Fibrinogen γ' promotes host survival during Staphylococcus aureus septicemia in mice.
Fibrinogen γ' promotes host survival during Staphylococcus aureus septicemia in mice.
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DOI：
10.1016/j.jtha.2023.03.019
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发表时间：
2023-08
影响因子：
10.4
通讯作者：
Flick, Matthew J.
中科院分区：
文献类型：
--
作者：
Negron, Oscar;Weggeman, Miranda;Grimbergen, Jos;Clark, Emily G.;Abrahams, Sara;Hur, Woosuk S.;Koopman, Jaap;Flick, Matthew J.
金黄色葡萄球菌是一种常见的革兰氏阳性细菌，是多种人类疾病（包括败血症）的病原体。一个关键的毒力机制是病原体通过γ链的C末端区域与宿主纤维蛋白原结合。先前的工作表明，表达缺乏S.金黄色葡萄球菌结合基序显著改善了S.金黄色葡萄球菌败血症。纤维蛋白原γ′是一种人类剪接变体，占血浆中总纤维蛋白原的约10%至15%，并以纤维蛋白原γ′-γ异二聚体（phFibγ′-γ）形式循环。预计纤维蛋白原γ′链也缺乏S。金黄色葡萄球菌结合功能。确定人纤维蛋白原γ′-γ在S.金黄色葡萄球菌败血症。分析了S.在FggΔ5小鼠和用纯化的phFibγ′-γ或phFibγ-γ重建的小鼠中的金黄色葡萄球菌败血症攻击。相对于用纯化的phFibγ-γ重建的小鼠，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提供了宿主存活的显著延长，这上级于用杂合FggΔ5小鼠观察到的。存活率的提高不能通过纤维蛋白原依赖性粘附或凝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，在感染后施用phFibγ′-γ还通过相对于施用phFibγ-γ延长宿主存活而提供治疗益处。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以为细菌感染和潜在的其他疾病提供显着的治疗潜力。
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 FggΔ5 mice expressing mutant fibrinogen γΔ5 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 FggΔ5 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 FggΔ5 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.
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影响因子：
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