Doctor of Philosophy (PhD)
Immunology, Pathology & Infectious Disease
Staphylococcus aureus (S. aureus) is a versatile pathogen that can occupy a wide range of niches within the human body, including implanted medical devices such as in prosthetic joint infection (PJI). S. aureus adheres to these medical devices and forms a biofilm, which is a community of bacteria contained within an extracellular matrix that leads to gradients in nutrient and oxygen availability. During PJI, the biofilm is recalcitrant to antibiotics and immune-mediated clearance, leading to treatment failure, mortality, and a high healthcare burden. This is partially due to skewing of the host immune system to an anti-inflammatory state, highlighted by the abundance of granulocytic myeloid-derived suppressor cells (G-MDSCs) and production of IL-10 at the site of infection, which inhibit the bactericidal activity of other immune cells. In these studies, we demonstrate that S. aureus biofilms lacking functional ATP synthase (∆atpA) or the ability to generate the fermentative metabolite formate (∆pflB) had altered biofilm structure. These metabolic alterations to S. aureus also led to a heightened pro-inflammatory immune response and enhanced bacterial clearance in vivo in a mouse PJI model. Recent evidence has also demonstrated that S. aureus can survive and replicate within macrophages. We showed that S. aureus survival within human monocyte-derived macrophages (HMDMs) led to macrophage lysis, serving as a nucleation point for biofilm development. This study also revealed donor-dependent variability in HMDM metabolism, which may affect S. aureus survival. Finally, we explored the fate of G-MDSCs during PJI where a small population of these cells acquire F4/80 and MHC class II, while retaining immunosuppressive properties. We then used cellular indexing of transcriptomes by sequencing (CITE-seq) to analyze the transcriptional profile of the F4/80+MHC class II+ MDSC population, which revealed increased production of tumor necrosis factor and transcriptional attributes of MDSCs, macrophages, and neutrophils. F4/80+MHCII+ MDSCs also exhibited increased mitochondrial gene expression compared to G-MDSCs and neutrophils, suggesting they may be more closely related to M-MDSCs. Collectively, these studies demonstrate the deep connection between metabolism and function of both leukocytes and S. aureus during PJI.
Bertrand, Blake P., "The Interface between Host and Bacterial Metabolism during Staphylococcus aureus Prosthetic Joint Infection" (2023). Theses & Dissertations. 742.
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