Myeloid-Derived Suppressor Cells Contribute to Staphylococcus aureus Orthopedic Biofilm Infection

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 nothing is known about MDSC function in the context of Staphylococcus aureus (S. aureus) infection. Since S. aureus biofilms are capable of subverting immune-mediated clearance, 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, accounting for over 75% of the CD45+ population. Biofilm-associated MDSCs inhibited T cell proliferation and cytokine production, which correlated with a paucity of T cell infiltrates at the infection site. Analysis of FACS-purified MDSCs recovered from S. aureus biofilms revealed increased Arg-1, iNOS, and IL-10 expression, key mediators of MDSC suppressive activity. Targeted depletion of MDSCs and neutrophils using the mAb 1A8 (anti-Ly6G) improved bacterial clearance by enhancing the intrinsic pro-inflammatory attributes of infiltrating monocytes and macrophages. Furthermore, the ability of monocytes/macrophages to promote biofilm clearance in the absence of MDSC action was revealed with RB6-C85 (anti-Gr-1 or anti-Ly6G/Ly6C) administration, which resulted in significantly increased S. aureus burdens both locally and in the periphery, since effector Ly-6C monocytes and by extension, mature macrophages, were also depleted. Collectively, these results are the first to 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.

IL-10 Plays Opposing Roles during Staphylococcus aureus Systemic and Localized Infections

“…In WT mice, appreciable concentrations of bacteria were still recoverable from the skin abscess site at this time point. These results support previous studies, demonstrating that during an S. aureus biofilm infection, IL-10 producing MDSCs prevent the initiation of an appropriate proinflammatory response required for bacterial clearance at this localized site of infection, thereby creating a microenvironment in which it can persist (22,23). Similar to its role during acute peritonitis, IL-10 appears to be controlling local effector T cell responses in the skin.…”

“…Importantly, during localized s.c. infection, we did not observe any systemic dissemination of bacteria in the absence of IL-10. This is similar to the local chronic biofilm infection model, where the absence of IL-10-producing MDSCs also did not lead to bacterial dissemination (22,23). Therefore, it appears that during localized S. aureus infection, IL-10 production facilitates bacterial persistence at the site of infection only, but does not promote systemic dissemination.…”

“…challenge (21). Similarly, during a chronic S. aureus orthopedic biofilm infection, Heim et al (22,23) observed an expansion of IL-10-producing MDSCs at the site of infection, which was associated with bacterial persistence. Targeted depletion of these cells resulted in an enhanced proinflammatory response that resulted in increased bacterial clearance (23,24).…”

Infectious Dose Dictates the Host Response during Staphylococcus aureus Orthopedic-Implant Biofilm Infection

“…To evaluate the importance of strain on infection outcome and inflammation, we compared three commonly used S. aureus isolates, namely, LAC, MW2, and UAMS-1, in a mouse model of orthopedic-implant biofilm infection that models PJI in humans. As previously reported in our laboratory with USA300 LAC (25)(26)(27), this is a well-established low dose infection model associated with rapid bacterial expansion, with titers most prominent in the soft tissue surrounding the infected knee joint followed by the tendons/ligaments comprising the joint, femur, and implant (Fig. 1).…”

“…Recent studies from our laboratory have focused on characterizing the immune response during S. aureus PJI using a mouse model of orthopedic-implant biofilm infection, which has provided a better understanding of the key leukocyte populations that contribute to chronic biofilm establishment. In particular, myeloid-derived suppressor cells (MDSCs) and anti-inflammatory polarized macrophages have been implicated in promoting S. aureus biofilm persistence (25)(26)(27). In this report, we determined whether biofilm formation or the resultant immune response was strain-dependent using our orthopedic-implant biofilm infection model with LAC, MW2, and UAMS-1.…”