Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon, Hong Kong SAR, China; State Key Lab of Chemical Biology and Drug Discovery and the Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China.
State Key Lab of Chemical Biology and Drug Discovery and the Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China.
EBioMedicine. 2024 Oct;108:105340. doi: 10.1016/j.ebiom.2024.105340. Epub 2024 Sep 19.
The continuous emergence of multidrug-resistant (MDR) Acinetobacter baumannii (Ab) strains poses further challenges in its control and clinical management. It is necessary to decipher the mechanisms underlying the high mortality of Ab infections to explore unconventional strategies for controlling outbreaks of drug-resistant infections.
The immune responses of Ab sepsis infection were investigated using flow cytometry, RNA-seq, qRT-PCR, and ELISA and scRNA-seq. The detailed pathways mediating Ab immune responses were also depicted and a specific therapy was developed based on the understanding of the mechanisms underlying Ab-induced cytokine storms.
The results highlighted the critical role of alveolar and interstitial macrophages as targets of Ab during the infection process. These cells were found to undergo polarization towards the M1 phenotype, triggering a cytokine storm that eventually caused the death of the host. The polarization and excessive inflammatory response mediated by macrophages were mainly regulated by the TLR2/Myd88/NF-κB signaling pathway. Suppression of Ab-triggered inflammatory responses and M1 polarization by the drug naproxen (NPXS) was shown to confer full protection of mice from lethal infections.
The findings in this work depict the major mechanisms underlying the high mortality rate of Ab infections and highlight the clinical potential application of anti-inflammatory drugs or immunosuppressants in reducing the mortality of such infections, including those caused by MDR strains.
Funding sources are described in the acknowledgments section.
多重耐药（MDR）鲍曼不动杆菌（Ab）菌株的不断出现给其控制和临床管理带来了更大的挑战。有必要破译 Ab 感染高死亡率的机制，以探索控制耐药感染爆发的非常规策略。
采用流式细胞术、RNA-seq、qRT-PCR 和 ELISA 和 scRNA-seq 研究 Ab 败血症感染的免疫反应。还描绘了介导 Ab 免疫反应的详细途径，并基于对 Ab 诱导细胞因子风暴机制的理解，开发了一种特定的治疗方法。
结果强调了肺泡和间质巨噬细胞作为 Ab 在感染过程中的靶细胞的关键作用。这些细胞被发现向 M1 表型极化，引发细胞因子风暴，最终导致宿主死亡。巨噬细胞介导的极化和过度炎症反应主要受 TLR2/Myd88/NF-κB 信号通路调节。抑制 Ab 触发的炎症反应和 M1 极化的药物萘普生（NPXS）可完全保护小鼠免受致死性感染。
这项工作中的发现描绘了 Ab 感染高死亡率的主要机制，并强调了抗炎药物或免疫抑制剂在降低此类感染（包括 MDR 菌株引起的感染）死亡率方面的临床应用潜力。
资助来源在致谢部分中描述。
