Date on Master's Thesis/Doctoral Dissertation

5-2015

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Microbiology and Immunology

Degree Program

Microbiology and Immunology, PhD

Committee Chair

Jonsson, Colleen B.

Committee Co-Chair (if applicable)

Fraig, Mostafa

Committee Member

Lawrenz, Matthew

Committee Member

Mitchell, Thomas

Committee Member

Uriarte, Silvia

Subject

H1N1 influenza; Influenza A virus; Virus diseases--Pathogenesis

Abstract

Influenza A virus (IAV) is a minus-sense, segmented, single-stranded RNA virus that infects the respiratory tract of humans and can cause severe illness. Novel IAV variants perpetually emerge on every continent, and the emergence of variants with increased transmissibility and/or pathogenesis in the human population is a serious concern for global public health. Infection with IAV typically causes an acute, self-limiting upper respiratory tract disease. However, severe IAV disease is characterized by infection of the lower respiratory tract which can lead to pneumonia and may result in the development of acute respiratory distress syndrome (ARDS). Viral and host contributions to the development of ARDS are poorly understood, however IAV pathogenesis has been linked mutations in the receptor binding protein and the viral polymerase. Ferrets and mice are two important laboratory animal models for studying IAV pathogenesis. In 2009, a novel H1N1 subtype IAV (H1N1pdm) emerged in the human population and displayed variable pathology in humans. Using a mouse model, we show the variability of clinical isolates of H1N1pdm is driven by viral mutations, and that the timing of the inflammatory response is correlated with disease severity. To investigate spatiotemporal aspects of potential host and viral contributions to influenza pathogenesis, we developed a live imaging platform for ferrets infected with a human clinical isolate of H1N1pdm. We detected an early recruitment of neutrophils into ferret lungs following infection, which accumulated at foci of H1N1pdm infection within specific anatomical regions of the lung by 24 hours post-infection. The neutrophil response was biphasic, characterized by the recruitment of two populations with differing gene expression profiles, and baseline neutrophil levels were increased throughout the entire lung, including areas with no apparent viral infection. Changes in the viral microenvironment resulted in the regeneration of lung epithelium during recovery phase of infection, and this was imaged with PET-CT using a radiolabeled glucose analog. In summary, these data illustrate critical features of the immune response to IAV, and emphasize important considerations about the timing and accuracy of innate immune responses in studying viral pathogenesis.

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