来源:Cell Research 发布时间:2019/8/13 16:39:09
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细胞研究:凝血因子或有助于对抗多重耐药的超级细菌 | Cell Research

论文标题:Coagulation factors VII, IX and X are effective antibacterial proteins against drug-resistant Gram-negative bacteria

期刊:Cell Research

作者:Jinwu Chen,Xiaojie Li,Ling Li,Ting Zhang,Qing Zhang,Fangming Wu,Diyue Wang,Hongze Hu,Changlin Tian,Dongsheng Liao,Liang Zhao,Danxia Song,Yongyun Zhao,Chuanfang Wu,Xu Song

发表时间:2019/08/09

数字识别码:10.1038/s41422-019-0202-3

微信链接: https://mp.weixin.qq.com/s/xWipR8_jxPTJVaazoVRAqg

最近发表在期刊《细胞研究》(Cell Research)上的一项研究发现,凝血因子——受伤后参与血液凝固的血液成分——或为对抗多重耐药细菌提供了新策略。

图1 图源:blindturtle / stock.adobe.com

多重耐药细菌导致的感染会造成紧急的公共卫生风险,因为目前缺乏对抗这类细菌的有效药物。体内缺乏凝血因子——例如像有凝血障碍的血友病患者那样——与罹患败血症、肺炎等细菌性疾病存在相关性,暗示这些凝血因子可能在凝血的同时也有抗感染的作用。

如今中国四川大学的一个研究团队发现,凝血因子VII、IX和X除了在凝血过程中有重要作用,可能还可以对抗革兰氏阴性菌,其中包括像绿脓杆菌(Pseudomonas aeruginosa)和鲍曼不动杆菌(Acetinobacter baumannii)这样广泛抗药的细菌。这两种细菌最近还被国际卫生组织(WHO)列入因抗药性而对人类健康威胁最大的12种细菌之列。革兰氏阴性菌的特点是具有由一层内细胞膜、一层薄的细胞壁和一层外细胞膜组成的包膜,这使得它们更难被杀灭。

论文的通讯作者宋旭说:“在研究中,我们发现人体内的一类抗菌性蛋白可以有效对抗耐药的‘超级细菌’。许多抗菌物质都是靶标细胞代谢过程或者细胞膜,但这些蛋白不同,它们是通过水解破坏细菌外膜的脂多糖来起作用的。脂多糖对于革兰氏阴性菌的存活十分重要。”

凝血因子这种水解细菌包膜中重要脂多糖的能力表明它们可能有抗革兰氏阴性菌的潜力。通过进一步探索其中机理,作者们发现凝血因子是通过轻链——两种蛋白组成部分之一——在细菌上起效的,另一个蛋白组分(重链)没有此效果。在实验室培养环境下,作者将轻链加入大肠杆菌中,清晰观察到细菌的细胞包膜先是出现损伤,然后在4个小时内整个细菌细胞几乎被完全破坏。

研究者发现凝血因子VII的轻链对所有被检测的革兰氏阴性菌都有效。轻链与凝血因子在感染绿脓杆菌和鲍曼不动菌的小鼠体内都可以有效抗感染,重链则无效果。

图2: FVII, FIX, FX, and their LCs exhibit antibacterial activity. a–h Growth kinetic measurements of E. coli DH5α exposed to different concentrations of lFVII (a), FVII (b), FVIIa (c), hFVII (d), lFIX (e), lFX (f), FIX (g) and FX (h). Untreated bacteria were included in all experiments. Data represent mean values from ?ve or more independent experiments. i Resistance to P. aeruginosa in BALB/c mice was weakened by neutralizing endogenous coagulation factors. The following antibodies (dose per mouse in parentheses), with saline as a blank control, were investigated in groups of eight mice: anti-mFVII Ab (1 µg), anti-mFIX Ab (8 µg), anti-mFX Ab (8 µg), Ab combination (1 µg of anti-mFVII Ab, 8 µg of anti-mFIX Ab and 8 µg of anti-mFX Ab), normal goat IgG (16 µg) and normal rabbit IgG (16 µg). After 1 h of antibody injections, each mouse was intravenously inoculated with 2 × 105 CFU of P. aeruginosa L93. j, k Increased bacterial load in blood (j) and liver (k) caused by neutralizing endogenous coagulation factors. Mice were treated as described in i. Bacterial titers remaining in blood and liver were assayed at 2 h post inoculation of P. aeruginosa. Bars indicate the means (n = 8). **P < 0.01, signi?cantly different from the saline-injected group

宋旭说:“目前已知没有任何一种抗菌物质是通过水解脂多糖起效的。明确以脂多糖水解为基础的抗菌机制和凝血因子的抗菌特点,结合以较低成本大规模生产这些凝血因子的能力,或能提供性价比高的新策略来对抗由抗药性革兰氏阴性菌引发的紧急公共卫生危机。”

摘要:Infections caused by drug-resistant “superbugs” pose an urgent public health threat due to the lack of effective drugs; however, certain mammalian proteins with intrinsic antibacterial activity might be underappreciated. Here, we reveal an antibacterial property against Gram-negative bacteria for factors VII, IX and X, three proteins with well-established roles in initiation of the coagulation cascade. These factors exert antibacterial function via their light chains (LCs). Unlike many antibacterial agents that target cell metabolism or the cytoplasmic membrane, the LCs act by hydrolyzing the major components of bacterial outer membrane, lipopolysaccharides, which are crucial for the survival of Gram-negative bacteria. The LC of factor VII exhibits in vitro efficacy towards all Gram-negative bacteria tested, including extensively drug-resistant (XDR) pathogens, at nanomolar concentrations. It is also highly effective in combating XDR Pseudomonas aeruginosa and Acinetobacter baumannii infections in vivo. Through decoding a unique mechanism whereby factors VII, IX and X behave as antimicrobial proteins, this study advances our understanding of the coagulation system in host defense, and suggests that these factors may participate in the pathogenesis of coagulation disorder-related diseases such as sepsis via their dual functions in blood coagulation and resistance to infection. Furthermore, this study may offer new strategies for combating Gram-negative “superbugs”.

(来源:科学网)

 
 
 
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