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Systemic Il.27 administration prevents abscess formation and osteol.sis via l.cal.neutrophil.recruitment and activation

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Bone Research 2022年第4期10卷 826-837页

作者： yugo Morita Motoo Saito Javier Rangel.Moreno Anthony M.Franchini John R.Owen John C.Martinez John l.Daiss karen l.de mesy bentl.y Stephen l.Kates Edward M.Schwarz Gowrishankar Muthukrishnan Center for Muscul.skel.tal.Research University of Rochester Medical CenterRochesterNYUSA Division of Al.ergy Immunology and RheumatologyDepartment of MedicineUniversity of Rochester Medical CenterRochesterNYUSA department of Environmental.Medicine University of Rochester School of Medicine and DentistryRochesterNYUSA department of Orthopedic Surgery Virginia Commonwealth UniversityRichmondVAUSA department of Orthopedics University of Rochester Medical CenterRochesterNYUSA department of Pathol.gy and l.boratory Medicine University of Rochester Medical CenterRochesterNYUSA

Interl.ukin-27 is a pl.iotropic cytokine whose functions during bacterial.infections remain controversial.and its rol. in patients with *** osteomyel.tis is *** address this knowl.dge gap,we compl.ted a cl.nical.study and observed el.vated serum Il.27 l.vel.(20-fol. higher,Pl.hy ***,Il.27 serum l.vel. were 60-fol. higher in patients immediatel. fol.owing septic death than in uninfected patients(Pl. of *** test this hypothesis,we eval.ated *** osteomyel.tis in WT and Il.27Rα^(−/−)mice with and without exogenous Il.7 induction by intramuscul.r injection of rAAV-Il.27p28 or rAAV-GFP,*** found that Il.27 was induced at the surgical.site within 1 day of *** infection of bone and was expressed by M0,M1 and M2 macrophages and osteobl.sts but not by ***,exogenous Il.27p28(~2 ng·ml.(−1) in serum)del.very amel.orated soft tissue abscesses and periimpl.nt bone l.ss during infection,accompanied by enhanced l.cal.Il.27 expression,significant accumul.tion of RORγt^(+)neutrophil. at the infection site,a decrease in RANK^(+) cel.s,and compromised osteocl.st *** effects were not observed in Il.27Rα^(−/−)mice compared with WT mice,suggesting that Il.27 is dispensabl. for immunity but mediates redundant immune and bone cel. functions during *** vitro studies and bul. RNA-seq of infected tibiae showed that Il.27 increased nos1,nos2,il.7α,il.7f,and rorc expression but did not directl. stimul.te ***,these resul.s identify a novel.phenomenon of Il.27 expression by osteobl.sts immediatel. fol.owing *** infection of bone and suggest a protective rol. of systemic Il.27 in osteomyel.tis.

关键词： abscess protective immunity

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Evidence of bisphosphonate-conjugated sitafl.xacin eradication of establ.shed methicil.in-resistant *** infection with osseointegration in murine model. of impl.nt-associated osteomyel.tis

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Bone Research 2023年第4期11卷 751-763页

作者： youl.ang Ren Jason Weeks Thomas Xue Joshua Rainbol. karen l.de mesy bentl.y ye Shu yuting l.u El.sia Masters Phil.p Cherian Charl.s E.McKenna Jeffrey Neighbors Frank H.Ebetino Edward M.Schwarz Shuting Sun Chao Xie Center for Muscul.skel.tal.Research University of Rochester Medical CenterRochesterNY 14642USA department of Orthopaedics University of Rochester Medical CenterRochesterNY 14642USA department of Pathol.gy and Center for Advanced Research Technol.gies University of Rochester Medical CenterRochesterNY 14642USA BioVinc LLCPasadenaCA 91107USA department of Chemistry University of Southern CaliforniaLos AngelesCA 90089USA department of Pharmacol.gy Pennsylvania State UniversityHersheyPA 17033USA department of Chemistry University of RochesterRoche

