IntroductionProtection against different classes of pathogens requires the activation of Ag-presenting dendritic cells (DCs) to express factors that promote the development of distinct effector Th-cell subsets, which are specialized to combat the class of pathogen involved. 1 Effective T cell-mediated immunity against extracellular bacteria requires DCs to produce IL-1␤, IL-6, and IL-23 that contribute to the development of Th17 cells. 2,3 The pathogen-induced production of cytokines by DCs is induced on sensing of pathogens by pattern-recognition receptors (PRRs), including TLRs, C-type lectins, Nod-like receptors, and RIG-I-like receptors. [4][5][6][7] Although triggering of individual PRRs is known to induce cytokine production, it is becoming increasingly clear that the ultimate amount and the profile of cytokine production by DCs crucially depends on cross-talk between multiple PRRs. 8-10 However, our knowledge on these cross-talk mechanisms is likely to be still largely incomplete. 10 In this respect, the role of Fc␥Rs, the family of high-and low-affinity receptors for IgG, in the induction of cytokine production did not receive much attention. IgG is the most prevalent immunoglobulin in the blood and body tissues. 11,12 Because of the high levels of IgG directed against numerous polyreactive bacterial Ags, invading bacteria are efficiently opsonized as soon as they penetrate the body's barriers, even during primary infection. [13][14][15][16][17] IgG opsonization can directly lead to pathogen inactivation via complement activation, but can also result in a variety of responses by different effector immune cells such as cell degranulation, production of reactive oxygen species (ROS), or Ab-dependent cellular cytotoxicity (ADCC). 18,19 In addition, binding of opsonized pathogens to low-affinity Fc␥Rs on DCs mediates phagocytosis, degradation and subsequent presentation of pathogen-derived Ags to T cells. 20 Fc␥R stimulation also induces DC maturation. [21][22][23] However, the triggering of Fc␥Rs on DCs results in no or only low production of cytokines and has not been demonstrated to play a major role in polarization of human T-cell responses in healthy donors. 21,22 In the present study, we have taken into account that in most conditions DCs will engage bacteria that are IgG opsonized and that such DCs will be simultaneous triggered via Fc␥Rs and bacterial sensors. We here report that the engagement of DCs with opsonized bacteria resulted in strongly up-regulated production of selected cytokines, including IL-1␤ and IL-23, which favored the development of Th17 cells. This effect was fully dependent on stimulation of the low-affinity IgG receptor Fc␥RIIa (also known as CD32a), which synergized with TLRs for the amplification of Th17-promoting cytokines by both enhancing cytokine transcription and by activating caspase-1. Taken together, these data identified cross-talk between TLRs and Fc␥RIIa as a novel mechanism by which DCs promote the development of protective effector T cells in response to bacteria. ...

Orthopaedic and trauma device-related infection (ODRI) remains one of the major complications in modern trauma and orthopaedic surgery.Despite best practice in medical and surgical management, neither prophylaxis nor treatment of ODRI is effective in all cases, leading to infections that negatively impact clinical outcome and significantly increase healthcare expenditure.The following review summarises the microbiological profile of modern ODRI, the impact antibiotic resistance has on treatment outcomes, and some of the principles and weaknesses of the current systemic and local antibiotic delivery strategies.The emerging novel strategies aimed at preventing or treating ODRI will be reviewed. Particular attention will be paid to the potential for clinical impact in the coming decades, when such interventions are likely to be critically important.The review focuses on this problem from an interdisciplinary perspective, including basic science innovations and best practice in infectious disease. IntroductionOrthopaedic and trauma device-related infection (ODRI) remains a major complication in modern trauma and orthopaedic surgery. 1 Despite best practice in medical and surgical management, neither prophylaxis nor treatment of ODRI is effective in all cases, and can lead to infections that negatively impact clinical outcome and significantly increase healthcare expenditure. 2 Pre-operative and correctly-timed prophylactic antibiotic intervention is mandatory for a majority of orthopaedic procedures. However, despite this, the incidence of infection following elective orthopaedic surgery is in the range of 0.7% to 4.2%, 3-7 while the incidence can be much higher in trauma cases where infection rates range from approximately 1% after operative fixation of closed low-energy fractures, to more than 30% in complex open tibia fractures. 8,9 Treatment success rates vary, with between 57% and 88% often reported. [10][11][12] Current curative approaches (radical debridement, revision surgery and prolonged antibiotic therapy) often result in significant socioeconomic costs, not to mention the risk of life-long functional impairment for the patient. Against this background, and with the increasing issue of antibiotic-resistant bacteria, the problem of ODRI is set to continue to pose a challenge for practising clinicians in the coming decades. The clinical and microbiological challenges of modern device-related infectionsThe most prevalent species in ODRIs are Staphylococci. [13][14][15][16][17] Staphylococcus (S.) aureus accounts for between 20% and 30% of cases of infection after fracture fixation and prosthetic joint infections (PJI), with coagulase-negative staphylococci (CoNS) accounting for 20%-40% of cases, [13][14][15][16] including small colony variants. 18 Other Gram-positive cocci including Streptococci (1%-10%) and Enterococci (3%-7%) are less frequently encountered. Infections caused by Gram-negative bacilli, including Pseudomonas aeruginosa and Enterobacteriaceae account for approximately 6%-17%, [13][14][15][16...

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