Staphylococcus aureus β-Toxin Exerts Anti-angiogenic Effects by Inhibiting Re-endothelialization and Neovessel Formation.
Staphylococcus aureus β-Toxin Exerts Anti-angiogenic Effects by Inhibiting Re-endothelialization and Neovessel Formation.
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DOI：
10.3389/fmicb.2022.840236
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发表时间：
2022
影响因子：
5.2
通讯作者：
Salgado-Pabón W
中科院分区：
文献类型：
--
作者：
Tran PM;Tang SS;Salgado-Pabón W
金黄色葡萄球菌引起严重的、危及生命的感染，这些感染通常并发严重的局部和全身性病理，具有不愈合的病变。一个典型的例子是S。金黄色葡萄球菌感染性心内膜炎（IE），其中分泌的溶血素β-毒素通过其鞘磷脂酶和生物膜连接酶活性增强疾病。尽管这些活性使人主动脉内皮细胞活化失调，但β-毒素对伤口愈合中内皮细胞功能的影响尚未得到解决。通过使用离体兔主动脉环模型，我们提供了β-毒素阻止分支微血管形成的证据，突出了其干扰组织血管重建和血管修复的能力。我们发现β毒素特异性靶向人主动脉内皮细胞增殖和细胞迁移，并抑制人脐静脉内皮细胞重排成毛细血管样网络。血管生成相关分子特异性蛋白质组阵列提供的证据表明，β-毒素促进内皮细胞单层中的抑制特性，特异性靶向TIMP-1、TIMP-4和IGFBP-3的产生，以对抗促血管生成环境的作用。已知这些分子产生中的失调会导致发芽缺陷（包括细胞增殖、迁移和存活缺陷）、血管不稳定和/或血管退化。当内皮细胞在再内皮化/伤口愈合条件下生长时，β-毒素降低促血管生成分子MMP-8并增加抗血管生成分子内皮抑制素。总之，这些数据表明β-毒素是一种抗血管生成的毒力因子，并强调了β-毒素加重S.金黄色葡萄球菌侵袭性感染，通过干扰组织再血管化和血管修复。
Staphylococcus aureus causes severe, life-threatening infections that often are complicated by severe local and systemic pathologies with non-healing lesions. A classic example is S. aureus infective endocarditis (IE), where the secreted hemolysin β-toxin potentiates the disease via its sphingomyelinase and biofilm ligase activities. Although these activities dysregulate human aortic endothelial cell activation, β-toxin effect on endothelial cell function in wound healing has not been addressed. With the use of the ex vivo rabbit aortic ring model, we provide evidence that β-toxin prevents branching microvessel formation, highlighting its ability to interfere with tissue re-vascularization and vascular repair. We show that β-toxin specifically targets both human aortic endothelial cell proliferation and cell migration and inhibits human umbilical vein endothelial cell rearrangement into capillary-like networks in vitro. Proteome arrays specific for angiogenesis-related molecules provided evidence that β-toxin promotes an inhibitory profile in endothelial cell monolayers, specifically targeting production of TIMP-1, TIMP-4, and IGFBP-3 to counter the effect of a pro-angiogenic environment. Dysregulation in the production of these molecules is known to result in sprouting defects (including deficient cell proliferation, migration, and survival), vessel instability and/or vascular regression. When endothelial cells are grown under re-endothelialization/wound healing conditions, β-toxin decreases the pro-angiogenic molecule MMP-8 and increases the anti-angiogenic molecule endostatin. Altogether, the data indicate that β-toxin is an anti-angiogenic virulence factor and highlight a mechanism where β-toxin exacerbates S. aureus invasive infections by interfering with tissue re-vascularization and vascular repair.
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影响因子：
10.8
作者：
Fang, Changcun;Wen, Guanmei;Xiao, Qingzhong
通讯作者：
Xiao, Qingzhong
影响因子：
5.6
作者：
Cabral-Pacheco GA;Garza-Veloz I;Castruita-De la Rosa C;Ramirez-Acuña JM;Perez-Romero BA;Guerrero-Rodriguez JF;Martinez-Avila N;Martinez-Fierro ML
通讯作者：
Martinez-Fierro ML
影响因子：
11.8
作者：
Demaria, Marco;Ohtani, Naoko;Youssef, Sameh A.;Rodier, Francis;Toussaint, Wendy;Mitchell, James R.;Laberge, Remi-Martin;Vijg, Jan;Van Steeg, Harry;Dolle, Martijn E. T.;Hoeijmakers, Jan H. J.;de Bruin, Alain;Hara, Eiji;Campisi, Judith
通讯作者：
Campisi, Judith
影响因子：
7.3
作者：
Brown AF;Leech JM;Rogers TR;McLoughlin RM
通讯作者：
McLoughlin RM
影响因子：
4.2
作者：
Barron, Gemma A.;Goua, Marie;Bermano, Giovanna
通讯作者：
Bermano, Giovanna