Solberg, Sajen
(2019)
Caspase-1 mediated pro-inflammatory cytokine pathway in highly pathogenic H5N1 avian influenza infection in the non-human primate model.
Master's Thesis, University of Pittsburgh.
(Unpublished)
Abstract
Similar to human disease, inhalation of small particle aerosols of H5N1 highly pathogenic avian influenza virus by cynomologus macaques leads to fulminant pneumonia, acute respiratory disease syndrome (ARDS), and fatality. Although aspects of the viral pathogenesis are understood, many of the finer mechanisms of H5N1 disease progression remain unclear. The severity of disease and associated mortality rate highlight the necessity to better understand this public health threat and potential bioweapon. During H5N1 infection, interferon-α and proinflammatory cytokines and chemokines markedly increase in expression within lung epithelial tissue and distal airways. This profound inflammation is characteristic of the pro-inflammatory cell death pathway known as pyroptosis. Yet, the role of pyroptosis and its initiator, caspase-1, in H5N1 influenza pathogenesis is unknown. Using immunofluorescent microscopy in situ, I identified active caspase-1, active IL-1β, and neutrophil extracellular traps (NETs) in association with influenza A nucleoprotein. I hypothesized that after H5N1 aerosol inoculation lung epithelial cells undergo caspase-1 dependent pyroptosis, leading to recruitment signaling of neutrophils to the site of infection and the production of NETs as secondary host immune response. NETosis, or the presentation of neutrophil extracellular traps from living or suicidal neutrophils, complicates the fulminant pneumonia present during H5N1 influenza disease progression. By trapping fluid and viral particles within the lung, it is likely that NETs prevent clearance of fluid buildup and viral particles within the highly inflamed lung tissue. I further identified and characterized apoptosis-associated speck like proteins (ASC) containing a caspase recruitment domain (CARD) within lung epithelial cells that generate IL-1β. I found that the expression of caspase-1 correlated with NET expression and disease severity after aerosol challenge. These data suggest that caspase-1 driven inflammation of lung tissues, including pyroptotic cell death, contribute to disease severity in H5N1 influenza. What’s more, in terms of public health significance; these findings help clarify cellular mechanisms associated with H5N1 disease progression furthering the understanding of H5N1 disease and could support research into the identification of novel therapeutics, such as using caspase-1 inhibitors to control inflammation and prevent severe disease progression in infected subjects.
Share
| Citation/Export: |
|
| Social Networking: |
|
Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
30 January 2019 |
| Date Type: |
Publication |
| Defense Date: |
11 December 2018 |
| Approval Date: |
30 January 2019 |
| Submission Date: |
26 November 2018 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
78 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Infectious Diseases and Microbiology |
| Degree: |
MS - Master of Science |
| Thesis Type: |
Master's Thesis |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
H5N1, Pathogenic, Influenza, Caspase-1, Pyroptosis |
| Date Deposited: |
30 Jan 2019 17:34 |
| Last Modified: |
01 Jan 2020 06:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/35589 |
Metrics
Monthly Views for the past 3 years
Plum Analytics
Actions (login required)
 |
View Item |
![[feed]](/images/feed-icon-32x32.png){kind=icon}