Mutations in haemagglutinin that affect receptor binding and pH stability increase replication of a PR8 influenza virus with H5 HA in the upper respiratory tract of ferrets and may contribute to transmissibility

Shelton, Holly; Roberts, Kim L.; Molesti, Eleonora; Temperton, Nigel; Barclay, William

doi:10.1099/vir.0.050526-0

Cited by 64 publications

(64 citation statements)

References 47 publications

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“…We speculate that the high pH optimum of HA-mediated fusion can be responsible for the pathogenicity of this virus. Dependence of replication efficiency and pathogenicity of influenza viruses on fusion pH was well documented previously (Brown et al, 2001;Hsu et al, 2006;Reed et al, 2010;Shelton et al, 2013).…”

Section: Discussionmentioning

confidence: 62%

Immunization with live nonpathogenic H5N3 duck influenza virus protects chickens against highly pathogenic H5N1 virus

As¹,

Ey²,

Nf³

et al. 2016

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Section: Discussionmentioning

confidence: 62%

Immunization with live nonpathogenic H5N3 duck influenza virus protects chickens against highly pathogenic H5N1 virus

As¹,

Ey²,

Nf³

et al. 2016

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“…Similarly, two independent studies showed that adaptation of H5 viruses to the upper respiratory tracts of ferrets and the acquisition of airborne transmissibility required a mutation that lowered the HA activation pH from 5.6 to 5.2-5.4 (7,8). In addition, α-2,6 sialic acid receptor specificity and efficient polymerase activity at 33°C (the temperature of mammalian upper airways) were also required (8,23,25). In contrast to the upper respiratory tract, in the lungs, a lower HA activation pH has been associated with reduced virus growth and reduced or delayed pathogenicity for H5N1 viruses (23,26).…”

Section: Discussionmentioning

confidence: 99%

“…A higher HA activation pH (5.6-6.0) enhances replication of HPAI viruses in the enteric and respiratory tracts of ducks and chickens by facilitating membrane fusion (20,22). Such facile activation of the HA protein leads to virion inactivation in mildly acidic pH environments, such as the mammalian upper respiratory tract (7,8,23,25). The airways of mammals are mildly acidic (pH 5.5-6.9) (27) and become more acidic (pH 5.2) during influenza virus infection (28).…”

Section: Discussionmentioning

confidence: 99%

Molecular requirements for a pandemic influenza virus: An acid-stable hemagglutinin protein

Russier

Yang

Rehg

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

210

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Influenza pandemics require that a virus containing a hemagglutinin (HA) surface antigen previously unseen by a majority of the population becomes airborne-transmissible between humans. Although the HA protein is central to the emergence of a pandemic influenza virus, its required molecular properties for sustained transmission between humans are poorly defined. During virus entry, the HA protein binds receptors and is triggered by low pH in the endosome to cause membrane fusion; during egress, HA contributes to virus assembly and morphology. In 2009, a swine influenza virus (pH1N1) jumped to humans and spread globally. Here we link the pandemic potential of pH1N1 to its HA acid stability, or the pH at which this one-time-use nanomachine is either triggered to cause fusion or becomes inactivated in the absence of a target membrane. In surveillance isolates, our data show HA activation pH values decreased during the evolution of H1N1 from precursors in swine (pH 5.5–6.0), to early 2009 human cases (pH 5.5), and then to later human isolates (pH 5.2–5.4). A loss-of-function pH1N1 virus with a destabilizing HA1-Y17H mutation (pH 6.0) was less pathogenic in mice and ferrets, less transmissible by contact, and no longer airborne-transmissible. A ferret-adapted revertant (HA1-H17Y/HA2-R106K) regained airborne transmissibility by stabilizing HA to an activation pH of 5.3, similar to that of human-adapted isolates from late 2009–2014. Overall, these studies reveal that a stable HA (activation pH ≤ 5.5) is necessary for pH1N1 influenza virus pathogenicity and airborne transmissibility in ferrets and is associated with pandemic potential in humans.

