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.
Highlights
A new, hypervirulent variant of K. pneumoniae, which typically presents as community-acquired pyogenic liver abscess with sepsis, is an emerging infectious disease that poses an urgent threat to human health
We investigated whether an hypervirulent variant of K. pneumoniae (hvKP) isolate ESKPK1 can stimulate NET formation ex vivo independent of a priming agent such as phorbol 12-myristate 13-acetate, using neutrophils isolated from three different Klebsiella liver abscess (KLA) patients
A recent study showed that K1 isolates could delay human neutrophil apoptosis and survive neutrophil killing, again postulating that a “Trojan horse” mechanism could be at work in humans (Lee et al, 2017)
Summary
A new, hypervirulent variant of K. pneumoniae (hvKP), which typically presents as community-acquired pyogenic liver abscess with sepsis, is an emerging infectious disease that poses an urgent threat to human health. The vast majority of hvKP that cause KLA are K1 and K2 capsule types, accounting for 59–69 and 5–20%, respectively, of the cases described in Taiwan, Korea, Singapore, and China (Fung et al, 2002; Chung et al, 2007; Qu et al, 2015; Lee et al, 2016) In these countries, diabetes mellitus (DM) is the most commonly associated comorbidity, present in 40–78% of KLA patients (Fung et al, 2002; Chung et al, 2007; Qu et al, 2015; Lee et al, 2016). Beyond the general understanding that DM is a risk factor for development of KLA and possibly KLA-associated complications, little is known about how DM affects the innate immune system in response to the different capsule types
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