Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore.
Infect Immun. 2014 Mar;82(3):1112-22. doi: 10.1128/IAI.01459-13. Epub 2013 Dec 23.
Acinetobacter baumannii is a major extensively drug-resistant lethal human nosocomial bacterium. However, the host innate immune mechanisms controlling A. baumannii are not well understood. Although viewed as an extracellular pathogen, A. baumannii can also invade and survive intracellularly. However, whether host innate immune pathways sensing intracellular bacteria contribute to immunity against A. baumannii is not known. Here, we provide evidence for the first time that intracellular antibacterial innate immune receptors Nod1 and Nod2, and their adaptor Rip2, play critical roles in the sensing and clearance of A. baumannii by human airway epithelial cells in vitro. A. baumannii infection upregulated Rip2 expression. Silencing of Nod1, Nod2, and Rip2 expression profoundly increased intracellular invasion and prolonged the multiplication and survival of A. baumannii in lung epithelial cells. Notably, the Nod1/2-Rip2 axis did not contribute to the control of A. baumannii infection of human macrophages, indicating that they play cell type-specific roles. The Nod1/2-Rip2 axis was needed for A. baumannii infection-induced activation of NF-κB but not mitogen-activated protein kinases. Moreover, the Nod1/2-Rip2 axis was critical to induce optimal cytokine and chemokine responses to A. baumannii infection. Mechanistic studies showed that the Nod1/2 pathway contributed to the innate control of A. baumannii infection through the production of β-defensin 2 by airway epithelial cells. This study revealed new insights into the immune control of A. baumannii and may contribute to the development of effective immune therapeutics and vaccines against A. baumannii.
鲍曼不动杆菌是一种主要的广泛耐药性致命人类医院获得性细菌。然而，宿主固有免疫机制控制鲍曼不动杆菌的机制尚不清楚。虽然被认为是一种细胞外病原体，但鲍曼不动杆菌也可以入侵和在细胞内生存。然而，宿主固有免疫途径感知细胞内细菌是否有助于对鲍曼不动杆菌的免疫尚不清楚。在这里，我们首次提供证据表明，细胞内抗菌固有免疫受体 Nod1 和 Nod2 及其衔接蛋白 Rip2，在体外对人呼吸道上皮细胞中鲍曼不动杆菌的检测和清除中发挥关键作用。鲍曼不动杆菌感染上调 Rip2 的表达。沉默 Nod1、Nod2 和 Rip2 的表达显著增加了细胞内入侵，并延长了鲍曼不动杆菌在肺上皮细胞中的增殖和存活。值得注意的是，Nod1/2-Rip2 轴不参与控制人巨噬细胞中鲍曼不动杆菌的感染，表明它们发挥细胞类型特异性作用。Nod1/2-Rip2 轴是鲍曼不动杆菌感染诱导 NF-κB 激活所必需的，但不是丝裂原激活蛋白激酶。此外，Nod1/2-Rip2 轴对于诱导对鲍曼不动杆菌感染的最佳细胞因子和趋化因子反应是必需的。机制研究表明，Nod1/2 途径通过气道上皮细胞产生β-防御素 2 来促进对鲍曼不动杆菌感染的固有控制。这项研究揭示了对鲍曼不动杆菌免疫控制的新见解，并可能有助于开发针对鲍曼不动杆菌的有效免疫治疗和疫苗。
