Pan-caspase inhibition as a potential host-directed immunotherapy against MRSA and other bacterial skin infections.
Pan-caspase inhibition as a potential host-directed immunotherapy against MRSA and other bacterial skin infections.
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泛半胱氨酸氨基转移酶抑制作为一种潜在的宿主导向免疫疗法来治疗MRSA和其他细菌性皮肤感染。
DOI：
10.1126/scitranslmed.abe9887
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发表时间：
2021-07-07
影响因子：
17.1
通讯作者：
Miller LS
中科院分区：
文献类型：
--
作者：
Alphonse MP;Rubens JH;Ortines RV;Orlando NA;Patel AM;Dikeman D;Wang Y;Vuong I;Joyce DP;Zhang J;Mumtaz M;Liu H;Liu Q;Youn C;Patrick GJ;Ravipati A;Miller RJ;Archer NK;Miller LS
金黄色葡萄球菌引起人类大多数皮肤感染，耐甲氧西林的S。金黄色葡萄球菌（MRSA）菌株是严重的公共卫生威胁。临床上迫切需要非抗生素免疫疗法来治疗MRSA感染并防止抗生素耐药性的传播。在这里，我们研究了泛半胱天冬酶抑制剂喹啉-缬氨酸-天冬氨酸-二氟苯氧基甲基酮（Q-VD-OPH）对MRSA皮肤感染的有效性。与溶剂处理或未处理的小鼠相比，单次全身剂量的Q-VD-OPH减少了皮肤病变大小并降低了细菌负荷。尽管Q-VD-OPH抑制了炎性小体依赖性凋亡相关的斑点样蛋白（含半胱天冬酶激活和募集结构域（ASC）斑点形成和半胱天冬酶-1介导的白细胞介素-1 β（IL-1β）产生），但Q-VD-OPH在IL-1β、ASC、半胱天冬酶-1、半胱天冬酶-11或gasdermin D缺陷小鼠中保持了疗效。因此，Q-VD-OPH疗效与炎性小体介导的焦亡无关。相反，Q-VD-OPH减少单核细胞和中性粒细胞的凋亡。此外，Q-VD-OPH增强了巨噬细胞的坏死性凋亡，伴随着血清TNF和产生TNF的中性粒细胞、单核细胞/巨噬细胞和感染皮肤中的中性粒细胞的增加。与此一致，Q-VD-OPH在TNF缺陷小鼠（伴有相关的中性粒细胞流入减少和坏死性凋亡）、TNF/IL-1 R缺陷小鼠和抗TNF抗体处理的WT小鼠中缺乏疗效。体外研究表明，联合caspase-3、caspase-8和caspase-9抑制可减少细胞凋亡，联合caspase-1、caspase-8和caspase-11抑制可增加TNF，这表明Q-VD-OPH体内疗效的机制。最后，Q-VD-OPH对小鼠化脓性链球菌和铜绿假单胞菌皮肤感染也有治疗作用。总的来说，泛半胱天冬酶抑制代表了针对MRSA和其他细菌皮肤感染的潜在宿主导向免疫疗法。
Staphylococcus aureus causes most skin infections in humans, and the emergence of methicillin-resistant S. aureus (MRSA) strains is a serious public health threat. There is an urgent clinical need for nonantibiotic immunotherapies to treat MRSA infections and prevent the spread of antibiotic resistance. Here, we investigated the pan-caspase inhibitor quinoline–valine–aspartic acid–difluorophenoxymethyl ketone (Q-VD-OPH) for efficacy against MRSA skin infection in mice. A single systemic dose of Q-VD-OPH decreased skin lesion sizes and reduced bacterial burden compared with vehicle-treated or untreated mice. Although Q-VD-OPH inhibited inflammasome-dependent apoptosis-associated speck-like protein containing caspase activation and recruitment domain (ASC) speck formation and caspase-1–mediated interleukin-1β (IL-1β) production, Q-VD-OPH maintained efficacy in mice deficient in IL-1β, ASC, caspase-1, caspase-11, or gasdermin D. Thus, Q-VD-OPH efficacy was independent of inflammasome-mediated pyroptosis. Rather, Q-VD-OPH reduced apoptosis of monocytes and neutrophils. Moreover, Q-VD-OPH enhanced necroptosis of macrophages with concomitant increases in serum TNF and TNF-producing neutrophils, monocytes/macrophages, and neutrophils in the infected skin. Consistent with this, Q-VD-OPH lacked efficacy in mice deficient in TNF (with associated reduced neutrophil influx and necroptosis), in mice deficient in TNF/IL-1R and anti-TNF antibody-treated WT mice. In vitro studies revealed that combined caspase-3, caspase-8, and caspase-9 inhibition reduced apoptosis, and combined caspase-1, caspase-8, and caspase-11 inhibition increased TNF, suggesting a mechanism for Q-VD-OPH efficacy in vivo. Last, Q-VD-OPH also had a therapeutic effect against Streptococcus pyogenes and Pseudomonas aeruginosa skin infections in mice. Collectively, pan-caspase inhibition represents a potential host-directed immunotherapy against MRSA and other bacterial skin infections.
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影响因子：
5.5
作者：
Holzinger, Dirk;Gieldon, Laura;Loeffler, Bettina
通讯作者：
Loeffler, Bettina
影响因子：
15.9
作者：
Genestier, AL;Michallet, MC;Genestier, L
通讯作者：
Genestier, L
影响因子：
4.9
作者：
Guo, Yi;Ramos, Romela Irene;Miller, Lloyd S.
通讯作者：
Miller, Lloyd S.
影响因子：
15.9
作者：
Dillen, Carly A.;Pinsker, Bret L.;Miller, Lloyd S.
通讯作者：
Miller, Lloyd S.
影响因子：
6.4
作者：
Kebaier, Chahnaz;Chamberland, Robin R.;Duncan, Joseph A.
通讯作者：
Duncan, Joseph A.