Streptococcus pyogenes Arginine and Citrulline Catabolism Promotes Infection and Modulates Innate Immunity
Streptococcus pyogenes Arginine and Citrulline Catabolism Promotes Infection and Modulates Innate Immunity
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DOI：
10.1128/iai.00916-13
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发表时间：
2014-01-01
影响因子：
3.1
通讯作者：
Caparon, Michael G.
中科院分区：
文献类型：
--
作者：
Cusumano, Zachary T.;Watson, Michael E., Jr.;Caparon, Michael G.
细菌在感染期间从其宿主获得营养的能力是发病机理的重要组成部分。对于革兰氏阳性病原体化脓性链球菌，通过精氨酸脱亚胺酶（ADI）途径催化氨基酸精氨酸补充能量产生并提供体外抗酸应激的保护。其表达在感染的鼠模型中增强，表明在体内的重要作用。为了深入了解ADI途径在发病机制中的功能，检查了其每种酶缺陷的突变体的毒力。在无症状粘膜定植的小鼠模型中，对不能使用精氨酸（Δ ArcA）或瓜氨酸（Δ ArcB）的突变体进行减毒。然而，在皮肤组织炎性感染的小鼠模型中，Δ ArcA突变体减弱，但Δ ArcB突变体过度减弱，揭示了瓜氨酸代谢在发病机制中的意外组织特异性作用。当用Δ ArcA突变体感染一氧化氮（iNOS（-/-））依赖于精氨酸的产生缺陷的小鼠时，皮肤毒力被拯救，表明S。化脓性链球菌利用精氨酸的能力在一氧化氮介导的先天免疫不存在的情况下被抑制。这项工作证明了精氨酸和瓜氨酸催化剂的重要性，并提出了一种新的毒力机制，S。化脓性链球菌利用其代谢通过消耗必需的宿主营养来调节先天免疫。
A bacterium's ability to acquire nutrients from its host during infection is an essential component of pathogenesis. For the Gram-positive pathogen Streptococcus pyogenes, catabolism of the amino acid arginine via the arginine deiminase (ADI) pathway supplements energy production and provides protection against acid stress in vitro. Its expression is enhanced in murine models of infection, suggesting an important role in vivo. To gain insight into the function of the ADI pathway in pathogenesis, the virulence of mutants defective in each of its enzymes was examined. Mutants unable to use arginine (Delta ArcA) or citrulline (Delta ArcB) were attenuated for carriage in a murine model of asymptomatic mucosal colonization. However, in a murine model of inflammatory infection of cutaneous tissue, the Delta ArcA mutant was attenuated but the Delta ArcB mutant was hyperattenuated, revealing an unexpected tissue-specific role for citrulline metabolism in pathogenesis. When mice defective for the arginine-dependent production of nitric oxide (iNOS(-/-)) were infected with the Delta ArcA mutant, cutaneous virulence was rescued, demonstrating that the ability of S. pyogenes to utilize arginine was dispensable in the absence of nitric oxide-mediated innate immunity. This work demonstrates the importance of arginine and citrulline catabolism and suggests a novel mechanism of virulence by which S. pyogenes uses its metabolism to modulate innate immunity through depletion of an essential host nutrient.