Antos, Danielle
(2024)
Regulation of Myeloid Cell Function and Inflammation by Interferon λ During Pulmonary Super-Infection.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Influenza infections represent a significant cause of death annually, caused by both seasonal and pandemic strains of the virus. While many hospitalizations and mortalities occur in individuals with comorbidities, recovery from primary influenza infection can be complicated or prolonged by secondary bacterial infection, commonly caused by methicillin-resistant Staphylococcus aureus (MRSA). The higher mortality rates and prevalence of super-infection makes understanding mechanisms by which super-infection is worsened and prolonged of the utmost importance. Interferon λs (IFNλs), which are produced highly during influenza infection, have been studied for their dual anti-viral and anti-inflammatory nature. Studies have shown that IFNλs restrict viral replication without over-activation of inflammatory responses against both influenza and SARS-CoV-2. However, newer data has uncovered several mechanisms by which IFNλ may worsen super-infection, including suppression of bacterial uptake by neutrophils and epithelial cell repair. These data are in line with work from our laboratory, showing suppression of type 17 immune responses and bacterial clearance during secondary MRSA infection by type I IFNs. Based on these data, I sought to elucidate the impact that IFNλ has on immune cells during super-infection to potentially better inform clinical use of IFNλ during respiratory viral infections. To this end, I employed the use of multiple mouse models to deplete the IFNλ receptor (IFNLR1) from various cell types. I found that depletion of IFNLR1 in all cells enhanced bacterial uptake by phagocytes, leading to increased bacterial clearance and reduced inflammation, while more specific IFNLR1 deletion in myeloid cells, including interstitial macrophages, lung monocytes,
and inflammatory monocytes, enhanced the localization of bacterial within acidic phagolysosomes. Interestingly, IL-17 and IL-22 production were increased in global IFNLR1-/- mice while their upstream activators, IL-6, IL-23, and IL-1β, did not follow the same pattern. Based on this observation, I further investigated how alteration of IL-1 impacted bacterial clearance and whether this function was IFNλ-dependent. Modulation of both IL-1α and IL-1β showed that only IL-1β influenced bacterial clearance through enhanced neutrophil recruitment and AMP production, which was IFNλ-independent. The studies presented herein contribute further knowledge to how IFNλ impacts immune cell populations during super-infection and uncover new avenues for further study.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
14 October 2024 |
| Date Type: |
Publication |
| Defense Date: |
1 August 2024 |
| Approval Date: |
14 October 2024 |
| Submission Date: |
24 September 2024 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
152 |
| 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: |
immunology, influenza, interferons, MRSA, lung, interferon lambda |
| Date Deposited: |
14 Oct 2024 20:07 |
| Last Modified: |
22 Nov 2024 15:27 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46980 |
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