Monitoring immune responses in a mouse model of fracture fixation with and without Staphylococcus aureus osteomyelitis

Rochford, Edward T.J.; Sabaté‐Brescó, Marina; Zeiter, Stephan; Kluge, Katharina; Poulsson, Alexandra H.C.; Ziegler, Mario; Richards, R. Geoff; O’Mahony, Liam; Moriarty, T. Fintan

doi:10.1016/j.bone.2015.10.014

Cited by 48 publications

(54 citation statements)

References 39 publications

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“…In terms of S. aureus biofilm infection, some models utilize a large infectious inoculum or introduce implants that are precoated with bacteria (30)(31)(32)(33)(34)(35)(36). A high-challenge dose, particularly in a confined space such as the joint/bone, would be predicted to elicit a vigorous proinflammatory cascade that could likely alter the course of the resultant immune response and bacterial survival.…”

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confidence: 99%

Infectious Dose Dictates the Host Response during Staphylococcus aureus Orthopedic-Implant Biofilm Infection

Vidlak

Kielian

2016

Infect Immun

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Staphylococcus aureus is a leading cause of prosthetic joint infections (PJIs) that are typified by biofilm formation. Given the diversity of S. aureus strains and their propensity to cause community-or hospital-acquired infections, we investigated whether the immune response and biofilm growth during PJI were conserved among distinct S. aureus clinical isolates. Three S. aureus strains representing USA200 (UAMS-1), USA300 (LAC), and USA400 (MW2) lineages were equally effective at biofilm formation in a mouse model of PJI and elicited similar leukocyte infiltrates and cytokine/chemokine profiles. Another factor that may influence the course of PJI is infectious dose. In particular, higher bacterial inocula could accelerate biofilm formation and alter the immune response, making it difficult to discern underlying pathophysiological mechanisms. To address this issue, we compared the effects of two bacterial doses (10 3 or 10 5 CFU) on inflammatory responses in interleukin-12p40 (IL-12p40) knockout mice that were previously shown to have reduced myeloid-derived suppressor cell recruitment concomitant with bacterial clearance after low-dose challenge (10 3 CFU). Increasing the infectious dose of LAC to 10 5 CFU negated these differences in IL-12p40 knockout animals, demonstrating the importance of bacterial inoculum on infection outcome. Collectively, these observations highlight the importance of considering infectious dose when assessing immune responsiveness, whereas biofilm formation during PJI is conserved among clinical isolates commonly used in mouse S. aureus infection models.

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confidence: 99%

Infectious Dose Dictates the Host Response during Staphylococcus aureus Orthopedic-Implant Biofilm Infection

Vidlak

Kielian

2016

Infect Immun

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“…This indicates that poor Th1 cell development in BAIs may be responsible for inefficient S. epidermidis clearance. On the other hand, Th1/Th17 cell responses seem ineffective in the clearance of S. aureus murine prostheticimplant infections, whereas Th2 and regulatory T cell responses protect from the inflammation (Prabhakara et al, 2011;Rochford et al, 2016). These studies indicate that, in mice, the combination of staphylococci and a biomaterial can influence Th cell responses in favour of staphylococcal infection.…”

Section: Immune Responses To Staphylococci and Biomaterialsmentioning

confidence: 90%

“…Sensing of biomaterials by DCs is thought to be mediated by DC pattern recognition receptors, such as toll-like receptors (TLRs) and integrins (Rogers and Babensee, 2011;Shokouhi et al, 2010). These receptors may recognise structures in the layer of host proteins, which absorb to the biomaterial surface upon implantation, or may sense the biomaterial surface directly (Rogers and Babensee, 2011;Shokouhi et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…These receptors may recognise structures in the layer of host proteins, which absorb to the biomaterial surface upon implantation, or may sense the biomaterial surface directly (Rogers and Babensee, 2011;Shokouhi et al, 2010). Variations in the absorbed protein layer depending on biomaterial chemical characteristics such as hydrophobicity, will influence recognition by DC receptors and subsequent DC activation (Shankar et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

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Poly(trimethylene carbonate) and poly(D,L-lactic acid) modify human dendritic cell responses to staphylococci but do not affect Th1 and Th2 cell development

