The Short Stalk Length of Highly Pathogenic Avian Influenza H5N1 Virus Neuraminidase Limits Transmission of Pandemic H1N1 Virus in Ferrets

Blumenkrantz, Deena; Roberts, Kim L.; Shelton, Holly; Lycett, Samantha; Barclay, William

doi:10.1128/jvi.00967-13

Cited by 81 publications

(80 citation statements)

References 90 publications

(133 reference statements)

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“…We hypothesized that mucus may have been interfering with pH1N1 low -1 in ferrets, considering the low NA activity and increased binding affinity of the HA of this virus. Similar phenomena were observed in viruses expressing NA proteins of differing stalk lengths (39). Viruses expressing NA proteins with shorter stalk lengths showed a phenotype similar to that of pH1N1 low viruses.…”

Section: Discussionsupporting

confidence: 62%

“…Viruses expressing NA proteins with shorter stalk lengths showed a phenotype similar to that of pH1N1 low viruses. Replacing the NA of an efficiently transmitted H5N1 virus with an avian NA expressing a stalk 20 amino acids shorter than the NA originally in the virus abrogated AC transmission and reduced the efficiency of DC transmission in ferrets (39). The enzymatic activity of the short-stalk NA was significantly reduced compared to that of the NA with a longer stalk, and the inhibitory effects of mucus on the virus expressing NA proteins with short stalks were significantly greater than the effects on the virus with a long-stalk NA in vitro (39).…”

Section: Discussionmentioning

confidence: 99%

“…Replacing the NA of an efficiently transmitted H5N1 virus with an avian NA expressing a stalk 20 amino acids shorter than the NA originally in the virus abrogated AC transmission and reduced the efficiency of DC transmission in ferrets (39). The enzymatic activity of the short-stalk NA was significantly reduced compared to that of the NA with a longer stalk, and the inhibitory effects of mucus on the virus expressing NA proteins with short stalks were significantly greater than the effects on the virus with a long-stalk NA in vitro (39). This is in agreement with our study, in that NA activity appears to be important for transmission and that the virus-mucus interaction is important for efficient transmission, particularly via aerosol droplets.…”

Section: Discussionmentioning

confidence: 99%

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Pandemic Swine H1N1 Influenza Viruses with Almost Undetectable Neuraminidase Activity Are Not Transmitted via Aerosols in Ferrets and Are Inhibited by Human Mucus but Not Swine Mucus

Zanin

Marathe

Wong

et al. 2015

J Virol

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A balance between the functions of the influenza virus surface proteins hemagglutinin (HA) and neuraminidase (NA) is thought to be important for the transmission of viruses between humans. Here we describe two pandemic H1N1 viruses, A/swine/Virginia/1814-1/2012 and A/swine/Virginia/1814-2/2012 (pH1N1 low -1 and -2, respectively), that were isolated from swine symptomatic for influenza. The enzymatic activity of the NA of these viruses was almost undetectable, while the HA binding affinity for ␣2,6 sialic acids was greater than that of the highly homologous pH1N1 viruses A/swine/Pennsylvania/2436/2012 and A/swine/Minnesota/2499/2012 (pH1N1-1 and -2), which exhibited better-balanced HA and NA activities. The in vitro growth kinetics of pH1N1 low and pH1N1 viruses were similar, but aerosol transmission of pH1N1 low -1 was abrogated and transmission via direct contact in ferrets was significantly impaired compared to pH1N1-1, which transmitted by direct and aerosol contact. In normal human bronchial epithelial cells, pH1N1 low -1 was significantly inhibited by mucus but pH1N1-1 was not. In Madin-Darby canine kidney cell cultures overlaid with human or swine mucus, human mucus inhibited pH1N1 low -1 but swine mucus did not. These data show that the interaction between viruses and mucus may be an important factor in viral transmissibility and could be a barrier for interspecies transmission between humans and swine for influenza viruses. IMPORTANCEA balance between the functions of the influenza virus surface proteins hemagglutinin (HA) and neuraminidase (NA) is thought to be important for transmission of viruses from swine to humans. Here we show that a swine virus with extremely functionally mismatched HA and NAs (pH1N1 low -1) cannot transmit via aerosol in ferrets, while another highly homologous virus with HA and NAs that are better matched functionally (pH1N1-1) can transmit via aerosol. These viruses show similar growth kinetics in Madin-Darby canine kidney (MDCK) cells, but pH1N1 low -1 is significantly inhibited by mucus in normal human bronchial epithelial cells whereas pH1N1-1 is not. Further, human mucus could inhibit these viruses, but swine mucus could not. These data show that the interaction between viruses and mucus may be an important factor in viral transmissibility and could be a species barrier between humans and swine for influenza viruses. H emagglutinin (HA) and neuraminidase (NA), the surface glycoproteins of influenza virus, play vital roles in the virus life cycle. HA binds to sialic acids on the cell surface, initiating fusion of the cell and viral membranes. NA enzymatically cleaves sialic acids from glycans on the host cell surface, facilitating the release of budding progeny viruses (1, 2). Thus, HA and NA have opposing roles in the viral life cycle and both are required for viral replication. A functional balance between HA and NA is important for both efficient replication and respiratory droplet transmission in humans. Four pandemic human viruses, A/California/04/2009 (H1N1) (...

