Section for Comparative Pediatrics and Nutrition, Department of Veterinary and Animal Sciences, University of Copenhagen, Denmark.
Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 47392, Republic of Korea.
Biochim Biophys Acta Mol Basis Dis. 2024 Dec;1870(8):167482. doi: 10.1016/j.bbadis.2024.167482. Epub 2024 Aug 29.
Two distinct defense strategies, disease resistance (DR) and disease tolerance (DT), enable a host to survive infectious diseases. Newborns, constrained by limited energy reserves, predominantly rely on DT to cope with infection. However, this approach may fail when pathogen levels surpass a critical threshold, prompting a shift to DR that can lead to dysregulated immune responses and sepsis. The mechanisms governing the interplay between DR and DT in newborns remain poorly understood. Here, we compare metabolic traits and defense strategies between survivors and non-survivors in Staphylococcus epidermidis (S. epidermidis)-infected preterm piglets, mimicking infection in preterm infants. Compared to non-survivors, survivors displayed elevated DR during the initial phase of infection, followed by stronger DT in later stages. In contrast, non-survivors showed clear signs of respiratory and metabolic acidosis and hyperglycemia, together with exaggerated inflammation and organ dysfunctions. Hepatic transcriptomics revealed a strong association between the DT phenotype and heightened oxidative phosphorylation in survivors, coupled with suppressed glycolysis and immune signaling. Plasma metabolomics confirmed the findings of metabolic regulations associated with DT phenotype in survivors. Our study suggests a significant association between the initial DR and subsequent DT, which collectively contributes to improved infection survival. The regulation of metabolic processes that optimize the timing and balance between DR and DT holds significant potential for developing novel therapeutic strategies for neonatal infection.
两种不同的防御策略，疾病抗性（DR）和疾病容忍度（DT），使宿主能够在传染病中存活下来。新生儿由于能量储备有限，主要依赖 DT 来应对感染。然而，当病原体水平超过临界阈值时，这种方法可能会失败，促使转向 DR，这可能导致免疫反应失调和败血症。在新生儿中，DR 和 DT 之间相互作用的机制仍知之甚少。在这里，我们比较了表皮葡萄球菌（S. epidermidis）感染的早产儿小猪中幸存者和非幸存者之间的代谢特征和防御策略，模拟了早产儿的感染。与非幸存者相比，幸存者在感染的初始阶段表现出更高的 DR，随后在后期阶段表现出更强的 DT。相比之下，非幸存者表现出明显的呼吸和代谢性酸中毒以及高血糖，同时伴有炎症和器官功能障碍的加剧。肝转录组学显示，幸存者的 DT 表型与氧化磷酸化增强之间存在很强的关联，同时伴有糖酵解和免疫信号的抑制。血浆代谢组学证实了幸存者中与 DT 表型相关的代谢调节的发现。我们的研究表明，初始 DR 和随后的 DT 之间存在显著关联，这共同有助于提高感染的存活率。优化 DR 和 DT 之间的时机和平衡的代谢过程的调节对于开发新生儿感染的新治疗策略具有重要意义。
