[Source: PLoS ONE, full text: (LINK). Abstract, edited.]
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 B. Jonsson
Affiliations: [Full list on source page.]
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.
Citation: Camp JV, Chu Y-K, Chung D-H, McAllister RC, Adcock RS, et al. (2013) Phenotypic Differences in Virulence and Immune Response in Closely Related Clinical Isolates of Influenza A 2009 H1N1 Pandemic Viruses in Mice. PLoS ONE 8(2): e56602. doi:10.1371/journal.pone.0056602
Editor: Earl G. Brown, University of Ottawa, Canada
Received: October 24, 2012; Accepted: January 14, 2013; Published: February 18, 2013
Copyright: © 2013 Camp et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: Support was provided in part by the Commonwealth of Kentucky as a Clinical and Translational Science Pilot Project Program at the University of Louisville to CBJ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.