Introduction of Virulence Markers in PB2 of Pandemic Swine-Origin Influenza Virus Does Not Result in Enhanced Virulence or Transmission

Herfst, Sander; Chutinimitkul, Salin; Ye, Jianqiang; Wit, Emmie de; Munster, Vincent J.; Schrauwen, Eefje J. A.; Bestebroer, Theo M.; Jonges, Marcel; Meijer, Adam; Koopmans, Marion; Rimmelzwaan, Guus F.; Osterhaus, Albert D. M. E.; Pérez, Daniel R.; Fouchier, Ron A. M.

doi:10.1128/jvi.02634-09

Cited by 123 publications

(126 citation statements)

References 32 publications

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“…17,88,133 Surprisingly, the pandemic 2009 H1N1 virus, which was more virulent than most seasonal influenza viruses for humans and in experimental mammalian hosts, did not have the reputed virulence marker mutations in its PB2 protein. 45 When the molecular mutations in PB2 suggested to be virulence markers for avian viruses were introduced individually into the avianorigin PB2 of the pandemic 2009 H1N1 virus, virulence was not altered. 45 In summary, the polymerases appear to influence virulence through control of protein synthesis processes that favor virus production over cell maintenance functions, but sequence variations between polymerases will likely preclude identification of definitive virulence markers for all viruses.…”

Section: Polymerasesmentioning

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: Polymerasesmentioning

confidence: 99%

Influenza A Virus Infections in Swine

Janke

2013

Vet Pathol

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“…Sequence survey implied that the common host shift markers in the proteins of avian or swine influenza are not present in the pandemic 2009 H1N1 virus. Moreover, introduction of known virulence markers into 2009 H1N1 does not increase its virulence [26,27]. The combination of its pandemic potential and absence of traditional host markers has remained a source for concern and justifies the search for its own host markers outside of the space of classical host markers [28,29].…”

Section: Discussionmentioning

confidence: 99%

Correlated mutations in the four influenza proteins essential for viral RNA synthesis, host adaptation, and virulence: NP, PA, PB1, and PB2

Hu¹

2010

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The NP, PA, PB1, and PB2 proteins of influenza viruses together are responsible for the transcription and replication of viral RNA, and the latter three proteins comprise the viral polymerase. Two recent reports indicated that the mutation at site 627 of PB2 plays a key role in host range and increased virulence of influenza viruses, and could be compensated by multiple mutations at other sites of PB2, suggesting the association of this mutation with those at other sites. The objective of this study was to analyze the co-mutated sites within and between these important proteins of influenza. With mutual information, a set of statistically significant comutated position pairs (P value = 0) in NP, PA, PB1, and PB2 of avian, human, pandemic 2009 H1N1, and swine influenza were identified, based on which several highly connected networks of correlated sites in NP, PA, PB1, and PB2 were discovered. These correlation networks further illustrated the inner functional dependence of the four proteins that are critical for host adaptation and pathogenicity. Mutual information was also applied to quantify the correlation of sites within each individual protein and between proteins. In general, the inter protein correlation of the four proteins was stronger than the intra protein correlation. Finally, the correlation patterns of the four proteins of pandemic 2009 H1N1 were found to be closer to those of avian and human than to swine influenza, thus rendering a novel insight into the interaction of the four proteins of the pandemic 2009 H1N1 virus when compared to avian, human, and swine influenza and how the origin of these four proteins might affect the correlation patterns uncovered in this analysis.

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“…Similarly, positions 627 and 701 in the viral polymerase basic 2 protein, residues shown to affect virulence in other influenza viruses, [57][58][59][60] had no effect in the context of the A(H1N1)pdm09 viruses. 47 In mice, some mutations are involved in A(H1N1)pdm09 virus virulence, such as polymerase basic 2 protein E158G/A, or polymerase acidic L295P. These mutations occurred upon serial passage in mice and were shown to be responsible for enhanced transcription and replication of the virus.…”

Section: Molecular Markers Of Virulencementioning

confidence: 99%

“…46 The introduction of molecular markers of virulence into the polymerase basic 2 protein were likewise unable to affect the transmissibility of A(H1N1)pdm09 viruses. 47 Ramakrishnan et al hypothesized that a truncated polymerase basic 1-F2 (PB1-F2) protein may play a role in enhancing the virus transmission, 48 but experimental validation of this theory is lacking.…”

mentioning

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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Introduction of Virulence Markers in PB2 of Pandemic Swine-Origin Influenza Virus Does Not Result in Enhanced Virulence or Transmission

Cited by 123 publications

References 32 publications

Influenza A Virus Infections in Swine

Influenza A Virus Infections in Swine

Correlated mutations in the four influenza proteins essential for viral RNA synthesis, host adaptation, and virulence: NP, PA, PB1, and PB2

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

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