Schirm Sabine, Liu Xu, Jennings Lori L, Jedrzejewski Paul, Dai Yumin, Hardy Stephen
Novartis Institutes for Biomedical Research, Emeryville, California 94608, USA.
J Infect Dis. 2009 Jun 15;199(12):1807-15. doi: 10.1086/599097.
Tissue factor pathway inhibitor (TFPI) is a major regulator of blood clotting. Receipt of recombinant TFPI (rTFPI) protected animals from death in Escherichia coli-induced severe sepsis models and is under evaluation in a phase III clinical trial involving patients with severe community-acquired pneumonia. Because the mechanism of action of rTFPI in acute bacterial infection is not well understood, we sought to identify and map rTFPI peptides that have antimicrobial activity against E. coli.
Fragmented rTFPI and C-terminal TFPI peptide activities against pathogenic E. coli strains were measured in ex vivo blood cultures and in serum.
The C-terminal peptides exhibited complement-dependent antibacterial activity and directly interacted with the bacterial cell surface of E. coli. Both complement-mediated killing and cell-surface binding were reversed by low amounts of heparin.
Our investigation revealed a previously unidentified mechanism of antibacterial activity for TFPI. C-terminal rTFPI fragments kill serum-resistant E. coli though the complement pathway of the innate immune system, suggesting a multimodal mechanism of action of rTFPI that may assist in reducing mortality in animal models of severe sepsis and contribute to therapeutic effectiveness.
组织因子途径抑制物（TFPI）是血液凝固的主要调节因子。在大肠杆菌诱导的严重脓毒症模型中，接受重组TFPI（rTFPI）可使动物免于死亡，目前rTFPI正在一项涉及重症社区获得性肺炎患者的III期临床试验中接受评估。由于rTFPI在急性细菌感染中的作用机制尚不清楚，我们试图鉴定并绘制出对大肠杆菌具有抗菌活性的rTFPI肽段。
在体外血液培养物和血清中测量片段化rTFPI和C末端TFPI肽对致病性大肠杆菌菌株的活性。
C末端肽表现出补体依赖性抗菌活性，并直接与大肠杆菌的细菌细胞表面相互作用。低剂量肝素可逆转补体介导的杀伤作用和细胞表面结合。
我们的研究揭示了TFPI一种此前未被发现的抗菌活性机制。C末端rTFPI片段通过先天性免疫系统的补体途径杀死血清抗性大肠杆菌，提示rTFPI的多模式作用机制，这可能有助于降低严重脓毒症动物模型的死亡率并提高治疗效果。
