BRGSF-HIS: genOway’s mouse model to evaluate the pathogenesis of Staphylococcus aureus Panton-Valentine leukocidin in acute implant-associated osteomyelitis

10 min read
April 12, 2024

Hofstee et al. Staphylococcus aureus Panton-Valentine Leukocidin worsens acuteimplant-associated osteomyelitis in humanized BRGSF mice. JBMR Plus, 2024

Mouse models have been used to investigate the pathogenesis of Staphylococcus aureus infection.(1-2) Although they have proven extremely useful in determining the role of S. aureus virulence factors,(3-4) controversial results support the conclusion that the mouse lacks all the necessary components to truly translate S. aureus infection.(5-7) It has been described that some of the S. aureus virulence factors, such as Panton-Valentine leukocidin (PVL), are highly species-specific toward the human molecular counterpart that they target. Indeed, mouse neutrophils appear to be insensitive to the action of PVL.(8) In contrast, PVL can lyse human and rabbit innate immune cells.(9)

In this paper,(10) BRGSF-HIS, a mouse reconstituted with a human immune system which has functional lymphoid and myeloid compartments,(11) was used by the research team, led by scientist Gowrishankar Muthukrishnan, to evaluate the contribution of PVL to S. aureus pathogenicity during acute implant-associated osteomyelitis. To do so, S. aureus infection with the community-acquired methicillin-resistant WT strain was compared to the isogenic mutant lacking PVL strain and complemented mutant strain.

BRGSF-HIS mice infected with WT PVL strain had significantly higher global clinical evaluation scores, weight loss, load bearing on the operated leg, bacterial load in bone, soft tissue and peripheral organs, along with staphylococcal abscess communities (SAC) formation in bone marrow, as shown in the figures below.

BRGSF-HIS infected mice with the isogenic mutant lacking PVL had significantly better clinical outcomes, reduced bacterial load in peripheral organs, bone and soft tissue, and no staphylococcal abscess communities (SAC) formation in bone marrow compared to mice infected with WT strain.

More interestingly, S. aureus infection induced human myeloid cells recruitment, mainly neutrophils, to the bone niche in BRGSF-HIS. This is also observed in the higher recruitment of human CD45+ as well as a higher HLA-DR+ in monocytes/macrophages, as shown in the figures below. Increased dead cells were also accounted in the WT infection in the BRGSF-HIS mice, indicating a higher severity disease reproduced in the model. These results indicate that human myeloid cells are most likely required for S. aureus pathogenesis in humanized BRGSF-HIS mice.

Finally, WT-infected BRGSF-HIS mice had a higher concentration of human IL-6 and IL-8 in their serum, as depicted below, which potentially results from a higher S. aureus dissemination to other organs via the bloodstream than PVL mutant-infected mice.

The authors showed for the first time that Panton-Valentine leukocidin (PVL) contributes to S. aureus virulence during acute implant-associated osteomyelitis in a humanized BRGSF mouse model. In addition, the use of BRGSF-HIS mice might contribute to the prediction of anti-staphylococcal vaccine efficacy or therapy responsiveness.

The humanized BRGSF mouse model is available at genOway, designer and provider of multiple preclinical models in several research areas, including immuno-oncology, metabolism, cardiovascular diseases and neuroscience.


  1. Gristina AG. Biomaterial-centered infection: microbial adhesion versus tissue integration. Science (New York, NY). Sep 25, 1987;237(4822):1588-95. Epub 1987/09/25.
  2. Inzana JA, Schwarz EM, Kates SL, Awad HA. A novel murine model of established Staphylococcal bone infection in the presence of a fracture fixation plate to study therapies utilizing antibiotic-laden spacers after revision surgery. Bone. Mar 2015;72:128-36. Epub 2014/12/03.
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  4. Dohin B, Gillet Y, Kohler R, Lina G, Vandenesch F, Vanhems P, et al. Pediatric bone and joint infections caused by Panton-Valentine leukocidin-positive Staphylococcus aureus. The Pediatric Infectious Disease Journal. Nov 2007;26(11):1042-8. Epub 2007/11/07. 
  5. Kavanagh N, Ryan EJ, Widaa A, Sexton G, Fennell J, O'Rourke S, et al. Staphylococcal Osteomyelitis: Disease Progression, Treatment Challenges, and Future Directions. Clin Microbiol Rev. Apr 2018;31(2). Epub 2018/02/16.
  6. Bubeck Wardenburg J, Palazzolo-Ballance AM, Otto M, Schneewind O, DeLeo FR. Panton-Valentine leukocidin is not a virulence determinant in murine models of community associated methicillin-resistant Staphylococcus aureus disease. J Infect Dis. Oct 15 2008;198(8):1166-70. Epub 2008/08/30.
  7. Peyrani P, Allen M, Wiemken TL, Haque NZ, Zervos MJ, Ford KD, et al. Severity of disease and clinical outcomes in patients with hospital-acquired pneumonia due to methicillin-resistant Staphylococcus aureus strains not influenced by the presence of the Panton-Valentine leukocidin gene. Clin Infect Dis. Oct 2011;53(8):766-71. Epub 2011/09/02.
  8. Tromp AT, Van Gent M, Abrial P, Martin A, Jansen JP, De Haas CJC, et al. Human CD45 is an Fcomponent-specific receptor for the staphylococcal toxin Panton–Valentine leukocidin. Nature Microbiology. 2018/06/01 2018;3(6):708-17.
  9. Spaan AN, Henry T, van Rooijen WJM, Perret M, Badiou C, Aerts PC, et al. The staphylococcal toxin Panton-Valentine Leukocidin targets human C5a receptors. Cell Host Microbe. May 15, 2013;13(5):584-94. Epub 2013/05/21.
  10. Hofstee, Marloes I, Claudia Siverino, Motoo Saito, Himanshu Meghwani, James Tapia-Dean, Samson Arveladze, Maria Hildebrand, et al. “Staphylococcus Aureus Panton-Valentine Leukocidin Worsens Acute Implant-Associated Osteomyelitis in Humanized BRGSF Mice.” JBMR Plus 8, nᵒ 2 (2024/02/15).
  11. Labarthe, Laura, Soledad Henriquez, Olivier Lambotte, James P. Di Santo, Roger Le Grand, Françoise Pflumio, Marie-Laure Arcangeli, Nicolas Legrand, et Christine Bourgeois. “Frontline Science: Exhaustion and Senescence Marker Profiles on Human T Cells in BRGSF-A2 Humanized Mice Resemble Those in Human Samples.” Journal of Leukocyte Biology 107, nᵒ 1 (2020/01/01): 27‑42.

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