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Pandemic Swine H1N1 Influenza Viruses with Almost Undetectable Neuraminidase Activity Are Not Transmitted via Aerosols in Ferrets and Are Inhibited by Human Mucus but Not Swine Mucus

Zanin

Marathe

Wong

et al. 2015

J Virol

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“…Returning to influenza as our example, analyses of data from ferret infection studies showed that different influenza strains can generate similar viral loads but contrasting transmission potential [76,77]. Because the ferrets, in this study, were housed in cages with presumably little change in contact behaviour between different study groups, differences in transmission are not attributable to differences in host contact behaviour or viral load, but instead must be attributed to other features, such as qualitative differences in the virus [78] or differences in host infectiousness mediated by symptoms (e.g. frequency of sneezing).…”

Section: Host Infectiousnessmentioning

confidence: 99%

Crossing the scale from within-host infection dynamics to between-host transmission fitness: a discussion of current assumptions and knowledge

Handel

Rohani

2015

Phil. Trans. R. Soc. B

109

181

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The progression of an infection within a host determines the ability of a pathogen to transmit to new hosts and to maintain itself in the population. While the general connection between the infection dynamics within a host and the population-level transmission dynamics of pathogens is widely acknowledged, a comprehensive and quantitative understanding that would allow full integration of the two scales is still lacking. Here, we provide a brief discussion of both models and data that have attempted to provide quantitative mappings from within-host infection dynamics to transmission fitness. We present a conceptual framework and provide examples of studies that have taken first steps towards development of a quantitative framework that scales from within-host infections to population-level fitness of different pathogens. We hope to illustrate some general themes, summarize some of the recent advances and—maybe most importantly—discuss gaps in our ability to bridge these scales, and to stimulate future research on this important topic.

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“…The shortened NA stalk was considered a relic of molecular evolution which resulted from the early adaptation of influenza virus from wild aquatic birds to terrestrial poultry (8,10,11). Viruses containing short-stalk NA were shown to have altered rates of virus growth, virulence, and transmission in chickens and mammals (9,12,13,(15)(16)(17), in which the functional balance between HA and NA in the influenza virion was found to be a critical determinant (18)(19)(20)(21)(22)(23). Hence, NA stalk length, levels of glycosylation on HA, and mutations in the HA and NA antigens represent potential evolutionary strategies for the control of HA-NA functional balance to optimize virus fitness (12,18,(20)(21)(22).…”

mentioning

confidence: 99%

Changes in the Length of the Neuraminidase Stalk Region Impact H7N9 Virulence in Mice

