Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229.
Department of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and the UNC Blood Research Center, University of North Carolina, Chapel Hill, NC 27599.
Proc Natl Acad Sci U S A. 2021 Jan 5;118(1). doi: 10.1073/pnas.2009837118. Epub 2020 Dec 21.
The blood-clotting protein fibrinogen has been implicated in host defense following infection, but precise mechanisms of host protection and pathogen clearance remain undefined. Peritonitis caused by staphylococci species is a complication for patients with cirrhosis, indwelling catheters, or undergoing peritoneal dialysis. Here, we sought to characterize possible mechanisms of fibrin(ogen)-mediated antimicrobial responses. Wild-type (WT) (Fib+) mice rapidly cleared following intraperitoneal infection with elimination of ∼99% of an initial inoculum within 15 min. In contrast, fibrinogen-deficient (Fib-) mice failed to clear the microbe. The genotype-dependent disparity in early clearance resulted in a significant difference in host mortality whereby Fib+ mice uniformly survived whereas Fib- mice exhibited high mortality rates within 24 h. Fibrin(ogen)-mediated bacterial clearance was dependent on (pro)thrombin procoagulant function, supporting a suspected role for fibrin polymerization in this mechanism. Unexpectedly, the primary host initiator of coagulation, tissue factor, was found to be dispensable for this antimicrobial activity. Rather, the bacteria-derived prothrombin activator was identified as the source of the thrombin-generating potential underlying fibrin(ogen)-dependent bacterial clearance. Mice failed to eliminate deficient in , but clearance of these same microbes in WT mice was restored if active thrombin was administered to the peritoneal cavity. These studies establish that the thrombin/fibrinogen axis is fundamental to host antimicrobial defense, offer a possible explanation for the clinical observation that coagulase-negative staphylococci are a highly prominent infectious agent in peritonitis, and suggest caution against anticoagulants in individuals susceptible to peritoneal infections.
纤维蛋白原作为一种凝血蛋白，已被证实与感染后的宿主防御有关，但宿主保护和病原体清除的确切机制仍未确定。葡萄球菌引起的腹膜炎是肝硬化、留置导管或腹膜透析患者的一种并发症。在这里，我们试图描述纤维蛋白（原）介导的抗微生物反应的可能机制。野生型（WT）（Fib+）小鼠在腹腔内感染后迅速清除了细菌，在 15 分钟内消除了初始接种物的约 99%。相比之下，纤维蛋白原缺陷（Fib-）小鼠未能清除微生物。这种基因型依赖性的早期清除差异导致宿主死亡率存在显著差异，Fib+小鼠普遍存活，而 Fib-小鼠在 24 小时内死亡率很高。纤维蛋白（原）介导的细菌清除依赖于（前）凝血酶原促凝功能，这支持了纤维蛋白聚合在该机制中的作用。出乎意料的是，凝血的主要宿主起始因子组织因子被发现对这种抗微生物活性是可有可无的。相反，细菌衍生的凝血酶原激活物被鉴定为纤维蛋白原依赖性细菌清除中产生凝血酶的潜在来源。缺乏 的小鼠未能清除 ，但如果将活性凝血酶注入腹腔，WT 小鼠中这些相同微生物的清除得到恢复。这些研究确立了凝血酶/纤维蛋白原轴是宿主抗微生物防御的基础，为临床上观察到凝固酶阴性葡萄球菌是腹膜炎中一种非常突出的感染因子提供了可能的解释，并建议对抗凝剂在易患腹膜感染的个体中保持谨慎。
