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.
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