A Factor H-Fc fusion protein increases complement-mediated opsonophagocytosis and killing of community associated methicillin-resistant Staphylococcus aureus.
A Factor H-Fc fusion protein increases complement-mediated opsonophagocytosis and killing of community associated methicillin-resistant Staphylococcus aureus.
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DOI：
10.1371/journal.pone.0265774
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发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
Sharp JA
中科院分区：
文献类型：
--
作者：
Sage MAG;Cranmer KD;Semeraro ML;Ma S;Galkina EV;Tran Y;Wycoff KL;Sharp JA
金黄色葡萄球菌使用多种免疫逃避策略来规避宿主防御，包括补体系统，补体系统是控制细菌感染的关键天然免疫组成部分。随着抗生素耐药性变得越来越普遍，迫切需要新的治疗方法。以前，我们已经证明金黄色葡萄球菌通过表面蛋白SdrE结合补体调节因子H(FH)来抑制补体。为了满足对新疗法的需求并利用FH：SdrE相互作用，我们研究了由FH的SdrE相互作用结构域与Ig G Fc组成的融合蛋白对补体介导的吞噬细胞功能和对社区相关的甲氧西林耐药金黄色葡萄球菌的细菌杀灭的影响。与Fc对照蛋白相比，金黄色葡萄球菌结合的FH-Fc明显增多，FH-Fc与血清FH竞争结合金黄色葡萄球菌。FH-FC处理增加了金黄色葡萄球菌对C3b和IC3b的C3片段调理，并促进了过敏性毒素C5a的产生。在5%和10%血清中，FH-FC可显著提高中性粒细胞对金黄色葡萄球菌的杀伤率。这种抗葡萄球菌作用在75%(3/4)的临床分离株中表现明显。本研究表明，FH-Fc融合蛋白有可能减轻结合血清FH的保护作用，使金黄色葡萄球菌更容易受到宿主免疫系统的攻击。因此，我们报告了毒力因子靶向融合蛋白有望成为未来抗葡萄球菌治疗发展的途径。
Staphylococcus aureus employs a multitude of immune-evasive tactics to circumvent host defenses including the complement system, a component of innate immunity central to controlling bacterial infections. With antibiotic resistance becoming increasingly common, there is a dire need for novel therapies. Previously, we have shown that S. aureus binds the complement regulator factor H (FH) via surface protein SdrE to inhibit complement. To address the need for novel therapeutics and take advantage of the FH:SdrE interaction, we examined the effect of a fusion protein comprised of the SdrE-interacting domain of FH coupled with IgG Fc on complement-mediated opsonophagocytosis and bacterial killing of community associated methicillin-resistant S. aureus. S. aureus bound significantly more FH-Fc compared to Fc-control proteins and FH-Fc competed with serum FH for S. aureus binding. FH-Fc treatment increased C3-fragment opsonization of S. aureus for both C3b and iC3b, and boosted generation of the anaphylatoxin C5a. In 5 and 10% serum, FH-Fc treatment significantly increased S. aureus killing by polymorphonuclear cells. This anti-staphylococcal effect was evident in 75% (3/4) of clinical isolates tested. This study demonstrates that FH-Fc fusion proteins have the potential to mitigate the protective effects of bound serum FH rendering S. aureus more vulnerable to the host immune system. Thus, we report the promise of virulence-factor-targeted fusion-proteins as an avenue for prospective anti-staphylococcal therapeutic development.
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影响因子：
2.8
作者：
Ram S;Shaughnessy J;DeOliveira RB;Lewis LA;Gulati S;Rice PA
通讯作者：
Rice PA
DOI：
10.4049/jimmunol.1700426
发表时间：
2017-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Blom AM;Magda M;Kohl L;Shaughnessy J;Lambris JD;Ram S;Ermert D
通讯作者：
Ermert D
DOI：
10.4049/jimmunol.0804031
发表时间：
2009-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ferreira VP;Herbert AP;Cortés C;McKee KA;Blaum BS;Esswein ST;Uhrín D;Barlow PN;Pangburn MK;Kavanagh D
通讯作者：
Kavanagh D
影响因子：
2.1
作者：
Battle SE;Rello J;Hauser AR
通讯作者：
Hauser AR
影响因子：
9.8
作者：
Gulati, Sunita;Beurskens, Frank J.;Ram, Sanjay
通讯作者：
Ram, Sanjay