Comparison of Diabetic and Non-diabetic Human Leukocytic Responses to Different Capsule Types of Klebsiella pneumoniae Responsible for Causing Pyogenic Liver Abscess

Abstract

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 Klebsiella pneumoniae (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 ex vivo, 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.

Clinical and computed tomography features of extended-spectrum β-lactamase-producing Klebsiella pneumoniae liver abscess

“…Moreover, these patients often undergo surgical interventions, chemotherapy, radiotherapy, and antibiotic therapy; this could negatively influence the gut flora and the immune system and my enhance the risk of ESBL-producing KPLA. Previous studies have reported that diabetes is an independent risk factor for KPLA [33][34][35]. However, in our study, both univariate and multivariate analyses showed that diabetes was not associated with ESBL-producing KPLA.…”

Protective Role of Kupffer Cells and Macrophages in Klebsiella pneumoniae-Induced Liver Abscess Disease

“…Several studies have examined the role of neutrophils during KLA infection (25). Neutrophils have been reported to effectively kill K. pneumoniae via myeloperoxidase and neutrophil elastase, and it has been shown that hvKp isolates were more resistant than cKp isolates to neutrophil phagocytosis and intracellular killing in vitro (26)(27)(28)(29). It was also shown that during K. pneumoniae infection, K1 bacteria were more resistant to intracellular killing after being phagocytosed by neutrophils and that their escape from neutrophils could potentially contribute to dissemination and metastasis of the disease (30).…”

Cyclic AMP-CRP Modulates the Cell Morphology of Klebsiella pneumoniae in High-Glucose Environment

“…Patients with diabetes have high susceptibility to K. pneumoniae infections (Yang et al, 2009;Lin et al, 2013c;Lee et al, 2017b). K. pneumoniae strains are more virulent in diabetic mice than in normal ones (Wu and Tsai, 2005).…”