Grousd, Jennifer
(2023)
Defining Staphylococcus aureus Virulence Factors in Bacterial Pneumonia and Influenza Super-infection.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Staphylococcus aureus is an important pulmonary pathogen that can cause severe pneumonia and often complicates influenza infections. The emergence of methicillin-resistant S. aureus (MRSA) over the past few decades has made treatment more difficult in staphylococcal pneumonia and super-infection, due to antibiotic resistance and increased virulence compared to methicillin-sensitive strains. Understanding how this pathogen can invade and establish infection in the lung is important for the development of future therapeutics. To understand the bacterial genetic requirements in both infection contexts, I established methods for S. aureus transposon sequencing in the lung. Successful establishment of infection by bacterial pathogens requires adhesion to host components. Staphylococcal species express a broad range of cell wall-anchored proteins (CWAs) that are involved in adhesion to host cells, extracellular matrix proteins, and bacterial biofilms as well as nutrient acquisition and immune evasion. CWAs have known roles in upper respiratory tract colonization; however, their role in the lung is unknown. Thus, I screened several CWA family members in the context of S. aureus pneumonia and influenza, S. aureus super-infection. Lacking individual CWAs during bacterial pneumonia had variable effects on bacterial burden, immune infiltrate, and acute lung injury. However, influenza was the main driver of super-infection susceptibility regardless of CWA mutant. CWAs did influence inflammatory signaling in both settings, suggesting that they maintain an impact on the immune system in the lung. To understand inflammation in the context of S. aureus pneumonia alone, I characterized the role of a cell membrane associated protein, second immunoglobulin-binding protein (Sbi). Sbi induced inflammation in the lung differently than the structurally related protein, staphylococcal protein A. Induction of inflammation was independent of Sbi antibody binding and may be due to its role in complement evasion. I then characterized a novel CWA, S. aureus surface protein D (SasD) in the context of pneumonia. Mice infected with a SasD mutant had decreased bacterial burden, inflammatory responses, and mortality compared to wildtype S. aureus. These data suggest that cell surface exposed proteins are important factors to investigate further in the context of S. aureus pulmonary infections and may be future therapeutic or vaccine targets.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Grousd, Jennifer | | | |
|
| ETD Committee: |
| Title | Member | Email Address | Pitt Username | ORCID |
|---|
| Committee Chair | Richardson, Anthony | | | | | Committee Member | Cooper, Vaughn | | | | | Committee Member | Bomberger, Jennifer | | | | | Committee Member | Williams, John | | | | | Thesis Advisor | Alcorn, John | | | |
|
| Date: |
4 October 2023 |
| Date Type: |
Publication |
| Defense Date: |
14 July 2022 |
| Approval Date: |
4 October 2023 |
| Submission Date: |
4 May 2023 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
232 |
| 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: |
Staphylococcus aureus; lung; Cell wall-anchored proteins; influenza; super-infection |
| Date Deposited: |
04 Oct 2023 16:10 |
| Last Modified: |
04 Oct 2023 16:10 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/44842 |
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