Development of systemic immune dysregulation in a rat trauma model of biomaterial-associated infection

• Type of Material: Article
• Authors: Casey E Vantucci, Georgia Institute of Technology; Hyunhee Ahn, The Atlanta Veterans Affairs Medical Center Atlanta; Travis Fulton, The Atlanta Veterans Affairs Medical Center Atlanta; Mara Schenker, Emory University; Pallab Pradhan, Georgia Institute of Technology; Levi B Wood, Georgia Institute of Technology; Robert Guldberg, Emory University; Krishnendu Roy, Emory University; Nick Willett, Emory University
• Language: English
• Date: 2021-01-01
• Publisher: ELSEVIER SCI LTD
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Published by Elsevier Ltd.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.biomaterials.2020.120405
• Title of Journal or Parent Work: BIOMATERIALS
• Volume: 264
• Start Page: 120405
• End Page: 120405
• Grant/Funding Information: This work was supported by an National Institutes of Health R01 grant (R01AR074960). Any opinion, findings, and conclusions or recommendations expressed in this material are those of the authors(s) and do not necessarily reflect the views of the National Science Foundation.; This research was supported partially by an ACTSI/REM Seed Grant from Emory University and Georgia Tech and Endowment to the Georgia Tech Foundation from Robert A. Milton. CEV acknowledges support by the National Science Foundation Graduate Research Fellowship under Grant No. DGE-1650044.
• Keywords: OSTEOMYELITIS; Orthopedic infection; Science & Technology; Staphylococcus aureus; MOUSE MODEL; STAPHYLOCOCCUS-AUREUS; IMMUNOSUPPRESSION; SUPPRESSOR-CELLS; PREVENTION; DIAGNOSIS; Myeloid-derived suppressor cells; Immune dysregulation; BONE; Materials Science, Biomaterials; Engineering; CATABOLISM; Technology; Materials Science; Severe trauma; Engineering, Biomedical; MESENCHYMAL STEM-CELLS

Abstract

Orthopedic biomaterial-associated infections remain a major clinical challenge, with Staphylococcus aureus being the most common pathogen. S. aureus biofilm formation enhances immune evasion and antibiotic resistance, resulting in a local, indolent infection that can persist long-term without symptoms before eventual hardware failure, bone non-union, or sepsis. Immune modulation is an emerging strategy to combat host immune evasion by S. aureus. However, most immune modulation strategies are focused on local immune responses at the site of infection, with little emphasis on understanding the infection-induced and orthopedic-related systemic immune responses of the host, and their role in local infection clearance and tissue regeneration. This study utilized a rat bone defect model to investigate how implant-associated infection affects the systemic immune response. Long-term systemic immune dysregulation was observed with a significant systemic decrease in T cells and a concomitant increase in immunosuppressive myeloid-derived suppressor cells (MDSCs) compared to non-infected controls. Further, the control group exhibited a regulated and coordinated systemic cytokine response, which was absent in the infection group. Multivariate analysis revealed high levels of MDSCs to be most correlated with the infection group, while high levels of T cells were most correlated with the control group. Locally, the infection group had attenuated macrophage infiltration and increased levels of MDSCs in the local soft tissue compared to non-infected controls. These data reveal the widespread impacts of an orthopedic infection on both the local and the systemic immune responses, uncovering promising targets for diagnostics and immunotherapies that could optimize treatment strategies and ultimately improve patient outcomes.