Date of Award

Summer 8-14-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pathology & Microbiology

First Advisor

Tammy Kielian, Ph.D.

Abstract

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature monocytes and granulocytes that are potent inhibitors of T cell activation. A role for MDSCs in bacterial infections has only recently emerged, and our laboratory was the first to demonstrate a functional role for MDSCs during Staphylococcus aureus (S. aureus) biofilm infection. Biofilm infections often lead to significant morbidity due to their recalcitrance to antibiotics and ability to subvert immune-mediated clearance by skewing the immune response toward an anti-inflammatory, pro-fibrotic phenotype. Therefore, we examined whether MDSCs could play a role in this process. CD11b+Gr-1+ MDSCs represented the main cellular infiltrate during S. aureus orthopedic biofilm infection, and biofilm-associated MDSCs inhibited T cells proliferation and cytokine production, which correlated with a paucity of T cell infiltrates at the infection site. Importantly, tissues obtained from patients undergoing revision surgery for prosthetic joint infections (PJIs) revealed similar patterns of immune cell influx, with increased MDSC-like infiltrates and significantly fewer T cells compared to aseptic revisions. Depletion of MDSCs and improved bacterial clearance by enhancing the intrinsic proinflammatory attributes of infiltrating monocytes and macrophages. However, the mechanisms responsible for MDSC homing to sites of biofilm infection and factors mediating immunosuppression remain unknown. In cancer, proinflammatory signals initially induce MDSC recruitment and activation, while the immunosuppressive functions of MDSCs are mediated through factors like IL-10, Arg-1 and iNOS. IL-12p40 and IL-10 are both significantly elevated during S. aureus biofilm infection. These studies demonstrate that IL-12 plays a key role in the recruitment of MDSCs into biofilm infection via a chemoattractant that remains to be identified, while IL-10 is produced by infiltrating MDSCs at the site of biofilm infection, whereupon it plays a critical role in polarizing monocyte/macrophages toward an anti-inflammatory phenotype. Loss of either IL-12 or IL-10 during the early MDSC recruitment or effector phases, respectively, promotes biofilm clearance, implicating key roles for each cytokine at distinct stages of infection. Collectively, these studies demonstrate that MDSCs are key contributors to the chronicity of S. aureus biofilm infection, as their immunosuppressive function prevents monocyte/macrophage proinflammatory activity, which facilitates biofilm persistence.

Included in

Immunity Commons

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