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“…Both a switch in receptor binding specificity to ␣2-6-linked SA and a lowered HA activation pH have been found to be essential for the heightened replicative ability in upper respiratory tract tissues and the aerosol transmissibility of H5N1 mutant viruses in ferrets (34,55,56). A few substitutions at the HA trimer interface and stem region have been identified to be responsible for the changes in the HA fusion threshold (34,55,56), though further study is required to identify the precise substi-tution(s) in the 2016 H7N2 virus compared with the sequence of other LPAI H7N2 viruses that may be present and might contribute to the reduced HA fusion threshold for NY/108 virus observed here. In addition to differences in activation pH, the presence of 702Arg in PB2 in both human and feline H7N2 isolates, in contrast to the 702Lys present in NY/107 virus, represents an additional marker for mammalian host adaptation (57) and was found in only a subset of H7N2 avian viruses isolated from 1999 to 2002.…”

Section: Discussionmentioning

confidence: 99%

A Novel A(H7N2) Influenza Virus Isolated from a Veterinarian Caring for Cats in a New York City Animal Shelter Causes Mild Disease and Transmits Poorly in the Ferret Model

Belser

Pulit-Penaloza

Sun

et al. 2017

J Virol

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In December 2016, a low-pathogenic avian influenza (LPAI) A(H7N2) virus was identified to be the causative source of an outbreak in a cat shelter in New York City, which subsequently spread to multiple shelters in the states of New York and Pennsylvania. One person with occupational exposure to infected cats became infected with the virus, representing the first LPAI H7N2 virus infection in a human in North America since 2003. Considering the close contact that frequently occurs between companion animals and humans, it was critical to assess the relative risk of this novel virus to public health. The virus isolated from the human case, A/New York/108/2016 (NY/108), caused mild and transient illness in ferrets and mice but did not transmit to naive cohoused ferrets following traditional or aerosol-based inoculation methods. The environmental persistence of NY/108 virus was generally comparable to that of other LPAI H7N2 viruses. However, NY/108 virus replicated in human bronchial epithelial cells with an increased efficiency compared with that of previously isolated H7N2 viruses. Furthermore, the novel H7N2 virus was found to utilize a relatively lower pH for hemagglutinin activation, similar to human influenza viruses. Our data suggest that the LPAI H7N2 virus requires further adaptation before representing a substantial threat to public health. However, the reemergence of an LPAI H7N2 virus in the northeastern United States underscores the need for continuous surveillance of emerging zoonotic influenza viruses inclusive of mammalian species, such as domestic felines, that are not commonly considered intermediate hosts for avian influenza viruses. IMPORTANCE Avian influenza viruses are capable of crossing the species barrier to infect mammals, an event of public health concern due to the potential acquisition of a pandemic phenotype. In December 2016, an H7N2 virus caused an outbreak in cats in multiple animal shelters in New York State. This was the first detection of this virus in the northeastern United States in over a decade and the first documented infection of a felid with an H7N2 virus. A veterinarian became infected following occupational exposure to H7N2 virus-infected cats, necessitating the evaluation of this virus for its capacity to cause disease in mammals. While the H7N2 virus was associated with mild illness in mice and ferrets and did not spread well between ferrets, it nonetheless possessed several markers of virulence for mammals. These data highlight the promiscuity of influenza viruses and the need for diligent surveillance across multiple species to quickly identify an emerging strain with pandemic potential.

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Mutations in haemagglutinin that affect receptor binding and pH stability increase replication of a PR8 influenza virus with H5 HA in the upper respiratory tract of ferrets and may contribute to transmissibility

Cited by 64 publications

References 47 publications

Immunization with live nonpathogenic H5N3 duck influenza virus protects chickens against highly pathogenic H5N1 virus

Immunization with live nonpathogenic H5N3 duck influenza virus protects chickens against highly pathogenic H5N1 virus

Molecular requirements for a pandemic influenza virus: An acid-stable hemagglutinin protein

A Novel A(H7N2) Influenza Virus Isolated from a Veterinarian Caring for Cats in a New York City Animal Shelter Causes Mild Disease and Transmits Poorly in the Ferret Model

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