van der Geest, Rick
(2023)
Investigating innate immune responses against pulmonary Klebsiella pneumoniae infection: a role for BATF2.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
This is the latest version of this item.
Abstract
The Gram-negative bacterium Klebsiella pneumoniae (Kp) is a common cause of hospital- acquired bacterial pneumonia, and Kp infections are increasingly resistant to antibiotic treatment, including to carbapenems, which are often used as last-resort antibiotics. A better understanding of the host mechanisms that protect against Kp infection may aid in the development of alternative strategies to combat the threat of multidrug-resistant Kp.
Our lab recently identified BATF2 as one of the most highly upregulated genes in LPS- treated human alveolar macrophages. BATF2 has recently emerged as a transcriptional regulator of the innate immune system, but the signaling pathways that induce BATF2 expression in macrophages in response to Gram-negative stimuli are incompletely understood, as is the role of BATF2 in the host response to pulmonary infection with Gram-negative bacteria like Kp. In this dissertation, we show that Kp-induced Batf2 gene expression in macrophages in vitro requires TRIF and type I IFN signaling, but not MyD88 signaling. In addition, using Batf2-/- macrophages and Batf2-/- mice, we show that BATF2 enhances pro-inflammatory cytokine responses in macrophages and contributes to the host defense against pulmonary Kp infection.
Prior studies have suggested that evasion of phagocytosis is an important virulence strategy of Kp, but few studies have examined this using clinical isolates. In the current dissertation, we therefore also investigated sensitivity to phagocytic uptake across clinical Kp isolates and show that there is significant heterogeneity in susceptibility to macrophage phagocytosis across respiratory Kp isolates. In addition, we show that pulmonary infection with the phagocytosis-sensitive isolate S17 results in a lower bacterial burden and a reduced inflammatory response compared to infection with the phagocytosis-resistant isolate W42. Importantly, we also show that depletion of alveolar macrophages impaired host defense against the phagocytosis-sensitive S17 isolate, while alveolar macrophage depletion did not significantly affect host defense against the phagocytosis-resistant W42 isolate. Altogether, the findings from this set of experiments show that sensitivity to phagocytosis is an important determinant of pulmonary clearance of clinical respiratory Kp isolates.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
8 December 2023 |
| Date Type: |
Publication |
| Defense Date: |
13 April 2023 |
| Approval Date: |
8 December 2023 |
| Submission Date: |
8 August 2023 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
160 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Cellular and Molecular Pathology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Innate immunity
Macrophages
BATF2
Klebsiella pneumoniae
Pulmonary infection
Host defense
Transcription factor
Phagocytosis |
| Date Deposited: |
08 Dec 2023 15:04 |
| Last Modified: |
08 Dec 2023 15:04 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/45291 |
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