Xiao

Chen

et al. 2016

J Virol

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The neuraminidase stalk of the newly emerged H7N9 influenza virus possesses a 5-amino-acid deletion. This study focuses on characterizing the biological functions of H7N9 with varied neuraminidase stalk lengths. Results indicate that the 5-amino-acid deletion had no impact on virus infectivity or replication in vitro or in vivo compared to that of a virus with a full-length stalk, but enhanced virulence in mice was observed for H7N9 encoding a 19-to 20-amino-acid deletion, suggesting that N9 stalk length impacts virulence in mammals, as N1 stalk length does. In February and March 2013, a novel influenza A (H7N9) virus emerged and spread quickly across China, resulting in a total of 672 laboratory-confirmed cases in humans, with at least 271 deaths as of 23 June 2015 (http://www.who.int/influenza/human _animal_interface/HAI_Risk_Assessment/en/) occurring during the subsequent years. Influenza A virus is an enveloped, negative-sense, single-stranded RNA virus, with a segmented genome comprising eight gene segments: hemagglutinin (HA), neuraminidase (NA), basic polymerase 2 (PB2), basic polymerase 1 (PB1), acidic polymerase (PA), nucleoprotein (NP), matrix protein (M), and nonstructural protein (NS). Influenza A viruses may encode up to 16 proteins: HA, NA, PB2, PB1, PB1-F2, PB1-N40, PA, PA-X, PA-N155, PA-N182, NP, M1, M2, M42, NS1, and NS2 (1, 2). Cleavage of the HA precursor polypeptide (HA0) into subunits HA1 and HA2 is required for virus infection, and the amino acid residues at the HA0 cleavage site are a molecular hallmark for virulence in chickens. Almost all of the highly pathogenic avian influenza viruses (HPAIVs) possess a multibasic amino acid motif in the HA cleavage site, unlike with low-pathogenicity avian influenza viruses (LPAIVs) (3-5). Based on the molecular characteristics of the HA0 cleavage site and asymptomatic infections in chickens, the new H7N9 virus was confirmed as an LPAIV (6, 7). Nevertheless, this H7N9 virus caused severe disease in humans, with a high mortality rate (ϳ40%). The underlying mechanisms behind the virulence of H7N9 influenza virus in humans are yet not fully understood.Apart from the human-strain-like mutations in HA and PB2, a 5-amino-acid deletion in the NA stalk region (69th to 73rd amino acids) was detected in this novel H7N9 virus (6). Notably, this deletion appeared for the first time in N9, based on NA sequences deposited in GenBank. Apart from that of H7N9, NAs with shortened stalks have previously been reported with different influenza subtypes, such as H5N1, H6N1, H7N1, H7N3, H9N2, and H2N2 (8-14). The shortened NA stalk was considered a relic of molecular evolution which resulted from the early adaptation of influenza virus from wild aquatic birds to terrestrial poultry (8, 10, 11). Viruses containing short-stalk NA were shown to have altered rates of virus

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The Short Stalk Length of Highly Pathogenic Avian Influenza H5N1 Virus Neuraminidase Limits Transmission of Pandemic H1N1 Virus in Ferrets

Cited by 81 publications

References 90 publications

Pandemic Swine H1N1 Influenza Viruses with Almost Undetectable Neuraminidase Activity Are Not Transmitted via Aerosols in Ferrets and Are Inhibited by Human Mucus but Not Swine Mucus

Pandemic Swine H1N1 Influenza Viruses with Almost Undetectable Neuraminidase Activity Are Not Transmitted via Aerosols in Ferrets and Are Inhibited by Human Mucus but Not Swine Mucus

Crossing the scale from within-host infection dynamics to between-host transmission fitness: a discussion of current assumptions and knowledge

Changes in the Length of the Neuraminidase Stalk Region Impact H7N9 Virulence in Mice

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