Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Fibriant BV, Leiden, The Netherlands.
J Thromb Haemost. 2023 Aug;21(8):2277-2290. doi: 10.1016/j.jtha.2023.03.019. Epub 2023 Mar 30.
Staphylococcus aureus is a common gram-positive bacterium that is the causative agent for several human diseases, including sepsis. A key virulence mechanism is pathogen binding to host fibrinogen through the C-terminal region of the γ-chain. Previous work demonstrated that Fgg mice expressing mutant fibrinogen γ lacking a S. aureus binding motif had significantly improved survival following S. aureus septicemia. Fibrinogen γ' is a human splice variant that represents about 10% to 15% of the total fibrinogen in plasma and circulates as a fibrinogen γ'-γ heterodimer (phFibγ'-γ). The fibrinogen γ'-chain is also expected to lack S. aureus binding function.
Determine if human fibrinogen γ'-γ confers host protection during S. aureus septicemia.
Analyses of survival and the host response following S. aureus septicemia challenge in Fgg mice and mice reconstituted with purified phFibγ'-γ or phFibγ-γ.
Reconstitution of fibrinogen-deficient or wildtype mice with purified phFibγ'-γ prior to infection provided a significant prolongation in host survival relative to mice reconstituted with purified phFibγ-γ, which was superior to that observed with heterozygous Fgg mice. Improved survival could not be accounted for by quantitative differences in fibrinogen-dependent adhesion or clumping, but phFibγ'-γ-containing mixtures generated notably smaller bacterial aggregates. Importantly, administration of phFibγ'-γ after infection also provided a therapeutic benefit by prolonging host survival relative to administration of phFibγ-γ.
These findings provide the proof-of-concept that changing the ratio of naturally occurring fibrinogen variants in blood could offer significant therapeutic potential against bacterial infection and potentially other diseases.
金黄色葡萄球菌是一种常见的革兰氏阳性菌，是包括败血症在内的几种人类疾病的病原体。一个关键的毒力机制是病原体通过 γ 链的 C 末端区域结合宿主纤维蛋白原。先前的工作表明，表达突变纤维蛋白原 γ 的 Fgg 小鼠，其 γ 链缺乏金黄色葡萄球菌结合基序，在金黄色葡萄球菌败血症后存活率显著提高。纤维蛋白原 γ'是一种人类剪接变体，约占血浆总纤维蛋白原的 10%至 15%，并作为纤维蛋白原 γ'-γ 异二聚体（phFibγ'-γ）循环。纤维蛋白原 γ'链也预计缺乏金黄色葡萄球菌结合功能。
确定人类纤维蛋白原 γ'-γ 在金黄色葡萄球菌败血症期间是否赋予宿主保护作用。
分析 Fgg 小鼠和用纯化的 phFibγ'-γ 或 phFibγ-γ 重建的小鼠在金黄色葡萄球菌败血症攻击后的存活和宿主反应。
在感染前用纯化的 phFibγ'-γ 重建纤维蛋白原缺陷或野生型小鼠，与用纯化的 phFibγ-γ 重建的小鼠相比，显著延长了宿主的存活时间，优于杂合子 Fgg 小鼠的观察结果。存活的改善不能用纤维蛋白原依赖性粘附或聚集的定量差异来解释，但含有 phFibγ'-γ 的混合物产生的细菌聚集体明显更小。重要的是，与给予 phFibγ-γ 相比，感染后给予 phFibγ'-γ 也提供了治疗益处，延长了宿主的存活时间。
这些发现提供了概念验证，即改变血液中天然存在的纤维蛋白原变体的比例可能为对抗细菌感染和潜在的其他疾病提供显著的治疗潜力。
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