{"doi":"10.1002/jbmr.4555","title":"What Are the Immune Responses That Allow Us to Live With Incurable Bone Infection, and How Can They Be Augmented to Improve Outcomes After Prosthetic Joint Infection?","abstract":"Staphylococcus aureus is a primordial human pathogen that remains very hard to treat after deep infections due to its vast array of immune evasion mechanisms.(1) Paramount among these are distinct S. aureus biofilms that form during the establishment of chronic osteomyelitis, and include glycocalyx that forms on implants and necrotic tissues,(2) Staphylococcus abscess communities in soft tissues,(3) and bacteria that colonize the osteocyte lacuno-canalicular network (OLCN) of cortical bone.(4) These biofilms serve as an impenetrable physical barrier separating the pathogen from host immune responses.(5) Thus, chronic S. aureus infection of bone, which is primarily infection of cancellous bone,(6) is broadly considered to be incurable. However, since pediatric osteomyelitis patients can live to old age with this infection,(7) sequestering host immunity that prevents sepsis must exist, and elucidating these protective innate and adaptive responses is essential for effective vaccine development. Equally important is understanding how host immunity against S. aureus toxins and superantigens does not get too robust, which can lead to toxic shock syndrome and death from cytokine storm.(8) Among the different forms of S. aureus osteomyelitis, periprosthetic joint infection (PJI) presents additional clinical challenges, most notably the decision for debridement, antibiotics, and implant retention (DAIR), or complete replacement of all the implants in one or two stages.(9) Although this critical decision has traditionally been guided by PJI duration (eg, DAIR is indicated up to 3 weeks post PJI diagnosis),(10) the question of which surgery to perform when proved to be the most controversial of the 652 consensus questions debated by 869 delegates from 92 countries at the 2018 International Consensus Meeting on musculoskeletal infection (ICM 2018, https://icmphilly.com), who failed to agree on any recommendations based on timing. Moreover, the Research Work Group of ICM 2018 concluded that of the 164 General Assembly consensus questions, developing a functional definition of “acute” versus “chronic” bone and implant-related infection is the greatest research priority in this field.(11) As the waxing and waning of host innate and adaptive immune responses to specific pathogens are known to be biomarkers of acute versus chronic infection and cure,(5) elucidating these variables in PJI is critical for patient management. To this end, Sokhi and colleagues analyzed histology, multiparametric flow cytometry, and gene expression profiles to characterize the immune response in a murine model that resembles PJI.(12) Specifically, the authors tested the hypothesis that persistent S. aureus infection induces feedback mechanisms that suppress immune cell activation, thereby affecting the course of infection. The results showed robust activation of multiple components of innate and adaptive immunity in animals with persistent PJI, as evidenced by high cytokine gene expression and severe neutrophil-dominated inflammation in infected joint and bone tissues. Evaluation of immune biomarkers in draining lymph nodes and bone marrow revealed that chronic PJI induces adaptive immunity and granulopoiesis during the late phase of infection, which are consistent with a vigorous host response against S. aureus. However, the authors also identified novel feedback mechanisms. These involved T-cell inhibitory receptors and evidence of T-cell exhaustion. They also identified upregulation of suppressive cytokines and regulatory T cells, which were activated and associated with decreased T-cell proliferation and tissue infiltration during chronic infection. Thus, there is concomitant immunity in this mouse model of S. aureus PJI in which the host appears to be keeping the biofilm bacteria sequestered with a perpetual pro-inflammatory phagocytic cell response to clear escaping planktonic bacteria and immunosuppression to diminish T-cell proliferation and tissue infiltr","journal":"Journal of Bone and Mineral Research","year":2020,"id":113852,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9601,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":388311,"name":"Edward M. Schwarz","orcid":"0000-0002-4854-9698","position":0,"is_corresponding":true}],"reference_count":12,"raw_metadata":null,"created_at":"2026-07-18T23:13:25.964732Z","pmid":"35435268","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}