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Myd88 and IL-1R Signaling Drive Antibacterial Immunity and Osteoclast-Driven Bone Loss During Staphylococcus Aureus Osteomyelitis

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Myd88 and IL-1R Signaling Drive Antibacterial Immunity and Osteoclast-Driven Bone Loss During Staphylococcus Aureus Osteomyelitis PHIL ROPER 2/18/2020 JOURNAL CLUB RESEARCH ARTICLE MyD88 and IL-1R signaling drive antibacterial immunity and osteoclast-driven bone loss during Staphylococcus aureus osteomyelitis 1 2☯ 2☯ 3 Nicole E. PutnamID , Laura E. Fulbright , Jacob M. CurryID , Caleb A. FordID , Jenna 1 2¤ 1,2,3,4,5 R. PetrongloID , Andrew S. Hendrix , James E. Cassat * 1 Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America, 2 Department of Pediatrics, Division of Pediatric Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America, 3 Department of a1111111111 Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, United States of America, 4 Vanderbilt a1111111111 Institute for Infection, Immunology and Inflammation (VI4), Vanderbilt University Medical Center, Nashville, a1111111111 Tennessee, United States of America, 5 Vanderbilt Center for Bone Biology, Vanderbilt University Medical a1111111111 Center, Nashville, Tennessee, United States of America a1111111111 ☯ These authors contributed equally to this work. ¤ Current address: College of Medicine and Life Sciences, The University of Toledo, Toledo, Ohio, United States of America * [email protected] OPEN ACCESS Citation: Putnam NE, Fulbright LE, Curry JM, Ford Abstract CA, Petronglo JR, Hendrix AS, et al. (2019) MyD88 and IL-1R signaling drive antibacterial immunity Staphylococcus aureus is able to infect virtually all organ systems and is a frequently iso- and osteoclast-driven bone loss during lated etiologic agent of osteomyelitis, a common and debilitating invasive infection of Staphylococcus aureus osteomyelitis. PLoS Pathog 15(4): e1007744. https://doi.org/10.1371/ bone. Treatment of osteomyelitis requires invasive surgical procedures and prolonged journal.ppat.1007744 antibiotic therapy, yet is frequently unsuccessful due to extensive pathogen-induced Editor: Lloyd S Miller, Johns Hopkins School of bone damage that can limit antibiotic penetration and immune cell influx to the infectious Medicine, UNITED STATES focus. We previously established that S. aureus triggers profound alterations in bone Received: December 19, 2018 remodeling in a murine model of osteomyelitis, in part through the production of osteolytic toxins. However, staphylococcal strains lacking osteolytic toxins still incite significant Accepted: April 1, 2019 bone destruction, suggesting that host immune responses are also major drivers of Published: April 12, 2019 pathologic bone remodeling during osteomyelitis. The objective of this study was to Copyright: © 2019 Putnam et al. This is an open identify host immune pathways that contribute to antibacterial immunity during S. aureus access article distributed under the terms of the osteomyelitis, and to define how these immune responses alter bone homeostasis and Creative Commons Attribution License, which permits unrestricted use, distribution, and contribute to bone destruction. We specifically focused on the interleukin-1 receptor (IL- reproduction in any medium, provided the original 1R) and downstream adapter protein MyD88 given the prominent role of this signaling author and source are credited. pathway in both antibacterial immunity and osteo-immunologic crosstalk. We discovered Data Availability Statement: All relevant data are that while IL-1R signaling is necessary for local control of bacterial replication during within the manuscript and its Supporting osteomyelitis, it also contributes to bone loss during infection. Mechanistically, we demon- Information files. strate that S. aureus enhances osteoclastogenesis of myeloid precursors in vitro, and Funding: JEC is supported by National Institute of increases the abundance of osteoclasts residing on bone surfaces in vivo. This enhanced Allergy and Infectious Diseases (https://www. niaid.nih.gov) grants 1R01AI132560 and osteoclast abundance translates to trabecular bone loss, and is dependent on intact IL-1R 5K08AI113107 and a Career Award for Medical signaling. Collectively, these data define IL-1R signaling as a critical component of the Scientists from the Burroughs Wellcome Fund host response to S. aureus osteomyelitis, but also demonstrate that IL-1R-dependent (https://www.bwfund.org). NEP is supported by the National Institute of Allergy and Infectious PLOS Pathogens | https://doi.org/10.1371/journal.ppat.1007744 April 12, 2019 1 / 31 Antibacterial immunity and bone remodeling during S. aureus osteomyelitis Diseases (https://www.niaid.nih.gov) grant immune responses trigger collateral bone damage through activation of osteoclast-medi- 1F31AI133926. CAF was supported