Reduced thrombin generation increases host susceptibility to group A streptococcal infection
Reduced thrombin generation increases host susceptibility to group A streptococcal infection
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DOI：
10.1182/blood-2008-07-170506
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发表时间：
2009-02-05
期刊：
影响因子：
20.3
通讯作者：
Ginsburg, David
中科院分区：
文献类型：
--
作者：
Sun, Hongmin;Wang, Xixi;Ginsburg, David
细菌纤溶酶原激活剂在微生物病原体中是常见的，这意味着宿主纤溶酶在支持细菌毒力中的核心作用。A组链球菌（GAS）分泌链激酶，一种人纤溶酶原（PLG）的特异性激活剂。最近使用表达人PLG的小鼠证明了链激酶-PLG相互作用对GAS致病性的关键贡献。为了研究凝血酶生成在抗微生物宿主防御中的重要性，我们挑战了血浆或血小板室中缺乏因子V（FV）的小鼠。减少FV在任一池中导致GAS感染后死亡率显着增加，与杂合F5缺陷小鼠相比，这表明血小板FV池在宿主防御中的作用以前未被认识到。与对照组相比，纤维蛋白原完全缺乏的小鼠对GAS感染的死亡率也明显增加。尽管FV Leiden可能在人类严重脓毒症的情况下具有保护作用，但在携带FV Leiden突变的GAS感染小鼠中未观察到显著的生存优势。综上所述，我们的数据支持局部血栓形成/纤维蛋白沉积限制至少一部分微生物病原体的存活和传播的假设，并表明人类止血因子的常见变异可能影响宿主对各种感染性疾病的易感性。（血。2009; 113：1358-1364）
Bacterial plasminogen activators are commonplace among microbial pathogens, implying a central role of host plasmin in supporting bacterial virulence. Group A streptococci (GAS) secrete streptokinase, a specific activator of human plasminogen (PLG). The critical contribution of the streptokinase-PLG interaction to GAS pathogenicity was recently demonstrated using mice expressing human PLG. To examine the importance of thrombin generation in antimicrobial host defense, we challenged mice with deficiency of factor V (FV) in either the plasma or platelet compartment. Reduction of FV in either pool resulted in markedly increased mortality after GAS infection, with comparison to heterozygous F5-deficient mice suggesting a previously unappreciated role for the platelet FV pool in host defense. Mice with complete deficiency of fibrinogen also demonstrated markedly increased mortality to GAS infection relative to controls. Although FV Leiden may be protective in the setting of severe sepsis in humans, no significant survival advantage was observed in GAS-infected mice carrying the FV Leiden mutation. Taken together, our data support the hypothesis that local thrombosis/fibrin deposition limits the survival and dissemination of at least a subset of microbial pathogens and suggest that common variation in hemostatic factors among humans could affect host susceptibility to a variety of infectious diseases. (Blood. 2009; 113: 1358-1364)