Huckestein, Brydie
(2023)
Understanding the Underlying Mechanisms of Persistent Inflammation following Severe Influenza Infections in Inbred and Juvenile, Outbred Mice.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Influenza viruses cause upper respiratory infections that lead to damage and persistent inflammation in the lung. While the pathogenesis of acute influenza infection is heavily studied, the long-term impacts these infections have on the lung is not as well understood. The current repertoire of influenza therapeutics treats the acute stage of disease, and has a very narrow window of efficacy in which administration will be effective. This leaves a gap in treatment options that are available for individuals suffering from the long-term impacts of influenza infections after the point of viral clearance. For this reason, we sought to develop a deeper understanding of persistent lung inflammation following influenza infection, in order to identify viable targetable pathways that may bridge this therapeutic gap. We found that persistent inflammation in the lungs of mice 21 days post-infection is perpetuated by T cells and macrophages that continue to reside in the lung well beyond the point of viral clearance, regardless of age, sex, or genetics. The mammalian target of rapamycin comlex 1 (mTORC1) is an energy sensing kinase that is elevated in activated immune cells to support the metabolic demand required to carry out effector functions. Treating mice with the mTORC1 inhibitor rapamycin reduced the frequency of lymphocytes and macrophages in the lung when treatment was initiated 11 days post-infection, a time period in which viral replication has ceased. Juvenile male and female outbred mice were examined to determine if biological sex impacts persistent lung inflammation in a pre-pubescent, genetically diverse model of influenza infection. We found that the lungs of juvenile female mice had broad hypercytokinemia, which correlated with a lack of regulatory T cells and higher frequencies of exudate macrophages. The lungs of juvenile male mice had lower production of inflammatory cytokines and a higher ratio of regulatory T cells to TH1 cells. Together, these data demonstrate that persistent lung inflammation is caused by T cells and macrophages, and that mTORC1 may be a viable target for individuals who continue to suffer from the long-term impacts of influenza infections.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
5 November 2023 |
| Defense Date: |
21 November 2023 |
| Approval Date: |
16 September 2024 |
| Submission Date: |
6 December 2023 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
124 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Microbiology and Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Influenza, mTORC1, rapamycin, post-viral sequelae, lung repair, immunology |
| Date Deposited: |
16 Sep 2024 18:50 |
| Last Modified: |
16 Sep 2024 18:50 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/45614 |
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