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, Hung Hom, 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, Hung Hom, Hong Kong SAR, China.
Microbiol Res. 2024 Aug;285:127769. doi: 10.1016/j.micres.2024.127769. Epub 2024 May 17.
Carbapenem-resistant Klebsiella pneumoniae (CRKP) has emerged as a global threat due to its high mortality in clinical patients. However, the specific mechanisms underlying this increased mortality remain unclear. The objective of this study is to investigate how the development of a resistance phenotype contributes to the significantly higher mortality associated with this pathogen. To achieve this, a collection of isogeneic strains was generated. The clinical carbapenem-susceptible K. pneumoniae (CSKP) strain HKU3 served as the control isolate, while HKU3-KPC was created through conjugation with a bla-bearing plasmid and served as clinical CRKP strain. Using a sepsis model, it was demonstrated that both HKU3 and HKU3-KPC exhibited similar levels of virulence. Flow cytometry, RNA-seq, and ELISA analysis were employed to assess immune cell response, M1 macrophage polarization, and cytokine storm induction, revealing that both strains elicited comparable types and levels of these immune responses. Subsequently, meropenem was utilized to treat K. pneumoniae infection, and it was found that meropenem effectively reduced bacterial load, inhibited M1 macrophage polarization, and suppressed serum cytokine production during HKU3 (CSKP) infection. However, these effects were not observed in the case of HKU3-KPC (CRKP) infection. These findings provide evidence that the high mortality associated with CRKP is attributed to its enhanced survival within the host during antibiotic treatment, resulting in a cytokine storm and subsequent host death. The development of an effective therapy for CRKP infections could significantly reduce the mortality caused by this pathogen.
耐碳青霉烯肺炎克雷伯菌（CRKP）因其在临床患者中的高死亡率而成为全球威胁。然而，导致这种高死亡率的具体机制尚不清楚。本研究旨在探讨耐药表型的发展如何导致与该病原体相关的死亡率显著增加。为了实现这一目标，生成了一组同基因菌株。临床碳青霉烯敏感肺炎克雷伯菌（CSKP）菌株 HKU3 作为对照分离株，而通过与 bla 携带质粒的接合产生的 HKU3-KPC 作为临床耐碳青霉烯肺炎克雷伯菌（CRKP）菌株。使用脓毒症模型表明，HKU3 和 HKU3-KPC 均表现出相似的毒力水平。流式细胞术、RNA-seq 和 ELISA 分析用于评估免疫细胞反应、M1 巨噬细胞极化和细胞因子风暴诱导，结果表明两种菌株均引发了相似类型和水平的这些免疫反应。随后，使用美罗培南治疗肺炎克雷伯菌感染，发现美罗培南可有效降低细菌负荷，抑制 M1 巨噬细胞极化，并抑制 HKU3（CSKP）感染期间血清细胞因子的产生。然而，在 HKU3-KPC（CRKP）感染的情况下，未观察到这些效应。这些发现表明，CRKP 相关的高死亡率归因于其在抗生素治疗期间在宿主内的生存能力增强，导致细胞因子风暴和随后的宿主死亡。开发针对 CRKP 感染的有效治疗方法可能会显著降低该病原体引起的死亡率。