Balraadjsing

Jong

Grijpma

et al. 2018

eCM

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Biomaterial-associated infections (BAIs) are frequent complications in the use of medical devices (biomaterials) correlated with considerable patient discomfort and high treatment costs. The presence of a biomaterial in the host causes derangement of local immune responses increasing susceptibility to infection. Dendritic cells (DCs) have an important role in directing the nature of immune responses by activating and controlling CD4 + T helper (Th) cell responses. To assess the immunomodulatory effect of the combined presence of biomaterials and Staphylococcus aureus (S. aureus) or Staphylococcus epidermidis (S. epidermidis), DC-mediated T cell proliferation and Th1/Th2 cell development were measured using an in vitro human cell system. Poly(trimethylene carbonate) (PTMC) and poly(D,L-lactic acid) (PDLLA) modified the production of the DC pro-inflammatory cytokines TNF-α, IL-6 and IL-23 in response to S. aureus and S. epidermidis. However, this modified cytokine production did not cause differences in Th1/Th2 cell polarisation, showing a Th1 cell predominance. In the absence of staphylococci, neither of the biomaterials induced DC-mediated T cell proliferation or Th1/Th2 cell polarisation. Moreover, either in the absence or presence of the biomaterials, S. aureus was a more potent inducer of DC cytokine secretion, T cell proliferation and Th1 cell development than S. epidermidis. In conclusion, although PTMC and PDLLA modulated DC cytokine responses to staphylococci, this did not alter the resulting Th cell development. This result suggested that, in this human cell model, Th1/Th2 cell responses were mainly determined by the species of bacteria and that PTMC or PDLLA did not detectably influence these responses.

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“…A few preclinical experimental studies (Friedrich and Klaue, 1977;Merritt and Dowd, 1987;Rittman and Perren, 1974;Worlock et al, 1994) provide supportive evidence for the association between stable fixation and reduced infection risk. However, there is poor standardisation of the stability of the fractures within these models and no studies to date have investigated this phenomenon for S. epidermidis FRI. S. aureus FRI has been intensively studied in both clinical and basic science, with numerous preclinical in vivo models available (Arens et al, 2015;Lindsey et al, 2010;Robinson et al, 2011;Rochford et al, 2016;Windolf et al, 2013;Worlock et al, 1988). However, the literature describing S. epidermidis FRI is comparatively scarce and fewer in vivo preclinical models are available (Lovati et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Influence of fracture stability on Staphylococcus epidermidis and Staphylococcus aureus infection in a murine femoral fracture model

Sabaté‐Brescó¹,

O’Mahony²,

Zeiter

et al. 2017

eCM

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Fracture-related infection (FRI) is a major complication in surgically fixed fractures. Instability of the fracture after fixation is considered a risk factor for infection; however, few experimental data are available confirming this belief. To study whether stable fractures led to higher infection clearance, mouse femoral osteotomies were fixed with either stable or unstable fixation and the surgical site was contaminated with either Staphylococcus epidermidis (S. epidermidis) or Staphylococcus aureus (S. aureus) clinical isolates. Infection progression was assessed at different time points by quantitative bacteriology, total cell counts in spleen and lymph node and histological analysis. Operated, non-inoculated mice were used as controls. Two inbred mouse strains (C57BL/6 and BALB/c) were included in the study to determine the influence of different host background in the outcome.Stable fixation allowed a higher proportion of C57BL/6 mice to clear S. epidermidis inoculation in comparison to unstable fixation. No difference associated with fixation type was observed for BALB/c mice. Inoculation with S. aureus resulted in a more severe infection for both stable and unstable fractures in both mouse strains; however, significant osteolysis around the screws rendered the stable group functionally unstable.Our results suggested that fracture stability could have an influence on S. epidermidis infection, although host factors also played a role. No differences were observed when using S. aureus, due to a more severe infection, leading to osteolysis and loss of stability in both groups. Further studies are required in order to address the biological features underlying the differences observed.

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Monitoring immune responses in a mouse model of fracture fixation with and without Staphylococcus aureus osteomyelitis

Cited by 48 publications

References 39 publications

Infectious Dose Dictates the Host Response during Staphylococcus aureus Orthopedic-Implant Biofilm Infection

Infectious Dose Dictates the Host Response during Staphylococcus aureus Orthopedic-Implant Biofilm Infection

Poly(trimethylene carbonate) and poly(D,L-lactic acid) modify human dendritic cell responses to staphylococci but do not affect Th1 and Th2 cell development

Influence of fracture stability on Staphylococcus epidermidis and Staphylococcus aureus infection in a murine femoral fracture model

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