Garcia Yuritzi M, Barwinska-Sendra Anna, Tarrant Emma, Skaar Eric P, Waldron Kevin J, Kehl-Fie Thomas E
Department of Microbiology, University of Illinois Urbana-Champaign, Urbana, IL, United States of America.
Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
PLoS Pathog. 2017 Jan 19;13(1):e1006125. doi: 10.1371/journal.ppat.1006125. eCollection 2017 Jan.
Staphylococcus aureus is a devastating mammalian pathogen for which the development of new therapeutic approaches is urgently needed due to the prevalence of antibiotic resistance. During infection pathogens must overcome the dual threats of host-imposed manganese starvation, termed nutritional immunity, and the oxidative burst of immune cells. These defenses function synergistically, as host-imposed manganese starvation reduces activity of the manganese-dependent enzyme superoxide dismutase (SOD). S. aureus expresses two SODs, denoted SodA and SodM. While all staphylococci possess SodA, SodM is unique to S. aureus, but the advantage that S. aureus gains by expressing two apparently manganese-dependent SODs is unknown. Surprisingly, loss of both SODs renders S. aureus more sensitive to host-imposed manganese starvation, suggesting a role for these proteins in overcoming nutritional immunity. In this study, we have elucidated the respective contributions of SodA and SodM to resisting oxidative stress and nutritional immunity. These analyses revealed that SodA is important for resisting oxidative stress and for disease development when manganese is abundant, while SodM is important under manganese-deplete conditions. In vitro analysis demonstrated that SodA is strictly manganese-dependent whereas SodM is in fact cambialistic, possessing equal enzymatic activity when loaded with manganese or iron. Cumulatively, these studies provide a mechanistic rationale for the acquisition of a second superoxide dismutase by S. aureus and demonstrate an important contribution of cambialistic SODs to bacterial pathogenesis. Furthermore, they also suggest a new mechanism for resisting manganese starvation, namely populating manganese-utilizing enzymes with iron.
金黄色葡萄球菌是一种极具破坏力的哺乳动物病原体，由于抗生素耐药性的普遍存在，迫切需要开发新的治疗方法。在感染过程中，病原体必须克服宿主施加的锰饥饿（称为营养免疫）和免疫细胞的氧化爆发这双重威胁。这些防御机制协同发挥作用，因为宿主施加的锰饥饿会降低锰依赖性酶超氧化物歧化酶（SOD）的活性。金黄色葡萄球菌表达两种SOD，分别为SodA和SodM。虽然所有葡萄球菌都拥有SodA，但SodM是金黄色葡萄球菌所特有的，然而金黄色葡萄球菌通过表达两种明显依赖锰的SOD所获得的优势尚不清楚。令人惊讶的是，两种SOD的缺失使金黄色葡萄球菌对宿主施加的锰饥饿更加敏感，这表明这些蛋白质在克服营养免疫方面发挥了作用。在本研究中，我们阐明了SodA和SodM在抵抗氧化应激和营养免疫方面各自的作用。这些分析表明，SodA在锰充足时对于抵抗氧化应激和疾病发展很重要，而SodM在锰缺乏的条件下很重要。体外分析表明，SodA严格依赖锰，而SodM实际上具有双功能性，在装载锰或铁时具有同等的酶活性。总的来说，这些研究为金黄色葡萄球菌获得第二种超氧化物歧化酶提供了一个机制上的解释，并证明了双功能SOD对细菌发病机制的重要贡献。此外，它们还提出了一种抵抗锰饥饿的新机制，即用铁填充利用锰的酶。
