could increase their pandemic potential (20,37,52).…”

Section: Discussionmentioning

confidence: 99%

“…Swine have been shown to play a role in the emergence of pandemic influenza A viruses in the past (15)(16)(17)(18)(19). Although there is no evidence of H7N9 infection of pigs thus far, hundreds of human infections occurred over a large geographic region in China in a short period of time, suggesting that this H7N9 lineage is widespread in China (20,21). The close contact between pigs and poultry and humans in China provides continual opportunities for transmission of H7N9 viruses to pigs.…”

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confidence: 99%

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Analysis of Recombinant H7N9 Wild-Type and Mutant Viruses in Pigs Shows that the Q226L Mutation in HA Is Important for Transmission

Liu

Zhou

et al. 2014

J Virol

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The fact that there have been more than 300 human infections with a novel avian H7N9 virus in China indicates that this emerging strain has pandemic potential. Furthermore, many of the H7N9 viruses circulating in animal reservoirs contain putative mammalian signatures in the HA and PB2 genes that are believed to be important in the adaptation of other avian strains to humans. To date, the definitive roles of these mammalian-signature substitutions in transmission and pathogenesis of H7N9 viruses remain unclear. To address this we analyzed the biological characteristics, pathogenicity, and transmissibility of A/Anhui/ 1/2013 (H7N9) virus and variants in vitro and in vivo using a synthetically created wild-type virus (rAnhui-WT) and two mutants (rAnhui-HA-226Q and rAnhui-PB2-627E). All three viruses replicated in lungs of intratracheally inoculated pigs, yet nasal shedding was limited. The rAnhui-WT and rAnhui-PB2-627E viruses were transmitted to contact animals. In contrast, the rAnhui-HA-226Q virus was not transmitted to sentinel pigs. Deep sequencing of viruses from the lungs of infected pigs identified substitutions arising in the viral population (e.g., PB2-T271A, PB2-D701N, HA-V195I, and PB2-E627K reversion) that may enhance viral replication in pigs. Collectively, the results demonstrate that critical mutations (i.e., HA-Q226L) enable the H7N9 viruses to be transmitted in a mammalian host and suggest that the myriad H7N9 genotypes circulating in avian species in China and closely related strains (e.g., H7N7) have the potential for further adaptation to human or other mammalian hosts (e.g., pigs), leading to strains capable of sustained human-to-human transmission. IMPORTANCEThe genomes of the zoonotic avian H7N9 viruses emerging in China have mutations in critical genes (PB2-E627K and HA-Q226L) that may be important in their pandemic potential. This study shows that (i) HA-226L of zoonotic H7N9 strains is critical for binding the ␣-2,6-linked receptor and enables transmission in pigs; (ii) wild-type A/Anhui/1/2013 (H7N9) shows modest replication, virulence, and transmissibility in pigs, suggesting that it is not well adapted to the mammalian host; and (iii) both wild-type and variant H7N9 viruses rapidly develop additional mammalian-signature mutations in pigs, indicating that they represent an important potential intermediate host. This is the first study analyzing the phenotypic effects of specific mutations within the HA and PB2 genes of the novel H7N9 viruses created by reverse genetics in an important mammalian host model. Finally, this study illustrates that loss-of-function mutations can be used to effectively identify residues critical to zoonosis/transmission.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Analysis of Recombinant H7N9 Wild-Type and Mutant Viruses in Pigs Shows that the Q226L Mutation in HA Is Important for Transmission

Liu

Zhou

et al. 2014

J Virol

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“…These amino acid mutations also alter binding to minor human-type glycans, suggesting that host adaptation may contribute to the selection of antigenically distinct H3N2 variants which pose a threat to public health. (2)(3)(4), with more than 300 laboratoryconfirmed cases in 2011 alone (5,6). Most of the A(H3N2)v cases have been children who had contact with swine at agricultural fairs (5,7,8).…”

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confidence: 99%

Amino Acids in Hemagglutinin Antigenic Site B Determine Antigenic and Receptor Binding Differences between A(H3N2)v and Ancestral Seasonal H3N2 Influenza Viruses

