Staphylococcus aureus is prevalent in surgical site infections (SSI) and leads to death in approximately 1% of patients. Phase IIB/III clinical trial results have demonstrated that vaccination against the iron-regulated surface determinant protein B (IsdB) is associated with an increased mortality rate in patients with SSI. Thus, we hypothesized that S . aureus induces nonneutralizing anti-IsdB antibodies, which facilitate bacterial entry into leukocytes to generate “Trojan horse” leukocytes that disseminate the pathogen. Since hemoglobin (Hb) is the primary target of IsdB, and abundant Hb-haptoglobin (Hb-Hp) complexes in bleeding surgical wounds are normally cleared via CD163-mediated endocytosis by macrophages, we investigated this mechanism in vitro and in vivo. Our results demonstrate that active and passive IsdB immunization of mice renders them susceptible to sepsis following SSI. We also found that a multimolecular complex containing S . aureus protein A–anti-IsdB–IsdB–Hb-Hp mediates CD163-dependent bacterial internalization of macrophages in vitro. Moreover, IsdB-immunized CD163 ^–/– mice are resistant to sepsis following S . aureus SSI, as are normal healthy mice given anti-CD163–neutralizing antibodies. These genetic and biologic CD163 deficiencies did not exacerbate local infection. Thus, anti-IsdB antibodies are a risk factor for S . aureus sepsis following SSI, and disruption of the multimolecular complex and/or CD163 blockade may intervene.

Peripheral helper T (T _PH ) cells can play pathogenic roles in human autoimmune diseases. T _PH cells are proposed to be the major B cell helpers in inflamed joints in rheumatoid arthritis (RA), but whether and how T _PH cells are engaged in tissue inflammation remains unclear. We demonstrate that T _PH cells comprise two subsets in RA: stem-like T _PH (S-T _PH ) and effector T _PH (E-T _PH ) cells. These two subsets differed in transcriptome, epigenome, B cell helper capacity, spatial localization, and cell interactions. S-T _PH cells displayed self-renewal capacity and were mainly found within tertiary lymphoid structures (TLSs) in synovial tissue together with B cells. S-T _PH cells potently induced B cells to produce immunoglobulins. By contrast, E-T _PH cells expressed effector molecules and colocalized with proinflammatory macrophages and CD8 ⁺ T cells outside TLSs. S-T _PH cells could differentiate into E-T _PH cells upon TCR stimulation and coculture with B cells. Collectively, our study shows that S-T _PH cells play a central role in promoting T _PH responses by undergoing self-renewal and seeding E-T _PH cells.

The use of local antibiotics to treat bone infections has been questioned due to a lack of clinical efficacy and emerging information about Staphylococcus aureus colonization of the osteocyte-lacuno canalicular network (OLCN). Here we propose bisphosphonate-conjugated antibiotics (BCA) using a “target and release” approach to deliver antibiotics to bone infection sites. A fluorescent bisphosphonate probe was used to demonstrate bone surface labeling adjacent to bacteria in a S. aureus infected mouse tibiae model. Bisphosphonate and hydroxybisphosphonate conjugates of sitafloxacin and tedizolid (BCA) were synthesized using hydroxyphenyl and aminophenyl carbamate linkers, respectively. The conjugates were adequately stable in serum. Their cytolytic activity versus parent drug on MSSA and MRSA static biofilms grown on hydroxyapatite discs was established by scanning electron microscopy. Sitafloxacin O-phenyl carbamate BCA was effective in eradicating static biofilm: no colony formation units (CFU) were recovered following treatment with 800 mg/L of either the bisphosphonate or α-hydroxybisphosphonate conjugated drug (p < 0.001). In contrast, the less labile tedizolid N-phenyl carbamate linked BCA had limited efficacy against MSSA, and MRSA. CFU were recovered from all tedizolid BCA treatments. These results demonstrate the feasibility of BCA eradication of S. aureus biofilm on OLCN bone surfaces and support in vivo drug development of a sitafloxacin BCA.

Human CD4 ⁺ T cells play a central role in the pathogenesis of autoimmune diseases, but their immunoregulatory mechanisms driving pathogenesis remain to be elucidated. We show that human T peripheral helper cells (T _PH cells) regulate peripheral immune responses via insulin-like growth factor–like family member 2 (IGFL2), an inflammatory factor found exclusively in primates. Single-cell RNA sequencing of seropositive rheumatoid arthritis (RA) synovium showed that IGFL2 is specifically expressed by CD4 ⁺ T cells, predominantly T _PH cells. IGFL2 promotes transforming growth factor–β–induced CXCL13 production in CD4 ⁺ T cells, activates nuclear factor κB signaling, and induces monocyte gene signatures like those of pathogenic macrophages. CRISPR-Cas9 knockout of IGFL2 in synovial T _PH cells suppressed this gene signature in cocultured monocytes. Blood IGFL2 protein levels correlated with RA disease severity and could be used as a potential biomarker. These findings highlight the involvement of IGFL2 in RA pathogenesis, emphasizing how human T _PH cells regulate local immune responses via IGFL2.

Several concepts may be used to restore normal knee kinematics after total knee arthroplasty. One is a kinematically aligned (KA) technique, which restores the native joint line and limb alignment, and the other is the use of a medial pivot knee (MPK) design, with a ball and socket joint in the medial compartment. This study aimed to compare motions, contact forces, and contact stress between mechanically aligned (MA) and KA (medial tilt 3° [KA3] and 5° [KA5]) models in MPK. An MPK design was virtually implanted with MA, KA3, and KA5 in a validated musculoskeletal computer model of a healthy knee, and the simulation of motion and contact forces was implemented. Anteroposterior (AP) positions, mediolateral positions, external rotation angles of the femoral component relative to the tibial insert, and tibiofemoral contact forces were evaluated at different knee flexion angles. Contact stresses on the tibial insert were calculated using finite element analysis. The AP position at the medial compartment was consistent for all models. From 0° to 120°, the femoral component in KA models showed larger posterior movement at the lateral compartment (0.3, 6.8, and 17.7 mm in MA, KA3, and KA5 models, respectively) and larger external rotation (4.2°, 12.0°, and 16.8° in the MA, KA3, and KA5 models, respectively) relative to the tibial component. Concerning the mediolateral position of the femoral component, the KA5 model was positioned more medially. The contact forces at the lateral compartment of all models were larger than those at the medial compartment at >60° of knee flexion. The peak contact stresses on the tibiofemoral joint at 90° and 120° of knee flexion were higher in the KA models. However, the peak contact stresses of the KA models at every flexion angle were <20 MPa. The KA technique in MPK can successfully achieve near-normal knee kinematics; however, there may be a concern for higher contact stresses on the tibial insert.