金黄色葡萄球菌潘通-瓦伦丁白细胞介素会加重人源化 BRGSF 小鼠急性植入物相关骨髓炎的病情

IF 3.4 Q2 ENDOCRINOLOGY & METABOLISM JBMR Plus Pub Date : 2024-01-04 DOI:10.1093/jbmrpl/ziad005
Marloes I. Hofstee, C. Siverino, Motoo Saito, Himanshu Meghwani, James Tapia-Dean, Samson Arveladze, M. Hildebrand, Javier Rangel-Moreno, M. Riool, S. Zeiter, S. Zaat, T. F. Moriarty, G. Muthukrishnan
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引用次数: 0

摘要

金黄色葡萄球菌是导致植入相关骨髓炎的最常见病原体,这是一种临床上无法治愈的疾病。金黄色葡萄球菌依靠各种机制躲避免疫,以便在骨龛中生存,其中包括分泌白细胞毒素,如潘顿-瓦伦丁白细胞介素(PVL)。PVL 是一种孔隙形成毒素,对中性粒细胞、单核细胞和巨噬细胞上的 C5a 受体(C5aR1 和 C5aR2)具有选择性的人类趋附性。PVL 是肺部、皮肤和软组织感染的重要毒力决定因素。关于 PVL 在骨感染过程中参与金黄色葡萄球菌致病机理的研究尚未广泛开展。为了研究这个问题,我们用社区获得性耐甲氧西林金黄色葡萄球菌(CA-MRSA)USA300野生型菌株(WT)、缺乏lukF/S-PV的同源突变体(Δpvl)或互补突变体(Δpvl+pvl)对人源化BALB/c Rag2-/-Il2rg-/-SirpaNODFlk2-/-(huBRGSF)小鼠进行了经胫骨植入相关性骨髓炎试验。手术后三天,与 WT 感染的小鼠相比,Δpvl 感染的 huBRGSF 小鼠的感染程度较轻,其特点是:1)临床结果有所改善;2)体内外细菌骨负荷较低;3)骨髓中没有葡萄球菌脓肿群落(SAC);4)MRSA 向内脏(肝、肾、脾、心脏)的扩散受到影响。有趣的是,与 WT 感染的小鼠相比,Δpvl 感染的 huBRGSF 小鼠骨龛中的人类髓系细胞、中性粒细胞和 HLA-DR+ 单核细胞较少。因此,在感染了Δpvl 的 huBRGSF 动物中,凋亡的人髓系细胞的比例也较小。综上所述,我们的研究强调了 PVL 在人源化小鼠急性植入物相关骨髓炎中的关键作用。
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Staphylococcus aureus Panton-Valentine Leukocidin worsens acute implant-associated osteomyelitis in humanized BRGSF mice
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) 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 study 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.
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来源期刊
JBMR Plus
JBMR Plus Medicine-Orthopedics and Sports Medicine
CiteScore
5.80
自引率
2.60%
发文量
103
审稿时长
8 weeks
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