Wang

Ilyushina

Lugovtsev

et al. 2017

J Virol

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Influenza A H3N2 variant [A(H3N2)v] viruses, which have caused human infections in the UnitedStates in recent years, originated from human seasonal H3N2 viruses that were introduced into North American swine in the mid-1990s, but they are antigenically distinct from both the ancestral and current circulating H3N2 strains. A reference A(H3N2)v virus, A/Minnesota/11/2010 (MN/10), and a seasonal H3N2 strain, A/Beijing/32/1992 (BJ/92), were chosen to determine the molecular basis for the antigenic difference between A(H3N2)v and the ancestral viruses. Viruses containing wild-type and mutant MN/10 or BJ/92 hemagglutinins (HAs) were constructed and probed for reactivity with ferret antisera against MN/10 and BJ/92 in hemagglutination inhibition assays. Among the amino acids that differ between the MN/10 and BJ/92 HAs, those in antigenic site A had little impact on the antigenic phenotype. Within antigenic site B, mutations at residues 156, 158, 189, and 193 of MN/10 HA to those in BJ/92 switched the MN/10 antigenic phenotype to that of BJ/ 92. Mutations at residues 156, 157, 158, 189, and 193 of BJ/92 HA to amino acids present in MN/10 were necessary for BJ/92 to become antigenically similar to MN/ 10. The HA amino acid substitutions responsible for switching the antigenic phenotype also impacted HA binding to sialyl receptors that are usually present in the human respiratory tract. Our study demonstrates that antigenic site B residues play a critical role in determining both the unique antigenic phenotype and receptor specificity of A(H3N2)v viruses, a finding that may facilitate future surveillance and risk assessment of novel influenza viruses. IMPORTANCE Influenza A H3N2 variant [A(H3N2)v] viruses have caused hundreds of human infections in multiple states in the UnitedStates since 2009. Most cases have been children who had contact with swine in agricultural fairs. These viruses originated from human seasonal H3N2 viruses that were introduced into the U.S. swine population in the mid-1990s, but they are different from both these ancestral viruses and current circulating human seasonal H3N2 strains in terms of their antigenic characteristics as measured by hemagglutination inhibition (HI) assay. In this study, we identified amino acids in antigenic site B of the surface glycoprotein hemagglutinin (HA) that explain the antigenic difference between A(H3N2)v and the ancestral H3N2 strains. These amino acid mutations also alter binding to minor human-type glycans, suggesting that host adaptation may contribute to the selection of antigenically distinct H3N2 variants which pose a threat to public health.

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“…An investigation of one of the first A(H3N2)v influenza cases detected at a U.S. state agricultural fair in 2011 identified 3 virologically confirmed cases, 4 seropositive probable cases, and a further 82 suspected cases of respiratory illness associated with a fair visit, suggesting that only a minority of A(H3N2)v influenza cases are laboratory confirmed (37). In a retrospective cohort study conducted among children of an agricultural club who attended a fair, the risk for suspected case status increased with increasing exposure to swine (37).…”

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confidence: 99%

Impact of Prior Seasonal H3N2 Influenza Vaccination or Infection on Protection and Transmission of Emerging Variants of Influenza A(H3N2)v Virus in Ferrets

Houser

Pearce

Katz

et al. 2013

J Virol

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Outbreak of Influenza A (H3N2) Variant Virus Infection among Attendees of an Agricultural Fair, Pennsylvania, USA, 2011

Abstract: Avoiding or limiting contact with swine at agricultural events may help prevent A(H3N2)v virus infections in such settings.

Cited by 72 publications

References 23 publications

Analysis of Recombinant H7N9 Wild-Type and Mutant Viruses in Pigs Shows that the Q226L Mutation in HA Is Important for Transmission

Analysis of Recombinant H7N9 Wild-Type and Mutant Viruses in Pigs Shows that the Q226L Mutation in HA Is Important for Transmission

Amino Acids in Hemagglutinin Antigenic Site B Determine Antigenic and Receptor Binding Differences between A(H3N2)v and Ancestral Seasonal H3N2 Influenza Viruses

Impact of Prior Seasonal H3N2 Influenza Vaccination or Infection on Protection and Transmission of Emerging Variants of Influenza A(H3N2)v Virus in Ferrets

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