IsdB antibody–mediated sepsis following S. aureus surgical site infection

Nishitani, Kohei; Ishikawa, Masahiro; Morita, Yoshifumi; Yokogawa, Noriaki; Xie, Chao; Bentley, Karen L. de Mesy; Ito, Hiromu; Kates, Stephen L.; Daiss, John L; Schwarz, Edward M.

doi:10.1172/jci.insight.141164

Cited by 27 publications

(51 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, the authors noted that huNSG mice required 10-100-fold fewer bacteria to have analogous pathology in the non-humanized mice ( 41 ). In our model, it is conceivable that the more severe infection phenotype in huNSG mice could be the result of higher bacterial inoculum that we routinely use for achieving reproducible implant-associated osteomyelitis in C57BL/6 mice ( 22 , 23 , 43 , 44 , 55 ). Nonetheless, this critical finding needs to be carefully examined in our humanized mouse model of implant-associated osteomyelitis.…”

Section: Discussionmentioning

confidence: 99%

“…Murine models have greatly facilitated our understanding of S. aureus pathogenesis and identified critical virulence factors such as staphylococcal protein A, iron-scavenging proteins, fibrinogen binding proteins, penicillin-binding proteins, hemolysins, autolysins, etc. ( 13 – 23 ). However, the knowledge acquired using these murine models does not necessarily translate into these targets becoming useful vaccine candidates in humans.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Humanized Mice Exhibit Exacerbated Abscess Formation and Osteolysis During the Establishment of Implant-Associated Staphylococcus aureus Osteomyelitis

et al. 2021

Self Cite

View full text Add to dashboard Cite

Staphylococcus aureus is the predominant pathogen causing osteomyelitis. Unfortunately, no immunotherapy exists to treat these very challenging and costly infections despite decades of research, and numerous vaccine failures in clinical trials. This lack of success can partially be attributed to an overreliance on murine models where the immune correlates of protection often diverge from that of humans. Moreover, S. aureus secretes numerous immunotoxins with unique tropism to human leukocytes, which compromises the targeting of immune cells in murine models. To study the response of human immune cells during chronic S. aureus bone infections, we engrafted non-obese diabetic (NOD)–scid IL2Rγnull (NSG) mice with human hematopoietic stem cells (huNSG) and analyzed protection in an established model of implant-associated osteomyelitis. The results showed that huNSG mice have increases in weight loss, osteolysis, bacterial dissemination to internal organs, and numbers of Staphylococcal abscess communities (SACs), during the establishment of implant-associated MRSA osteomyelitis compared to NSG controls (p < 0.05). Flow cytometry and immunohistochemistry demonstrated greater human T cell numbers in infected versus uninfected huNSG mice (p < 0.05), and that T-bet+ human T cells clustered around the SACs, suggesting S. aureus-mediated activation and proliferation of human T cells in the infected bone. Collectively, these proof-of-concept studies underscore the utility of huNSG mice for studying an aggressive form of S. aureus osteomyelitis, which is more akin to that seen in humans. We have also established an experimental system to investigate the contribution of specific human T cells in controlling S. aureus infection and dissemination.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Humanized Mice Exhibit Exacerbated Abscess Formation and Osteolysis During the Establishment of Implant-Associated Staphylococcus aureus Osteomyelitis

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Methicillin-resistant S. aureus (USA300 LAC) was used for all in vitro experiments, and a bioluminescent strain of USA300 (USA300 LAC::lux) was used for all in vivo experiments as previously described [32–34, 36, 59].…”

Section: Methodsmentioning

confidence: 99%

“…C57BL/6 and IL-27Rα deficient mice (IL-27Rα −/− ) in the C57BL/6 background used in the study were purchased from Jackson Laboratories and maintained at the University of Rochester animal facilities. All in vivo S. aureus challenge experiments in mice utilized our well-validated transtibial implant-associated osteomyelitis model [32–34, 36, 59]. Briefly, L-shaped stainless-steel implant was contaminated with USA300 LAC (5.0 × 10 5 CFU/mL) grown overnight, and surgically implanted into the tibia of 8-week-old female C57BL/6 mice from the medial to the lateral side.…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, L-shaped stainless-steel implant was contaminated with USA300 LAC (5.0 × 10 5 CFU/mL) grown overnight, and surgically implanted into the tibia of 8-week-old female C57BL/6 mice from the medial to the lateral side. Longitudinal body weight change and bioluminescent intensity at infection site were evaluated, and terminal assessment of CFU (implant, surgical site soft tissue and tibia), peri-implant osteolysis (high-resolution μCT imaging), biofilm formation on the implant (Zeiss Auriga SEM imaging), and histopathology were performed on day 14 post-septic surgery as described previously [32–34, 36, 59]. Murine infection studies were performed three independent times, and the resulting data was pooled from these experiments.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Biphasic effects of IL-27 during Staphylococcus aureus implant-associated osteomyelitis in mice

Morita

Franchini

Owen

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Interleukin-27 is a pleiotropic cytokine whose reported functions during bacterial infections are debated as an area of active research. To address this, we investigated the role of IL-27 signaling during Staphylococcus aureus osteomyelitis. Clinically, we observed elevated serum IL-27 levels (20-fold higher, p<0.05) in patients with S. aureus osteomyelitis compared to uninfected patients undergoing elective total joint replacement. Remarkably, IL-27 serum levels immediately following septic death were 60-fold higher vs. uninfected patients (p<0.05), suggesting that IL-27 may be a biomarker of end-stage infection and/or cytokine storm. To test this, we hypothesized that IL-27 mediates bacterial clearance during the acute phase of S. aureus osteomyelitis, and subsequently suppresses inflammation to prevent cytokine storm and osteolysis during chronic infection. In mice, we observed that systemic IL-27 delivery by a recombinant adeno-associated viral vector (rAAV-IL-27) ameliorates surgical site soft tissue infection and peri-implant bone loss during the establishment of implant-associated S. aureus osteomyelitis. This effect was not observed in IL-27 receptor α knock-out mice, suggesting a direct role of IL-27/IL-27R signaling on immune and bone cell functions. Examination of IL-27-mediated immune responses via transcriptome analyses of infected tibiae demonstrated that IL-27 is a biphasic cytokine with IL-27/IL-27R activating immunostimulatory responses including Th17, IL-2, TLR, and iNOS signaling early, and subsequently suppressing these pathways during chronic infection. Ex vivo confirmation using murine macrophages revealed that IL-27 co-stimulates TLR signaling to increase the production of nitric oxide, and immunomodulatory cytokines such as IL-10, IL-21, IL-31, and TNF-β, but is not a chemokine.

show abstract

Immune Response to Persistent Staphyloccocus Aureus Periprosthetic Joint Infection in a Mouse Tibial Implant Model

Sokhi

Xia

Sosa

et al. 2020

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

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.

show abstract

IsdB antibody–mediated sepsis following S. aureus surgical site infection

Cited by 27 publications

References 50 publications

Humanized Mice Exhibit Exacerbated Abscess Formation and Osteolysis During the Establishment of Implant-Associated Staphylococcus aureus Osteomyelitis

Humanized Mice Exhibit Exacerbated Abscess Formation and Osteolysis During the Establishment of Implant-Associated Staphylococcus aureus Osteomyelitis

Biphasic effects of IL-27 during Staphylococcus aureus implant-associated osteomyelitis in mice

Immune Response to Persistent Staphyloccocus Aureus Periprosthetic Joint Infection in a Mouse Tibial Implant Model

Contact Info

Product

Resources

About