Staphylococcus aureus Panton-Valentine Leukocidin worsens acute implant-associated osteomyelitis in humanized BRGSF mice

Author:

Hofstee Marloes I123,Siverino Claudia1,Saito Motoo45,Meghwani Himanshu45,Tapia-Dean James1,Arveladze Samson1,Hildebrand Maria1,Rangel-Moreno Javier67,Riool Martijn238,Zeiter Stephan1,Zaat Sebastian A J23,Moriarty T Fintan1,Muthukrishnan Gowrishankar459ORCID

Affiliation:

1. AO Research Institute Davos , 7270 Davos , Switzerland

2. Department of Medical Microbiology and Infection Prevention , Amsterdam UMC, Amsterdam institute for Infection and Immunity, , 1105 AZ Amsterdam , The Netherlands

3. University of Amsterdam , Amsterdam UMC, Amsterdam institute for Infection and Immunity, , 1105 AZ Amsterdam , The Netherlands

4. Center for Musculoskeletal Research, University of Rochester Medical Center , Rochester, NY 14642 , United States

5. Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center , Rochester, NY 14618 , United States

6. Division of Allergy , Immunology and Rheumatology, Department of Medicine, , Rochester, NY 14620 , United States

7. University of Rochester Medical Center , Immunology and Rheumatology, Department of Medicine, , Rochester, NY 14620 , United States

8. Department of Trauma Surgery, University Hospital Regensburg , 93053 Regensburg , Germany

9. Department of Microbiology and Immunology, University of Rochester Medical Center , Rochester, NY 14642 , United States

Abstract

Abstract Staphylococcus aureus is the most common pathogen that causes implant-associated osteomyelitis, a clinically incurable disease. Immune evasion of S. aureus relies on various mechanisms to survive within the bone niche, including the secretion of leukotoxins such as Panton-Valentine leukocidin (PVL). PVL is a pore-forming toxin exhibiting selective human tropism for C5a receptors (C5aR1 and C5aR2) and CD45 on neutrophils, monocytes, and macrophages. PVL is an important virulence determinant in lung, skin and soft tissue infections. The involvement of PVL in S. aureus pathogenesis during bone infections has not been studied extensively yet. To investigate this, humanized BALB/c Rag2−/−Il2rg−/−SirpaNODFlk2−/− (huBRGSF) mice were subjected to transtibial implant-associated osteomyelitis with community-acquired methicillin-resistant S. aureus (CA-MRSA) USA300 wild type strain (WT), an isogenic mutant lacking lukF/S-PV (Δpvl), or complemented mutant (Δpvl+pvl). Three days post-surgery, Δpvl-infected huBRGSF mice had a less severe infection compared to WT-infected animals as characterized by 1) improved clinical outcomes, 2) lower ex vivo bacterial bone burden, 3) absence of staphylococcal abscess communities (SACs) in their bone marrow, and 4) compromised MRSA dissemination to internal organs (liver, kidney, spleen, heart). Interestingly, Δpvl-infected huBRGSF mice had fewer human myeloid cells, neutrophils, and HLA-DR+ monocytes in the bone niche compared to WT-infected animals. Expectedly, a smaller fraction of human myeloid cells were apoptotic in the Δpvl-infected huBRGSF animals. Taken together, our study highlights the pivotal role of PVL during acute implant-associated osteomyelitis in humanized mice.

Funder

Swiss National Science Foundation

URMC University Research Award

NIH NIAID

NIH NIAMS

Publisher

Oxford University Press (OUP)

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