Department of Microbiology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA.
Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA.
mBio. 2023 Feb 28;14(1):e0322322. doi: 10.1128/mbio.03223-22. Epub 2023 Jan 4.
The preferred carbon source of Staphylococcus aureus and many other pathogens is glucose, and its consumption is critical during infection. However, glucose utilization increases the cellular demand for manganese, a nutrient sequestered by the host as a defense against invading pathogens. Therefore, bacteria must balance glucose metabolism with the increasing demand that metal-dependent processes, such as glycolysis, impose upon the cell. A critical regulator that enables S. aureus to resist nutritional immunity is the ArlRS two-component system. This work revealed that ArlRS regulates the expression of FdaB, a metal-independent fructose 1,6-bisphosphate aldolase. Further investigation revealed that when S. aureus is metal-starved by the host, FdaB functionally replaces the metal-dependent isozyme FbaA, thereby allowing S. aureus to resist host-imposed metal starvation in culture. Although metal-dependent aldolases are canonically zinc-dependent, this work uncovered that FbaA requires manganese for activity and that FdaB protects S. aureus from manganese starvation. Both FbaA and FdaB contribute to the ability of S. aureus to cause invasive disease in wild-type mice. However, the virulence defect of a strain lacking FdaB was reversed in calprotectin-deficient mice, which have defects in manganese sequestration, indicating that this isozyme contributes to the ability of this pathogen to overcome manganese limitation during infection. Cumulatively, these observations suggest that the expression of the metal-independent aldolase FdaB allows S. aureus to alleviate the increased demand for manganese that glucose consumption imposes, and highlights the cofactor flexibility of even established metalloenzyme families. Staphylococcus aureus and other pathogens consume glucose during infection. Glucose utilization increases the demand for transition metals, such as manganese, a nutrient that the host limits as a defense mechanism against invading pathogens. Therefore, pathogenic bacteria must balance glucose and manganese requirements during infection. The two-component system ArlRS is an important regulator that allows S. aureus to adapt to both glucose and manganese starvation. Among the genes regulated by ArlRS is the metal-independent fructose 1,6-bisphosphate aldolase , which functionally substitutes for the metal-dependent isoenzyme FbaA and enables S. aureus to survive host-imposed manganese starvation. Unexpectedly, and differing from most characterized metal-dependent aldolases, FbaA requires manganese for activity. Cumulatively, these findings reveal a new mechanism for overcoming nutritional immunity as well as the cofactor plasticity of even well-characterized metalloenzyme families.
金黄色葡萄球菌和许多其他病原体的首选碳源是葡萄糖，在感染过程中消耗葡萄糖至关重要。然而，葡萄糖的利用会增加细胞对锰的需求，而锰是宿主用来抵御入侵病原体的一种营养物质。因此，细菌必须在感染过程中平衡葡萄糖代谢和金属依赖性过程（如糖酵解）对细胞的需求。一种能够使金黄色葡萄球菌抵抗营养免疫的关键调节因子是 ArlRS 双组分系统。这项工作表明，ArlRS 调节金属非依赖性果糖 1,6-二磷酸醛缩酶 FdaB 的表达。进一步的研究表明，当宿主使金黄色葡萄球菌金属饥饿时，FdaB 可替代金属依赖性同工酶 FbaA，从而使金黄色葡萄球菌能够在培养物中抵抗宿主施加的金属饥饿。尽管金属依赖性醛缩酶通常是锌依赖性的，但这项工作揭示了 FbaA 活性需要锰，而 FdaB 可保护金黄色葡萄球菌免受锰饥饿。FbaA 和 FdaB 均有助于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，缺乏 FdaB 的菌株在钙卫蛋白缺陷型小鼠中的毒力缺陷得到了逆转，钙卫蛋白缺陷型小鼠存在锰螯合缺陷，表明该同工酶有助于该病原体在感染过程中克服锰限制的能力。总之，这些观察结果表明，金属非依赖性醛缩酶 FdaB 的表达使金黄色葡萄球菌能够减轻葡萄糖消耗所带来的对锰的需求增加，并突出了即使是成熟的金属酶家族的辅因子灵活性。金黄色葡萄球菌和其他病原体在感染过程中消耗葡萄糖。葡萄糖的利用增加了对过渡金属（如锰）的需求，而锰是宿主作为防御机制限制的一种营养物质，以抵御入侵病原体。因此，致病菌必须在感染过程中平衡葡萄糖和锰的需求。双组分系统 ArlRS 是一种重要的调节因子，可使金黄色葡萄球菌适应葡萄糖和锰饥饿。在 ArlRS 调节的基因中，有一种金属非依赖性果糖 1,6-二磷酸醛缩酶，它可替代金属依赖性同工酶 FbaA，使金黄色葡萄球菌能够在宿主施加的锰饥饿中存活。出乎意料的是，与大多数特征明确的金属依赖性醛缩酶不同，FbaA 活性需要锰。总之，这些发现揭示了一种克服营养免疫的新机制，以及即使是特征明确的金属酶家族的辅因子灵活性。
