A humanized mouse model for investigating Staphylococcus aureus implant-associated infections (HuMouse)

AO Trauma
S Zeiter, F Moriarty

Background

Staphylococcus aureus, continues to be the leading cause of implant-associated osteomyelitis, including fracture related infections (FRI) and peri-prosthetic joint infection (PJI). To date, no vaccine for this important pathogen exists. As the unique specificity of S. aureus as a human pathogen becomes better understood, it seems that reliance on murine models to produce pre-clinical data presents many shortcomings and may have contributed to previous failures in vaccine development.

Humanized mice exhibit increased disease severity to S. aureus osteomyelitis induced sepsis. (D, F, H) demonstrates extensive osteolysis revealed by bone histology in huNSG. Brown & Brenn (B&B) staining (E, G, I) reveals numerous staphylococcal abscesses (SACs) formed in huNSG mice (red arrows). In sharp contrast, NSG and C57BL/6 WT mice exhibited fewer SACs and less osteolysis

 

Goal

Develop a humanized mouse model of osteomyelitis.

 

Results

Immunodeficient non-obese diabetic (NOD)–scid IL2Rγnull (NSG) mice are engrafted with human hematopoietic stem cells (HSC), and subjected to S. aureus transtibial implant-associated osteomyelitis.  Interestingly, we observed that humanized mice have: 1) increased weight loss, staphylococcal abscess colonies (SACs), and extensive osteolysis during MRSA infection, 2) increased S. aureus dissemination to distant organs, 3) more severe S. aureus bacteraemia resulting from osteomyelitis when human T-cell numbers are low. This study presents significant step towards an appropriate animal model for studying a human-specific pathogen such as S. aureus. 

  • Publication

    de Mesy Bentley KL, Galloway CA, Muthukrishnan G, Echternacht SR, Masters EA, Zeiter S, Schwarz EM, Leckenby JI. Emerging electron microscopy and 3D methodologies to interrogate Staphylococcus aureus osteomyelitis in murine models. J Orthop Res. 2021; epub. https://doi.org/10.1002/jor.24968

     

    Muthukrishnan G, Wallimann A, Rangel-Moreno J, de Mesy Bentley KL, Hildebrand M, Mys K, Kenney HM, Sumrall ET, Daiss JL, Zeiter S, Richards RG, Schwarz EM, Moriarty TF. Humanized mice exhibit exacerbated abscess formation and osteolysis during the establishment of implant-associated Staphylococcus aureus osteomyelitis. Front Immunol. 2021;12(809). https://doi.org/10.3389/fimmu.2021.651515

  • Presentation

    Sumrall E, Wallimann A, Hildebrand M, Zeiter S, Richards RG, Schwarz E, Moriarty TF, Muthukrishnan G. A humanized mouse model to exhibit Staphyloccocus aureus osteomyelitis. 2020 OBIC virtual (poster).

     

    de Mesy Bentley KL, Galloway CA, Muthukrishnan G, Echternacht SR, Masters EA, Zeiter S, Leckenby JI, Schwarz EM. Emerging methods for 3-dimensional volume interrogation of Staphylococcus aureus pathogenesis in the osteocyte canalicular network. 2021 ORS virtual (oral)

     
  • Partner

    Muthukrishnan G (PhD), University of Rochester, USA

    Schwarz E (Prof), University of Rochester, USA

    Daiss J (PhD), University of Rochester, USA

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