{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T02:47:14Z","timestamp":1791946034966,"version":"4.3.4"},"reference-count":64,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2020,12,1]],"date-time":"2020-12-01T00:00:00Z","timestamp":1606780800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"},{"start":{"date-parts":[[2022,1,3]],"date-time":"2022-01-03T00:00:00Z","timestamp":1641168000000},"content-version":"vor","delay-in-days":398,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["asbmr.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,12,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Staphyloccocus aureus is one of the major pathogens in orthopedic periprosthetic joint infection (PJI), a devastating complication of total joint arthroplasty that often results in chronic and persistent infections that are refractory to antibiotics and require surgical interventions. Biofilm formation has been extensively investigated as a reason for persistent infection. The cellular composition, activation status, cytokine profile, and role of the immune response during persistent S. aureus PJI are incompletely understood. In this study, we used histology, multiparametric flow cytometry, and gene expression analysis to characterize the immune response in a clinically relevant orthopedic PJI model. We tested the hypothesis that persistent S. aureus infection induces feedback mechanisms that suppress immune cell activation, thereby affecting the course of infection. Surprisingly, persistent infection was characterized by strikingly high cytokine gene expression indicative of robust activation of multiple components of innate and adaptive immunity, along with ongoing severe neutrophil-dominated inflammation, in infected joint and bone tissues. Activation and expansion of draining lymph nodes and a bone marrow stress granulopoiesis reaction were also maintained during late phase infection. In parallel, feedback mechanisms involving T-cell inhibitory receptors and exhaustion markers, suppressive cytokines, and regulatory T cells were activated and associated with decreased T-cell proliferation and tissue infiltration during the persistent phase of infection. These results identify the cellular and molecular components of the mouse immune response to persistent S. aureus PJI and indicate that neutrophil infiltration, inflammatory cytokine responses, and ongoing lymph node and bone marrow reactions are insufficient to clear infection and that immune effector mechanisms are suppressed by feedback inhibitory pathways. These immune-suppressive mechanisms are associated with diminished T-cell proliferation and tissue infiltration and can be targeted as part of adjuvant immunotherapeutic strategies in combination with debridement of biofilm, antibiotics, and other therapeutic modalities to promote eradication of infection. \u00a9 2021 American Society for Bone and Mineral Research (ASBMR).<\/jats:p>","DOI":"10.1002\/jbmr.4489","type":"journal-article","created":{"date-parts":[[2021,12,13]],"date-time":"2021-12-13T02:11:59Z","timestamp":1639361519000},"page":"577-594","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Immune Response to Persistent Staphyloccocus Aureus Periprosthetic Joint Infection in a Mouse Tibial Implant Model"],"prefix":"10.1093","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5907-5646","authenticated-orcid":false,"given":"Upneet K","family":"Sokhi","sequence":"first","affiliation":[{"name":"David Z. Rosensweig Genomics Research Center Hospital for Special Surgery New York NY USA"},{"name":"Research Institute, Hospital for Special Surgery New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunwei","family":"Xia","sequence":"additional","affiliation":[{"name":"David Z. Rosensweig Genomics Research Center Hospital for Special Surgery New York NY USA"},{"name":"Research Institute, Hospital for Special Surgery New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Branden","family":"Sosa","sequence":"additional","affiliation":[{"name":"Arthroplasty Research Laboratory Hospital for Special Surgery New York NY USA"},{"name":"Research Institute, Hospital for Special Surgery New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Turajane","sequence":"additional","affiliation":[{"name":"Arthroplasty Research Laboratory Hospital for Special Surgery New York NY USA"},{"name":"Research Institute, Hospital for Special Surgery New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sita N","family":"Nishtala","sequence":"additional","affiliation":[{"name":"Arthroplasty Research Laboratory Hospital for Special Surgery New York NY USA"},{"name":"Research Institute, Hospital for Special Surgery New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania","family":"Pannellini","sequence":"additional","affiliation":[{"name":"Department of Pathology Hospital for Special Surgery New York NY USA"},{"name":"Research Institute, Hospital for Special Surgery New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias P","family":"Bostrom","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics Weill Cornell Medicine New York NY USA"},{"name":"Arthroplasty Research Laboratory Hospital for Special Surgery New York NY USA"},{"name":"Research Institute, Hospital for Special Surgery New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto V","family":"Carli","sequence":"additional","affiliation":[{"name":"Arthroplasty Research Laboratory Hospital for Special Surgery New York NY USA"},{"name":"Research Institute, Hospital for Special Surgery New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8377-077X","authenticated-orcid":false,"given":"Xu","family":"Yang","sequence":"additional","affiliation":[{"name":"Arthroplasty Research Laboratory Hospital for Special Surgery New York NY USA"},{"name":"Research Institute, Hospital for Special Surgery New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lionel B","family":"Ivashkiv","sequence":"additional","affiliation":[{"name":"Immunology and Microbial Pathogenesis Program Weill Cornell Medicine New York NY USA"},{"name":"Department of Medicine Weill Cornell Medicine New York NY USA"},{"name":"David Z. Rosensweig Genomics Research Center Hospital for Special Surgery New York NY USA"},{"name":"Research Institute, Hospital for Special Surgery New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,12,12]]},"reference":[{"issue":"7","key":"2024012714035257600_jbmr4489-bib-0001","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1002\/jor.24595","article-title":"New developments and future challenges in prevention, diagnosis, and treatment of prosthetic joint infection","volume":"38","author":"Ricciardi","year":"2020","journal-title":"J Orthop Res."},{"issue":"2","key":"2024012714035257600_jbmr4489-bib-0002","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1128\/CMR.00111-13","article-title":"Prosthetic joint infection","volume":"27","author":"Tande","year":"2014","journal-title":"Clin Microbiol 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