Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Infect Immun. 2023 Apr 18;91(4):e0052922. doi: 10.1128/iai.00529-22. Epub 2023 Mar 6.
Hyperglycemia, or elevated blood glucose, renders individuals more prone to developing severe Staphylococcus aureus infections. S. aureus is the most common etiological agent of musculoskeletal infection, which is a common manifestation of disease in hyperglycemic patients. However, the mechanisms by which S. aureus causes severe musculoskeletal infection during hyperglycemia are incompletely characterized. To examine the influence of hyperglycemia on S. aureus virulence during invasive infection, we used a murine model of osteomyelitis and induced hyperglycemia with streptozotocin. We discovered that hyperglycemic mice exhibited increased bacterial burdens in bone and enhanced dissemination compared to control mice. Furthermore, infected hyperglycemic mice sustained increased bone destruction relative to euglycemic controls, suggesting that hyperglycemia exacerbates infection-associated bone loss. To identify genes contributing to S. aureus pathogenesis during osteomyelitis in hyperglycemic animals relative to euglycemic controls, we used transposon sequencing (TnSeq). We identified 71 genes uniquely essential for S. aureus survival in osteomyelitis in hyperglycemic mice and another 61 mutants with compromised fitness. Among the genes essential for S. aureus survival in hyperglycemic mice was the gene encoding superoxide dismutase A (), one of two S. aureus superoxide dismutases involved in detoxifying reactive oxygen species (ROS). We determined that a mutant exhibits attenuated survival in high glucose and during osteomyelitis in hyperglycemic mice. SodA therefore plays an important role during growth in high glucose and promotes S. aureus survival in bone. Collectively, these studies demonstrate that hyperglycemia increases the severity of osteomyelitis and identify genes contributing to S. aureus survival during hyperglycemic infection.
高血糖，即血液中葡萄糖水平升高，会使个体更容易发生严重的金黄色葡萄球菌感染。金黄色葡萄球菌是肌肉骨骼感染最常见的病原体，也是高血糖患者疾病的常见表现。然而，高血糖状态下金黄色葡萄球菌导致严重肌肉骨骼感染的机制尚未完全阐明。为了研究高血糖对侵袭性感染过程中金黄色葡萄球菌毒力的影响，我们使用了骨髓炎的小鼠模型，并使用链脲佐菌素诱导高血糖。我们发现，与对照小鼠相比，高血糖小鼠的骨内细菌负荷增加，播散更严重。此外，与血糖正常的对照小鼠相比，感染高血糖的小鼠持续存在更多的骨破坏，表明高血糖加重了感染相关的骨丢失。为了确定在高血糖动物骨髓炎中相对于血糖正常对照与金黄色葡萄球菌发病机制相关的基因，我们使用转座子测序（TnSeq）。我们鉴定出 71 个基因在高血糖小鼠骨髓炎中对金黄色葡萄球菌的生存是必需的，而另外 61 个突变体的适应性降低。在高血糖小鼠中金黄色葡萄球菌生存所必需的基因中，编码超氧化物歧化酶 A（）的基因，它是参与解毒活性氧（ROS）的两种金黄色葡萄球菌超氧化物歧化酶之一。我们确定一个突变体在高葡萄糖和高血糖小鼠骨髓炎中表现出存活能力降低。因此，SodA 在高葡萄糖生长期间和金黄色葡萄球菌在骨内的存活中发挥重要作用。综上所述，这些研究表明高血糖会加重骨髓炎的严重程度，并确定了在高血糖感染期间与金黄色葡萄球菌生存相关的基因。
