Virulence determinants of pandemic influenza viruses

Tscherne, Donna M.; Garcı́a-Sastre, Adolfo

doi:10.1172/jci44947

Cited by 179 publications

(173 citation statements)

References 116 publications

(143 reference statements)

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“…Exceptions to these generalizations abound. 72,143,174 Insertion of genes for the full-length protein into viruses with truncated forms does not necessarily enhance virulence, calling into question the protein's role as a virulence factor. Similarly in swine, most but not all swine triple reassortant H3N2 viruses express full-length PB1-F2 proteins, but in vitro and in vivo studies have not consistently associated the presence of these proteins with increased virulence.…”

Section: Pb1-f2mentioning

confidence: 99%

Influenza A Virus Infections in Swine

Janke

2013

Vet Pathol

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Influenza has been recognized as a respiratory disease in swine since its first appearance concurrent with the 1918 ''Spanish flu'' human pandemic. All influenza viruses of significance in swine are type A, subtype H1N1, H1N2, or H3N2 viruses. Influenza viruses infect epithelial cells lining the surface of the respiratory tract, inducing prominent necrotizing bronchitis and bronchiolitis and variable interstitial pneumonia. Cell death is due to direct virus infection and to insult directed by leukocytes and cytokines of the innate immune system. The most virulent viruses consistently express the following characteristics of infection: (1) higher or more prolonged virus replication, (2) excessive cytokine induction, and (3) replication in the lower respiratory tract. Nearly all the viral proteins contribute to virulence. Pigs are susceptible to infection with both human and avian viruses, which often results in gene reassortment between these viruses and endemic swine viruses. The receptors on the epithelial cells lining the respiratory tract are major determinants of infection by influenza viruses from other hosts. The polymerases, especially PB2, also influence cross-species infection. Methods of diagnosis and characterization of influenza viruses that infect swine have improved over the years, driven both by the availability of new technologies and by the necessity of keeping up with changes in the virus. Testing of oral fluids from pigs for virus and antibody is a recent development that allows efficient sampling of large numbers of animals.Keywords influenza virus, swine, pathogenesis, cytokines, apoptosis, virulence, cross-species infection, hemagglutinin, receptors, polymerases, diagnosisThe evolution and epidemiology of influenza A virus (IAV) infections in swine have been integrally tied to the segmented nature of the genome of the virus, which facilitates gene reassortment, and to the adaptability of these genes through mutation, which sometimes facilitates replication in a new host. 8,19,77,85,89 Influenza was first recognized as a respiratory disease entity in swine during the 1918 human Spanish flu pandemic. 67 The virus was not isolated until 1931, when nasal discharge from pigs was inoculated into ferrets and subsequently into embryonated chicken eggs. 129 In 1933, a similar virus was recovered from humans with this technique. 131 The viruses were essentially identical and served as the prototype for type A subtype H1N1 influenza viruses.All influenza viruses of significance that infect swine are type A viruses, defined by the highly conserved internal nucleoproteins and matrix proteins. Influenza A virus subtypes are based on the external hemagglutinin (HA) and neuraminidase (NA) proteins. The predominant viruses in swine populations in different parts of the world may have genes of different origin, even though the subtypes may be similar. 10,73,171 The original classic H1N1 swine influenza virus, which remained the predominant influenza virus in North American swine populations for nearl...