through the ated bone resorption. National Institute of General Medical Sciences (https://www.nigms.nih.gov) Medical Scientist Training Program grant T32GM007347 and is currently supported by the National Institute of Allergy and Infectious Diseases (https://www. Author summary niaid.nih.gov) grant 1F30AI138424. JRP is supported by the National Institute of Arthritis Osteomyelitis is a common, debilitating infection of bone that rarely resolves without pro- and Musculoskeletal and Skin Diseases (https:// longed antibiotics and invasive surgical procedures. This study explores the role of host www.niams.nih.gov) Interdisciplinary Training in inflammation during osteomyelitis. Our findings highlight innate immune responses that Rheumatic Diseases grant 5T32AR059039. The research support for the μCT50 and computer are critical for control of S. aureus burdens in bone, prevention of bacterial dissemination, cluster is maintained by National Institutes of and death. Conversely, these same immune pathways were found to contribute to disease Health (https://www.nih.gov) grant pathogenesis by activating infection-associated bone loss. Such bone loss is associated S10RR027631. The funders had no role in study with detrimental outcomes during osteomyelitis, including pathologic fractures and irre- design, data collection and analysis, decision to versible changes in bone growth plates. Alterations in bone remodeling that occur during publish, or preparation of the manuscript. S. aureus osteomyelitis are multifaceted, driven by bacterial toxins and inflammation- Competing interests: The authors have declared mediated changes. We found that inflammation incited by S. aureus in bone contributes that no competing interests exist. to pathologic bone loss. We highlight a mechanism by which S. aureus stimulates forma- tion of bone-resorbing osteoclasts both in vitro and in vivo. Our data illustrate connec- tions between innate immune signaling pathways and bone homeostasis. These connections may be relevant to other autoinflammatory bone and joint conditions charac- terized by bone loss, such as rheumatoid arthritis. Collectively, this work outlines the fine balance between promotion of bacterial clearance and protection from collateral tissue damage. Introduction Osteomyelitis, or inflammation of bone, is most commonly caused by invasive bacterial infec- tion [1]. S. aureus is the most frequently isolated etiologic agent of both acute and chronic bacterial osteomyelitis [2, 3]. S. aureus can colonize bone through hematogenous dissemina- tion, contamination of bone following surgical or accidental trauma, or direct spread from a surrounding soft tissue infection [2, 4]. Bone represents a unique niche for invading bacterial pathogens as it is constantly undergoing turnover by bone-forming osteoblasts and bone- resorbing osteoclasts. Bone also represents a distinctive immunological niche, as bone mar- row houses hematopoietic stem cells that give rise to lymphocytes and myeloid cells [5]. Bone infections rarely resolve without medical intervention, and are difficult to treat due to the widespread antimicrobial resistance of S. aureus as well as induction of bone damage that effectively limits antibiotic delivery and immune cell influx [2, 3]. Osteomyelitis elicits pathologic bone remodeling, which in addition to contributing to treatment failure, can enhance the likelihood of complications such as pathologic fractures [2, 6±11]. In order to explore mechanisms of bone loss during osteomyelitis, we previously estab- lished a murine model of post-traumatic osteomyelitis [6]. Using this model, we identified a subset of staphylococcal toxins, the alpha-type phenol soluble modulins (PSMs), that are responsible for killing primary bone cells in vitro and that enhance bone destruction in vivo [6, 7]. However, a S. aureus strain lacking the alpha-type PSMs still incites substantial bone dam- age, causing approximately 70% of the bone loss that is observed in femurs infected with a wild-type (WT) S. aureus strain [6]. PSMα toxins, along with many other staphylococcal toxins and proteases, are regulated by the agr quorum sensing system. In rabbit and murine models PLOS Pathogens | https://doi.org/10.1371/journal.ppat.1007744 April 12, 2019 2 / 31 Antibacterial immunity and bone remodeling during S. aureus osteomyelitis of experimental osteomyelitis, inactivation of agr further reduced bone destruction [6, 11]. However, significant cortical bone loss still occurred even with this virulence-attenuated strain in our model of post-traumatic osteomyelitis [6]. Taken together, these findings indicate that while bacterial factors directly contribute to bone damage, a substantial proportion of bone loss during osteomyelitis may be caused by host factors [12]. In order to maintain skeletal strength and structure, bone must be continuously
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