Brynes, Adam
(2025)
Human Metapneumovirus Small Hydrophobic Protein Degrades JAKs to Block Immune Signals.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Human metapneumovirus (HMPV) is an enveloped, single-stranded negative-sense RNA virus in the family Pneumoviridae and is a leading cause of acute lower respiratory tract infections in pediatric and geriatric populations. Since its discovery in 2001, HMPV has been appreciated as a major source of morbidity and mortality. Infection promotes elevation of many inflammatory cytokines, and animal models suggest that these innate immune signals, especially the interferon response, may play an outsized role in causing severe HMPV disease. As a result, understanding how HMPV interacts with and modulates the innate immune response is critically important. Our previous research indicated a role for the HMPV small hydrophobic (SH) protein in inhibiting the JAK/STAT signaling-mediated interferon response in infected cells; however, no mechanism was established. Other research indicated that HMPV infection could deplete JAK signaling proteins in infected cells and separately that HMPV infection could block the IL-6 JAK/STAT signaling pathway, though the viral protein(s) responsible were not identified. Our research established for the first time that SH is responsible for IL-6 signaling inhibition during HMPV infection and that this is accomplished through an SH-dependent depletion of JAK signaling factors required for both interferon and IL-6 signal transduction. This dissertation also provides a summary of JAK/STAT signaling inhibition in the viral families Pneumoviridae and Paramyxoviridae and reviews existing research on SH proteins expressed in the same. This research enhances our understanding of critical mechanisms of immune evasion and interference by diverse pathogens important to public health.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
13 February 2025 |
| Date Type: |
Publication |
| Defense Date: |
4 December 2024 |
| Approval Date: |
13 February 2025 |
| Submission Date: |
13 December 2024 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
116 |
| 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: |
Innate immune inhibition; viral interference with host defense; signaling inhibition; Pneumoviruses; Pneumoviridae |
| Date Deposited: |
13 Feb 2025 17:03 |
| Last Modified: |
13 Feb 2025 17:03 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/47273 |
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