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.
Highlights
The 2009 pandemic H1N1 influenza virus (H1N1pdm) arose through reassortment of two preexisting swine influenza viruses, a Eurasian avian-like virus and a North American triple reassortant virus [1,2,3]
H1N1 pandemic (H1N1pdm) strains were isolated from nasopharyngeal swab samples obtained from nine de-identified patients enrolled in the Severe Influenza Pneumonia Surveillance (SIPS) project, a clinical study of hospitalized patients with severe community-acquired pneumonia in Kentucky from December 2008– December 2011 (Table 1)
The age of the patients ranged from 31 to 58 and included 5 females and 4 males. Many of those patients had underlying comorbidities commonly associated with severe influenza disease such as obesity, diabetes and chronic obstructive pulmonary disorder (COPD) (Table S1)
Summary
The 2009 pandemic H1N1 influenza virus (H1N1pdm) arose through reassortment of two preexisting swine influenza viruses, a Eurasian avian-like virus and a North American triple reassortant virus [1,2,3]. Retrospective clinical studies focused on surveillance of H1N1pdm sequences present in ICU admissions suggest that pre-existing medical conditions may be a more important factor in severity rather than particular viral variants [10]. This does not explain why a greater proportion of persons with pre-existing medical conditions had more severe disease than typically observed for seasonal influenza. Previously unreported comorbidities such as morbid obesity have been widely suggested for H1N1pdm for increased risk for admission to the ICU and death [11] At this time, it is difficult to rule out the contribution of viral variants to the resulting illness observed with the various comorbidities. The course of illness and the progression to more severe disease are most likely due to the combined interplay of the individual’s health, the intrinsic phenotype of the infecting viral variant and the treatment regime
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