Increased Susceptibility of Humanized NSG Mice to Panton-Valentine Leukocidin and Staphylococcus aureus Skin Infection.
Increased Susceptibility of Humanized NSG Mice to Panton-Valentine Leukocidin and Staphylococcus aureus Skin Infection.
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DOI：
10.1371/journal.ppat.1005292
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发表时间：
2015
期刊：
影响因子：
6.7
通讯作者：
Liu GY
中科院分区：
文献类型：
--
作者：
Tseng CW;Biancotti JC;Berg BL;Gate D;Kolar SL;Müller S;Rodriguez MD;Rezai-Zadeh K;Fan X;Beenhouwer DO;Town T;Liu GY
金黄色葡萄球菌是全球皮肤和软组织感染的主要原因。小鼠是最常用于人类葡萄球菌感染建模的动物。然而，超生理S。需要金黄色葡萄球菌接种物来建立大体鼠皮肤病理学。此外，许多葡萄球菌因子，包括由社区相关耐甲氧西林葡萄球菌阐述的Panton-Valentine杀白细胞素（PVL）。金黄色葡萄球菌（CA-MRSA）表现出选择性的人向性，并且不能在小鼠中充分研究。为了克服这些缺陷，我们调查了S。在植入人CD 34+脐带血细胞的非肥胖糖尿病（NOD）/严重联合免疫缺陷（SCID）/IL 2 r γ缺失（NSG）小鼠中，观察金黄色葡萄球菌感染的小鼠模型。与对照小鼠相比，这些“人源化”NSG小鼠需要1至2个对数更低的接种物来诱导一致的皮肤损伤，并且在用PVL+感染时相对于用同基因PVL-S感染时表现出更大的皮肤损伤。金黄色。中性粒细胞似乎对PVL病理学很重要，因为将人中性粒细胞单独过继转移至NSG小鼠足以诱导PVL+ S攻毒后的皮肤坏死。金黄色葡萄球菌而不是PVL-S。金黄色。人C5 aR抑制剂PMX 53在体外阻断PVL诱导的细胞毒性，并减少PVL+和PVL- S诱导的病变尺寸差异。金黄色葡萄球菌，但PMX 53也减少了中性粒细胞的募集并加剧了感染。总之，我们的研究结果建立了人源化小鼠作为一个重要的翻译工具的研究S。金黄色葡萄球菌感染，并提供了强有力的证据，PVL是一种人类毒力因子。 S.金黄色葡萄球菌感染在过去十年中已经成为公共卫生的主要负担，并且是临床前研究激增的原因。小鼠是最常用于人类S.金黄色葡萄球菌感染。然而，越来越明显的是，现有的小鼠模型很难模拟人类S。金黄色葡萄球菌病此外，需要超生理接种物来建立软组织病理学。此外，许多S。金黄色葡萄球菌因子表现出独特的人类向性，并且不能在啮齿动物中充分研究。在这里，我们研究了S。金黄色葡萄球菌感染与人脐带CD 34+细胞移植的NSG小鼠。我们发现，一个一到两个低对数感染接种的S。金黄色葡萄球菌在人源化NSG小鼠中建立了一致的皮肤损伤。该接种物与已发表的诱导人体感染所需的接种物相当。此外，我们还发现了由S.金黄色葡萄球菌，有助于人源化小鼠中皮肤坏死的发展，并且其与人中性粒细胞和人C5 a受体的相互作用似乎对于免疫病理学是重要的。总的来说，我们的研究表明，人源化小鼠是一种改进的人类S。金黄色葡萄球菌感染。
Staphylococcus aureus is a leading cause of skin and soft-tissue infections worldwide. Mice are the most commonly used animals for modeling human staphylococcal infections. However a supra-physiologic S. aureus inoculum is required to establish gross murine skin pathology. Moreover, many staphylococcal factors, including Panton-Valentine leukocidin (PVL) elaborated by community-associated methicillin-resistant S. aureus (CA-MRSA), exhibit selective human tropism and cannot be adequately studied in mice. To overcome these deficiencies, we investigated S. aureus infection in non-obese diabetic (NOD)/severe combined immune deficiency (SCID)/IL2rγnull (NSG) mice engrafted with human CD34+ umbilical cord blood cells. These “humanized” NSG mice require one to two log lower inoculum to induce consistent skin lesions compared with control mice, and exhibit larger cutaneous lesions upon infection with PVL+ versus isogenic PVL- S. aureus. Neutrophils appear important for PVL pathology as adoptive transfer of human neutrophils alone to NSG mice was sufficient to induce dermonecrosis following challenge with PVL+ S. aureus but not PVL- S. aureus. PMX53, a human C5aR inhibitor, blocked PVL-induced cellular cytotoxicity in vitro and reduced the size difference of lesions induced by the PVL+ and PVL- S. aureus, but PMX53 also reduced recruitment of neutrophils and exacerbated the infection. Overall, our findings establish humanized mice as an important translational tool for the study of S. aureus infection and provide strong evidence that PVL is a human virulence factor. S. aureus infection has emerged in the past decade as a major burden to public health and is responsible for a surge in preclinical research. Mice are the most commonly studied animals for modeling of human S. aureus infection. However, it is increasingly evident that available murine models poorly mimic human S. aureus disease. Routinely, a supra-physiologic inoculum is required to establish soft-tissue pathology. Additionally, many S. aureus factors exhibit unique human tropism and cannot be adequately investigated in rodents. Here we investigated S. aureus infection in NSG mice engrafted with human umbilical CD34+ cells. We showed that a one to two log lower infectious inoculum of S. aureus establishes consistent skin lesions in humanized NSG mice. This inoculum is comparable to published inocula required to induce infection in humans. In addition, we showed that Panton-Valentine Leucocidin, a human tropic factor secreted by S. aureus, contributes to the development of dermonecrosis in the humanized mice, and its interaction with human neutrophils and human C5a receptor appears to be important for immunopathology. Overall our study suggests that humanized mice are an improved tool for modeling of human S. aureus infection.