Phenotypic Differences in Virulence and Immune Response in Closely Related Clinical Isolates of Influenza A 2009 H1N1 Pandemic Viruses in Mice

Jeremy V. Camp, Yong Kyu Chu, Dong Hoon Chung, Ryan C. McAllister, Robert S. Adcock, Rachael L. Gerlach, Timothy L. Wiemken, Paula Peyrani, Julio A. Ramirez, James T. Summersgill, Colleen Jonsson

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Abstract

To capture the possible genotypic and phenotypic differences of the 2009 influenza A virus H1N1 pandemic (H1N1pdm) strains circulating in adult hospitalized patients, we isolated and sequenced nine H1N1pdm viruses from patients hospitalized during 2009-2010 with severe influenza pneumonia in Kentucky. Each viral isolate was characterized in mice along with two additional H1N1 pandemic strains and one seasonal strain to assess replication and virulence. All isolates showed similar levels of replication in nasal turbinates and lung, but varied in their ability to cause morbidity. Further differences were identified in cytokine and chemokine responses. IL-6 and KC were expressed early in mice infected with strains associated with higher virulence. Strains that showed lower pathogenicity in mice had greater IFNγ, MIG, and IL-10 responses. A principal component analysis (PCA) of the cytokine and chemokine profiles revealed 4 immune response phenotypes that correlated with the severity of disease. A/KY/180/10, which showed the greatest virulence with a rapid onset of disease progression, was compared in additional studies with A/KY/136/09, which showed low virulence in mice. Analyses comparing a low (KY/136) versus a high (KY/180) virulent isolate showed a significant difference in the kinetics of infection within the lower respiratory tract and immune responses. Notably by 4 DPI, virus titers within the lung, bronchoalveolar lavage fluid (BALf), and cells within the BAL (BALc) revealed that the KY/136 replicated in BALc, while KY/180 replication persisted in lungs and BALc. In summary, our studies suggest four phenotypic groups based on immune responses that result in different virulence outcomes in H1N1pdm isolates with a high degree of genetic similarity. In vitro studies with two of these isolates suggested that the more virulent isolate, KY/180, replicates productively in macrophages and this may be a key determinant in tipping the response toward a more severe disease progression.

Original languageEnglish (US)
Article numbere56602
JournalPLoS One
Volume8
Issue number2
DOIs
StatePublished - Feb 18 2013
Externally publishedYes

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H1N1 Subtype Influenza A Virus
Pandemics
pandemic
Viruses
influenza
Human Influenza
Virulence
virulence
immune response
viruses
mice
lungs
chemokines
Chemokines
disease course
Bronchoalveolar Lavage Fluid
cytokines
Disease Progression
Cytokines
Dimercaprol

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Phenotypic Differences in Virulence and Immune Response in Closely Related Clinical Isolates of Influenza A 2009 H1N1 Pandemic Viruses in Mice. / Camp, Jeremy V.; Chu, Yong Kyu; Chung, Dong Hoon; McAllister, Ryan C.; Adcock, Robert S.; Gerlach, Rachael L.; Wiemken, Timothy L.; Peyrani, Paula; Ramirez, Julio A.; Summersgill, James T.; Jonsson, Colleen.

In: PLoS One, Vol. 8, No. 2, e56602, 18.02.2013.

Research output: Contribution to journalArticle

Camp, JV, Chu, YK, Chung, DH, McAllister, RC, Adcock, RS, Gerlach, RL, Wiemken, TL, Peyrani, P, Ramirez, JA, Summersgill, JT & Jonsson, C 2013, 'Phenotypic Differences in Virulence and Immune Response in Closely Related Clinical Isolates of Influenza A 2009 H1N1 Pandemic Viruses in Mice', PLoS One, vol. 8, no. 2, e56602. https://doi.org/10.1371/journal.pone.0056602
Camp, Jeremy V. ; Chu, Yong Kyu ; Chung, Dong Hoon ; McAllister, Ryan C. ; Adcock, Robert S. ; Gerlach, Rachael L. ; Wiemken, Timothy L. ; Peyrani, Paula ; Ramirez, Julio A. ; Summersgill, James T. ; Jonsson, Colleen. / Phenotypic Differences in Virulence and Immune Response in Closely Related Clinical Isolates of Influenza A 2009 H1N1 Pandemic Viruses in Mice. In: PLoS One. 2013 ; Vol. 8, No. 2.
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abstract = "To capture the possible genotypic and phenotypic differences of the 2009 influenza A virus H1N1 pandemic (H1N1pdm) strains circulating in adult hospitalized patients, we isolated and sequenced nine H1N1pdm viruses from patients hospitalized during 2009-2010 with severe influenza pneumonia in Kentucky. Each viral isolate was characterized in mice along with two additional H1N1 pandemic strains and one seasonal strain to assess replication and virulence. All isolates showed similar levels of replication in nasal turbinates and lung, but varied in their ability to cause morbidity. Further differences were identified in cytokine and chemokine responses. IL-6 and KC were expressed early in mice infected with strains associated with higher virulence. Strains that showed lower pathogenicity in mice had greater IFNγ, MIG, and IL-10 responses. A principal component analysis (PCA) of the cytokine and chemokine profiles revealed 4 immune response phenotypes that correlated with the severity of disease. A/KY/180/10, which showed the greatest virulence with a rapid onset of disease progression, was compared in additional studies with A/KY/136/09, which showed low virulence in mice. Analyses comparing a low (KY/136) versus a high (KY/180) virulent isolate showed a significant difference in the kinetics of infection within the lower respiratory tract and immune responses. Notably by 4 DPI, virus titers within the lung, bronchoalveolar lavage fluid (BALf), and cells within the BAL (BALc) revealed that the KY/136 replicated in BALc, while KY/180 replication persisted in lungs and BALc. In summary, our studies suggest four phenotypic groups based on immune responses that result in different virulence outcomes in H1N1pdm isolates with a high degree of genetic similarity. In vitro studies with two of these isolates suggested that the more virulent isolate, KY/180, replicates productively in macrophages and this may be a key determinant in tipping the response toward a more severe disease progression.",
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