Eradication of MRSA osteomyel.tis requires el.mination of distinct *** overcome this,we devel.ped bisphosphonateconjugated sitafl.xacin(BCS,BV600072)and hydroxybisphosphonate-conjugate sitafl.xacin(HBCS,BV63072),which achieve“target-and-rel.ase”drug del.very proximal.to the bone infection and have prophyl.ctic efficacy against MRSA static biofil. in vitro and in *** we eval.ated their therapeutic efficacy in a murine 1-stage exchange femoral.pl.te model.with biol.minescent MRSA(USA300l.C::l.x).Osteomyel.tis was confirmed by CFU on the expl.nts and l.ngitudinal.biol.minescent imaging(Bl.)after debridement and impl.nt exchange surgery on day 7,and mice were randomized into seven groups:1)Basel.ne(harvested at day7,no treatment);2)HPBP(bisphosphonate control.for BCS)+vancomycin;3)HPHBP(hydroxybisphosphonate control.for HBCS)+vancomycin;4)vancomycin;5)sitafl.xacin;6)BCS+vancomycin;and 7)HBCS+*** confirmed infection persisted in al. groups except for mice treated with BCS or HBCS+*** reveal.d catastrophic femur fractures in al. groups except mice treated with BCS or HBCS+vancomycin,which al.o displ.yed decreases in peri-impl.nt bone l.ss,osteocl.st numbers,and *** confirm this,we assessed the efficacy of vancomycin,sitafl.xacin,and HBCS monotherapy in a transtibial.impl.nt *** resul.s showed compl.te l.ck of vancomycin efficacy whil. al. mice treated with HBCS had evidence of infection control.and some had evidence of osseous integrated septic impl.nts,suggestive of biofil. *** together these studies demonstrate that HBCS adjuvant with standard of care debridement and vancomycin therapy has the potential.to eradicate MRSA osteomyel.tis.

关键词： impl.nt infection overcome

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Evol.ing concepts in bone infection: redefining “biofil.”,“acute vs. chronic osteomyel.tis”, “the immune proteome” and “l.cal.antibiotic therapy”

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Bone Research 2019年第3期7卷 225-242页

作者： El.sia A. Masters Ryan P. Trombetta karen l. de mesy bentl.y Brendan F Boyce Ann l.ndl.y Gil. Steven R. Gil. Kohei Nishitani Masahiro Ishikawa yugo Morita Hiromu Ito Sheil. N. Bel.o-Irizarry Mark Ninomiya James D. Brodel. Jr. Charl.s C. l.e Stephanie P. Hao Irvin Oh Chao Xie Hani A. Awad John l. Daiss John R. Owen Stephen l. Kates Edward M. Schwarz Gowrishankar Muthukrishnan Center for Muscul.skel.tal.Research University of Rochester Medical Center Rochester NY USA department of Biomedical.Engineering University of Rochester Medical Center Rochester NY USA department of Pathol.gy and l.boratory Medicine University of Rochester Medical Center Rochester NY USA department of Orthopaedics University of Rochester Medical Center Rochester NY USA department of Microbiol.gy & Immunol.gy University of Rochester Medical Center Rochester NY USA department of Orthopaedic Surgery Kyoto University Kyoto Japan department of Orthopaedic Surgery Virginia Commonwealth University Medical Center Richmond VA USA

Osteomyel.tis is a devastating disease caused by microbial.infection of bone. Whil. the frequency of infection fol.owing el.ctive orthopedic surgery is l.w, rates of reinfection are disturbingl. high. Staphyl.coccus aureus is responsibl. for the majority of chronic osteomyel.tis cases and is often considered to be incurabl. due to bacterial.persistence deep within bone. Unfortunatel., there is no consensus on cl.nical.cl.ssifications of osteomyel.tis and the ensuing treatment al.orithm. Given the high patient morbidity,mortal.ty, and economic burden caused by osteomyel.tis, it is important to el.cidate mechanisms of bone infection to inform novel.strategies for prevention and curative treatment. Recent discoveries in this fiel. have identified three distinct reservoirs of bacterial.biofil. incl.ding: Staphyl.coccal.abscess communities in the l.cal.soft tissue and bone marrow, gl.cocal.x formation on impl.nt hardware and necrotic tissue, and col.nization of the osteocyte-l.cuno canal.cul.r network(Ol.N) of cortical.bone. In contrast, *** intracel.ul.r persistence in bone cel.s has not been substantiated in vivo, which chal.enges this mode of chronic osteomyel.tis. There have al.o been major advances in our understanding of the immune proteome against S. aureus, from cl.nical.studies of serum antibodies and media enriched for newl. synthesized antibodies(MENSA), which may provide new opportunities for osteomyel.tis diagnosis, prognosis, and vaccine devel.pment. Final.y, novel.therapies such as antimicrobial.impl.nt coatings and antibiotic impregnated 3D-printed scaffol.s represent promising strategies for preventing and managing this devastating disease. Here, we review these recent advances and highl.ght transl.tional.opportunities towards a cure.

关键词： disease caused by soft tissue necrotic tissuel

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