Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL, United States of America.
Departmento de Ciencias de la Vida, Universidad de las Fuerzas Armadas ESPE, Sangolquí, Ecuador.
PLoS Pathog. 2019 Jul 25;15(7):e1007971. doi: 10.1371/journal.ppat.1007971. eCollection 2019 Jul.
The ability of Staphylococcus aureus and other pathogens to consume glucose is critical during infection. However, glucose consumption increases the cellular demand for manganese sensitizing S. aureus to host-imposed manganese starvation. The current investigations were undertaken to elucidate how S. aureus copes with the need to consume glucose when metal-limited by the host. A critical component of host defense is production of the manganese binding protein calprotectin. S. aureus has two variants of phosphoglycerate mutase, one of which is manganese-dependent, GpmI, and another that is manganese-independent, GpmA. Leveraging the ability to impose metal starvation in culture utilizing calprotectin revealed that the loss of GpmA, but not GpmI, sensitized S. aureus to manganese starvation. Metabolite feeding experiments revealed that the growth defect of GpmA when manganese-starved was due to a defect in glycolysis and not gluconeogenesis. Loss of GpmA reduces the ability of S. aureus to cause invasive disease in wild type mice. However, GpmA was dispensable in calprotectin-deficient mice, which have defects in manganese sequestration, indicating that this isozyme contributes to the ability of S. aureus to overcome manganese limitation during infection. Cumulatively, these observations suggest that expressing a metal-independent variant enables S. aureus to consume glucose while mitigating the negative impact that glycolysis has on the cellular demand for manganese. S. aureus is not the only bacterium that expresses manganese-dependent and -independent variants of phosphoglycerate mutase. Similar results were also observed in culture with Salmonella enterica serovar Typhimurium mutants lacking the metal-independent isozyme. These similar observations in both Gram-positive and Gram-negative pathogens suggest that expression of metal-independent glycolytic isozymes is a common strategy employed by bacteria to survive in metal-limited environments, such as the host.
金黄色葡萄球菌和其他病原体消耗葡萄糖的能力在感染过程中至关重要。然而，葡萄糖的消耗增加了细胞对锰的需求，使金黄色葡萄球菌易受到宿主施加的锰饥饿的影响。目前的研究旨在阐明金黄色葡萄球菌在宿主金属限制的情况下如何应对消耗葡萄糖的需求。宿主防御的一个关键组成部分是产生锰结合蛋白钙卫蛋白。金黄色葡萄球菌有两种磷酸甘油酸变位酶变体，一种是依赖锰的 GpmI，另一种是不依赖锰的 GpmA。利用利用钙卫蛋白在培养中施加金属饥饿的能力表明，GpmA 的缺失而非 GpmI 的缺失使金黄色葡萄球菌对锰饥饿敏感。代谢物喂养实验表明，当锰饥饿时，GpmA 的生长缺陷是由于糖酵解而不是糖异生的缺陷。GpmA 的缺失降低了金黄色葡萄球菌在野生型小鼠中引起侵袭性疾病的能力。然而，在钙卫蛋白缺陷型小鼠中，GpmA 是 dispensable 的，这些小鼠在锰螯合方面存在缺陷，表明该同工酶有助于金黄色葡萄球菌在感染过程中克服锰限制。总之，这些观察结果表明，表达一种不依赖金属的变体使金黄色葡萄球菌能够消耗葡萄糖，同时减轻糖酵解对细胞对锰的需求的负面影响。金黄色葡萄球菌并不是唯一表达依赖金属和不依赖金属的磷酸甘油酸变位酶变体的细菌。在缺乏不依赖金属同工酶的沙门氏菌血清型鼠伤寒亚种的培养中也观察到了类似的结果。革兰氏阳性和革兰氏阴性病原体中的这些类似观察结果表明，表达不依赖金属的糖酵解同工酶是细菌在金属限制环境中生存的一种常见策略，例如宿主。
