Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon, 24341, Republic of Korea.
Functional Bio-material Reasearch Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup, 56212, Republic of Korea.
J Microbiol. 2022 Apr;60(4):444-449. doi: 10.1007/s12275-022-2007-1. Epub 2022 Mar 28.
Available antibiotics to treat Acinetobacter baumannii infection is limited due to increasing resistance and the emergence of multiple drug-resistant strains. Hence, discovering effective agents against A. baumannii to reduce the number of infection-related deaths is imperative. In search of novel and alternative antibiotics, the antibacterial function of lipocalin2 (Lcn2) was investigated to treat systemic infections of A. baumannii using a mouse neutropenia model. We observed a significant increase in serum Lcn2 levels upon bacterial injection into the mouse, and the administration of recombinant Lcn2 (rmLcn2) extended their survival. Such protective effects were also observed in rmLcn2-pretreated macrophages, where rmLcn2 reduced the survival of the pathogen inside the macrophages. The underlying molecular mechanism of Lcn2 protection was also investigated. We observed that pretreatment of the Raw-264.7 macrophages with rmLcn2 markedly altered the expression of tonB3, which encodes a component of the transporter for ferrisiderophores in A. baumannii. However, the expression of katG, the gene encoding catalase, remained unaffected. These indicate that Lcn2-mediated defense against the pathogen is related to nutritional immunity rather than reactive oxygen species (ROS) production. Furthermore, the addition of rmLcn2 in infected mice diminished bacterial burden in multiple organs and enhanced the expression of tonB3 in the liver, spleen, and lungs of the infected mice. Increased survival rate due to rmLcn2 treatment declined when the infection model was established using lcn2-defective (lcn2) mice, which indicated the necessity of endogenous Lcn2. Therefore, the antibacterial function of Lcn2 can be exploited to develop an alternative therapeutic agent against A. baumannii.
由于耐药性的增加和多种耐药菌株的出现，可用于治疗鲍曼不动杆菌感染的抗生素有限。因此，发现针对鲍曼不动杆菌的有效药物来减少感染相关死亡人数是当务之急。为了寻找新型替代抗生素，我们研究了载脂蛋白 2（Lcn2）的抗菌功能，以利用小鼠中性粒细胞减少症模型治疗鲍曼不动杆菌的全身感染。我们观察到，在向小鼠注射细菌后，血清 Lcn2 水平显著升高，而重组 Lcn2（rmLcn2）的给药延长了它们的存活时间。在 rmLcn2 预处理的巨噬细胞中也观察到了这种保护作用，其中 rmLcn2 减少了病原体在巨噬细胞内的存活。我们还研究了 Lcn2 保护的潜在分子机制。我们观察到，用 rmLcn2 预处理 Raw-264.7 巨噬细胞可显著改变编码鲍曼不动杆菌铁载体转运蛋白的 tonB3 的表达。然而，编码过氧化氢酶的 katG 基因的表达不受影响。这表明 Lcn2 介导的针对病原体的防御与营养免疫有关，而与活性氧（ROS）的产生无关。此外，在感染的小鼠中添加 rmLcn2 可减少多个器官中的细菌负荷，并增强感染小鼠的肝脏、脾脏和肺中的 tonB3 表达。当使用 lcn2 缺陷型（lcn2）小鼠建立感染模型时，由于 rmLcn2 治疗而导致的存活率增加下降，这表明内源性 Lcn2 的必要性。因此，可以利用 Lcn2 的抗菌功能来开发针对鲍曼不动杆菌的替代治疗药物。
