Macrophage sabotage

: undermining macrophage signalling by Klebsiella pneumoniae

Abstract

Klebsiella pneumoniae has been singled out as an urgent threat to human health due to the increasing number of multidrug resistant isolates. Notably, there are still significant knowledge gaps in our understanding of Klebsiella-innate immune system interface. In a previous work of the lab (Ivin et al., 2017), we demonstrated that type I IFN signalling plays an important role in host defence against the infection. In this work, we aim to shed mechanistic light into the role of type I IFN signalling in macrophage intrinsic immunity.

Wild Type and Interferon α/β receptor knockout (Ifnar1-/-) Immortalised Bone Marrow Derived Macrophages (iBMDMs) cells were infected. Inflammatory signals were quantified and intracellular bacteria quantified by plating assays and single cell microscopy analysis.

We observed an impaired formation of the phagocytic cup in Ifnar1-/- macrophages due increased cofilin inactivation. Intriguingly, type I IFN signalling is essential for the intracellular survival of Klebsiella in macrophages. Lastly, an increase of inflammation was observed in infected Ifnar1-/- macrophages suggesting that type I IFN signalling modulates inflammatory responses following Klebsiella infection.
Our results show that type I IFN signalling is essential for phagocytosis as well as intracellular survival of Klebsiella pneumoniae. We have also shown that interferon signalling is required for Klebsiella to limit inflammation. This work highlights the importance of using live pathogens to study immune responses as previous studies using Ifnar1-/- models have used LPS to simulate infection thus have missed this phenotype.

Date of Award	Dec 2023
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Northern Ireland Department for the Economy
Supervisor	Beckie Ingram (Supervisor), Adrien Kissenpfennig (Supervisor) & Jose Bengoechea (Supervisor)