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Interactions Between 2009 Pandemic H1N1 Influenza A Virus and Underlying Host Factors Dictate Host Response and Disease Outcome
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Interactions Between 2009 Pandemic H1N1 Influenza A Virus and Underlying Host Factors Dictate Host Response and Disease Outcome
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Dissertation
Interactions Between 2009 Pandemic H1N1 Influenza A Virus and Underlying Host Factors Dictate Host Response and Disease Outcome
2016
Overview
Host responses and disease during influenza A infection are shaped by multiple interactions between virus and host which may vary considerably between virus strains. The 2009 pandemic H1N1 influenza A (A(H1N1)pdm09) virus was recently introduced in the human population and now persists in worldwide circulation. Distinct clinical manifestations and distribution of severe illness among human cohorts including the young (< 5 years) and elderly (> 65 years) suggests relationships between virus and host factors governing A(H1N1)pdm09 pathogenesis may differ significantly from previously circulating viruses. In this thesis, we explored the roles of virus and host factors in A(H1N1)pdm09 infection outcome. We first investigated molecular mechanisms of A(H1N1)pdm09 host response induction using an in vitro human airway epithelial cell infection model. We detected specific, robust inflammatory activation (CXCL1/8/10, IL-6/36γ) during viral entry, implicating epithelial entry sensing as a determinant of the A(H1N1)pdm09 response. We next explored the role of A(H1N1)pdm09 inflammatory responses in pathogenesis, leveraging host genetic heterogeneity to identify host response signatures associated with severe disease. Integrating host response data from hospitalized A(H1N1)pdm09 patients and mouse A(H1N1)pdm09 pathogenicity studies we detected a strong association between IL-6 levels and adverse outcome suggesting potential prognostic but not therapeutic applications. Finally, we developed novel infant-mother and aged ferret in vivo infection models to elucidate host – virus interactions specific to these cohorts underlying increased A(H1N1)pdm09 disease severity. Using our infant-mother ferret model, we provide first evidence of A(H1N1)pdm09 mammary gland infection which may compromise maternal support of infant health and cause breast pathology for the nursing mother. Additionally, our aged ferret studies revealed age-associated deficiencies in the development of heterologous immunity which may predispose the elderly to severe A(H1N1)pdm09 infection. The studies described here thus yield a comprehensive A(H1N1)pdm09 host response profile and reveal interactions with underlying host factors which shape the clinical course of A(H1N1)pdm09 infection. These findings serve to significantly advance our understanding of A(H1N1)pdm09 pathogenesis with important implications for clinical management of the virus moving forward.
Publisher
ProQuest Dissertations & Theses
Subject
ISBN
9781339958460, 1339958465
