RANKL-mediated osteoclast formation is required for bone loss in a murine model of Staphylococcus aureus osteomyelitis

Campbell, Mara J.; Bustamante-Gomez, Cecile; Fu, Qiang; Beenken, Karen E.; Reyes-Pardo, Humberto; Smeltzer, Mark S.; O'Brien, Charles A.

doi:10.1016/j.bone.2024.117181

Bone

2024

DOI: 10.1016/j.bone.2024.117181

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RANKL-mediated osteoclast formation is required for bone loss in a murine model of Staphylococcus aureus osteomyelitis

Mara J. Campbell,

Cecile Bustamante-Gomez,

Qiang Fu

et al.

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2024

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Cited by 3 publications

References 35 publications

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Can bone SPECT/CT determine optimal sites for microbiological identification in post-traumatic or chronic osteomyelitis of extremities?

Lee,

Kim,

Jeon

2024

Injury

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Can bone SPECT/CT determine optimal sites for microbiological identification in post-traumatic or chronic osteomyelitis of extremities?

Lee,

Kim,

Jeon

2024

Injury

View full text Add to dashboard Cite

The ability of sarA to limit protease production plays a key role in the pathogenesis of Staphylococcus aureus osteomyelitis irrespective of the functional status of agr

Beenken,

Campbell,

Smeltzer

2024

Infect Immun

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We demonstrate that mutation of the staphylococcal accessory regulator A ( sarA ) in the USA300 strain LAC limits virulence in a murine osteomyelitis model to a greater extent than mutation of the accessory gene regulator ( agr ) and that it does so irrespective of the functional status of agr . Protease production was decreased in the agr mutant but increased in sarA and sarA/agr mutants to a degree that limited biofilm formation. Extracellular protein A (eSpa) and full-length extracellular nuclease (Nuc1) were absent in the conditioned medium (CM) from sarA and sarA / agr mutants, and their abundance was restored in both mutants by eliminating protease production. Cytotoxicity of CM for osteoblasts and osteoclasts was also reduced in both mutants. Cytotoxicity was restored in a protease-deficient sarA mutant but not in the protease-deficient sarA / agr mutant. Reduced cytotoxicity was correlated with the reduced abundance of full-length α-toxin, LukF, and LukS in sarA and sarA / agr mutants. The abundance of these toxins in their full-length form was increased in the protease-deficient sarA mutant by comparison to LAC, demonstrating that mutation of sarA increases the production of these toxins but increased protease production limits their abundance in full-length and presumably functional forms. Most importantly, eliminating protease production enhanced the virulence of sarA and sarA/agr mutants, but had no impact in the agr mutant. We conclude that a key factor in the attenuation of LAC sarA and sarA / agr mutants in osteomyelitis is the increased production of extracellular proteases and its impact on virulence factors that contribute to biofilm formation and cytotoxicity. IMPORTANCE The persistent emergence of antibiotic-resistant strains has rekindled interest in anti-virulence strategies to combat S. aureus infections. Numerous reports describe anti-virulence strategies focusing on key regulatory elements that globally influence virulence factor production, the two most commonly targeted being the accessory gene regulator ( agr ) and the staphylococcal accessory regulator A ( sarA ). We demonstrate that mutation of sarA limits virulence to a greater extent than mutation of agr and that this can be attributed to increased protease production in both sarA and sarA / agr mutants. This illustrates the critical role of sarA in protease-mediated post-translational regulation in S. aureus . It also suggests that an inhibitor of sarA would be more effective than an inhibitor of agr in overcoming the therapeutic recalcitrance of osteomyelitis and that such an inhibitor would remain effective even in the context of agr mutants known to arise in vivo during the transition from acute to chronic infection.

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Genomic Insights into Host Susceptibility to Periprosthetic Joint Infections: A Comprehensive Literature Review

Lizcano,

Visperas,

Piuzzi

et al. 2024

Microorganisms

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Periprosthetic joint infection (PJI) is a multifactorial disease, and the risk of contracting infection is determined by the complex interplays between environmental and host-related factors. While research has shown that certain individuals may have a genetic predisposition for PJI, the existing literature is scarce, and the heterogeneity in the assessed genes limits its clinical applicability. Our review on genetic susceptibility for PJI has the following two objectives: (1) Explore the potential risk of developing PJI based on specific genetic polymorphisms or allelic variations; and (2) Characterize the regulatory cascades involved in the risk of developing PJI. This review focused on clinical studies investigating the association between genetic mutations or variations with the development of PJI. The genes investigated in these studies included toll-like receptors and humoral pattern recognition molecules, cytokines, chemokines, mannose-binding lectin (MBL), bone metabolism molecules, and human leukocyte antigen. Among these genes, polymorphisms in IL-1, MBL, vitamin D receptors, HLA-C, and HLA-DQ might have a relevant impact on the development of PJI. The literature surrounding this topic is limited, but emerging transcriptomic and genome-wide association studies hold promise for identifying at-risk genes. This advancement could pave the way for incorporating genetic testing into preoperative risk stratification, enhancing personalized patient care.

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RANKL-mediated osteoclast formation is required for bone loss in a murine model of Staphylococcus aureus osteomyelitis

Cited by 3 publications

References 35 publications

Can bone SPECT/CT determine optimal sites for microbiological identification in post-traumatic or chronic osteomyelitis of extremities?

Can bone SPECT/CT determine optimal sites for microbiological identification in post-traumatic or chronic osteomyelitis of extremities?

The ability of sarA to limit protease production plays a key role in the pathogenesis of Staphylococcus aureus osteomyelitis irrespective of the functional status of agr

Genomic Insights into Host Susceptibility to Periprosthetic Joint Infections: A Comprehensive Literature Review

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