Department of Biochemistry, Yong Loo Lin School of Medicine, National University of SingaporeSingapore, Singapore.
Department of Medicine, Yong Loo Lin School of Medicine, National University of SingaporeSingapore, Singapore.
Front Cell Infect Microbiol. 2017 Sep 7;7:401. doi: 10.3389/fcimb.2017.00401. eCollection 2017.
The major risk factor for Klebsiella liver abscess (KLA) is type 2 diabetes mellitus (DM), but the immunological mechanisms involved in the increased susceptibility are poorly defined. We investigated the responses of neutrophils and peripheral blood mononuclear cells (PBMCs) to hypervirulent (hvKP), the causative agent of KLA. DNA and myeloperoxidase levels were elevated in the plasma of KLA patients compared to uninfected individuals indicating neutrophil activation, but diabetic status had no effect on these neutrophil extracellular trap (NET) biomarkers in both subject groups. Clinical hvKP isolates universally stimulated KLA patient neutrophils to produce NETs , regardless of host diabetic status. Ability of representative capsule types (K1, K2, and non-K1/K2 strains) to survive intra- and extra-cellular killing by type 2 DM and healthy neutrophils was subsequently examined. Key findings were: (1) type 2 DM and healthy neutrophils exhibited comparable total, phagocytic, and NETs killing against hvKP, (2) phagocytic and NETs killing were equally effective against hvKP, and (3) hypermucoviscous K1 and K2 strains were more resistant to total, phagocytic, and NETs killing compared to the non-mucoviscous, non-K1/K2 strain. The cytokine response and intracellular killing ability of type 2 DM as well as healthy PBMCs upon encounter with the different capsule types was also examined. Notably, the IL-12-IFNγ axis and its downstream chemokines MIG, IP-10, and RANTES were produced at slightly lower levels by type 2 DM PBMCs than healthy PBMCs in response to representative K1 and non-K1/K2 strains. Furthermore, type 2 DM PBMCs have a mild defect in its ability to control hvKP replication relative to healthy PBMCs. In summary, our work demonstrates that type 2 DM does not overtly impact neutrophil intra- and extra-cellular killing of hvKP, but may influence cytokine/chemokine production and intracellular killing by PBMCs.
产酸克雷伯菌肝脓肿（KLA）的主要危险因素是 2 型糖尿病（DM），但其易感性增加的免疫机制尚不清楚。我们研究了产超毒力（hvKP）的中性粒细胞和外周血单核细胞（PBMC）的反应，hvKP 是 KLA 的致病因子。与未感染者相比，KLA 患者的血浆中 DNA 和髓过氧化物酶水平升高，表明中性粒细胞活化，但两组患者的糖尿病状态对这些中性粒细胞胞外诱捕（NET）生物标志物均无影响。临床 hvKP 分离株普遍刺激 KLA 患者的中性粒细胞产生 NET，而与宿主的糖尿病状态无关。随后检查了代表性荚膜类型（K1、K2 和非 K1/K2 株）在 2 型 DM 和健康中性粒细胞体内和体外杀伤中的存活能力。主要发现如下：（1）2 型 DM 和健康中性粒细胞对 hvKP 的总杀伤、吞噬杀伤和 NET 杀伤能力相当；（2）吞噬杀伤和 NET 杀伤对 hvKP 同样有效；（3）与非粘液性、非 K1/K2 株相比，高粘液性 K1 和 K2 株对总杀伤、吞噬杀伤和 NET 杀伤的抵抗力更强。还研究了 2 型 DM 和健康 PBMC 与不同荚膜类型相遇时的细胞因子反应和细胞内杀伤能力。值得注意的是，与健康 PBMC 相比，2 型 DM PBMC 对代表性 K1 和非 K1/K2 株的反应中，IL-12-IFNγ 轴及其下游趋化因子 MIG、IP-10 和 RANTES 的产生水平略低。此外，与健康 PBMC 相比，2 型 DM PBMC 对 hvKP 复制的控制能力略有缺陷。总之，我们的工作表明，2 型 DM 不会明显影响中性粒细胞对 hvKP 的体内和体外杀伤，但可能影响 PBMC 的细胞因子/趋化因子产生和细胞内杀伤。