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Section: Pb1-f2mentioning

confidence: 99%

Influenza A Virus Infections in Swine

Janke

2013

Vet Pathol

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“…A(H1N1) pdm09 viruses contain the typical human virus-like aspartic acid residues at hemagglutinin protein amino acid locations 190 and 225 which have been shown to code for α2,6 sialic acid preference. 5,51 Although human virus-like in having α2,6 preference, A(H1N1)pdm09 viruses have maintained the receptor binding properties typical of swine viruses, as shown by more sensitive glycan arrays and receptor binding assays. 52,53 Further adaptation to a more classical human virus-like specificity could theoretically happen in the coming years.…”

Section: Molecular Markers Of Virulencementioning

confidence: 99%

Evolution and adaptation of the pandemic A/H1N1 2009 influenza virus

Ducatez¹,

Fabrizio²,

Webby³

2011

VAAT

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Abstract:The emergence of the 2009 H1N1 pandemic influenza virus [A(H1N1)pdm09] has provided the public health community with many challenges, but also the scientific community with an opportunity to monitor closely its evolution through the processes of drift and shift. To date, and despite having circulated in humans for nearly two years, little antigenic variation has been observed in the A(H1N1)pdm09 viruses. However, as the A(H1N1)pdm09 virus continues to circulate and the immunologic pressure within the human population increases, future antigenic change is almost a certainty. Several coinfections of A(H1N1)pdm09 and seasonal A(H1N1) or A(H3N2) viruses have been observed, but no reassortant viruses have been described in humans, suggesting a lack of fitness of reassortant viruses or a lack of opportunities for interaction of different viral lineages. In contrast, multiple reassortment events have been detected in swine populations between A(H1N1) pdm09 and other endemic swine viruses. Somewhat surprisingly, many of the well characterized influenza virus virulence markers appear to have limited impact on the phenotype of the A(H1N1)pdm09 viruses when they have been introduced into mutant viruses in laboratory settings. As such, it is unclear what the evolutionary path of the pandemic virus will be, but the monitoring of any changes in the circulating viruses will remain a global public and animal health priority.

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“…In addition, there are other intrinsic mechanisms that contribute to viral diversity, including RdRP replication speed, RNA genome structure and organization that permit recombination or reassortment (Elena et al 2006;Holmes 2009). For influenza viruses with segmented genomes, genetic reassortment (McCullers et al 1999;Tscherne and Garcia-Sastre 2011) and mutations generated by RdRP are likely to be two important contributing factors for the generation of genetic diversity.…”

Section: Introductionmentioning

confidence: 99%

Comparative mutational analyses of influenza A viruses

Cheung

Rogozin

Choy

et al. 2014

RNA

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The error-prone RNA-dependent RNA polymerase (RdRP) and external selective pressures are the driving forces for RNA viral diversity. When confounded by selective pressures, it is difficult to assess if influenza A viruses (IAV) that have a wide host range possess comparable or distinct spontaneous mutational frequency in their RdRPs. We used in-depth bioinformatics analyses to assess the spontaneous mutational frequencies of two RdRPs derived from human seasonal (A/Wuhan/359/95; Wuhan) and H5N1 (A/Vietnam/1203/04; VN1203) viruses using the mini-genome system with a common firefly luciferase reporter serving as the template. High-fidelity reverse transcriptase was applied to generate high-quality mutational spectra which allowed us to assess and compare the mutational frequencies and mutable motifs along a target sequence of the two RdRPs of two different subtypes. We observed correlated mutational spectra (τ correlation P < 0.0001), comparable mutational frequencies (H3N2:5.8 ± 0.9; H5N1:6.0 ± 0.5), and discovered a highly mutable motif "(A)AAG" for both Wuhan and VN1203 RdRPs. Results were then confirmed with two recombinant A/Puerto Rico/8/34 (PR8) viruses that possess RdRP derived from Wuhan or VN1203 (RG-PR8×Wuhan PB2, PB1, PA, NP and RG-PR8×VN1203 PB2, PB1, PA, NP ). Applying novel bioinformatics analysis on influenza mutational spectra, we provide a platform for a comprehensive analysis of the spontaneous mutation spectra for an RNA virus.

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Virulence determinants of pandemic influenza viruses

Cited by 179 publications

References 116 publications

Influenza A Virus Infections in Swine

Influenza A Virus Infections in Swine

Evolution and adaptation of the pandemic A/H1N1 2009 influenza virus

Comparative mutational analyses of influenza A viruses

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