Klebsiella pneumoniae manipulates human macrophages to acquire iron

Frontiers in Microbiology

Microbiology

Richard Hilbe¹  Clemens Michael Gehrer¹  Igor Theurl¹  Natascha Brigo¹  Philipp Grubwieser¹  Manfred Nairz¹  Sylvia Berger¹  Günter Weiss²  Alexander Hoffmann²  Markus Seifert²  Manuel Grander² 

[1] Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pulmonology, Medical University of Innsbruck, Innsbruck, Austria;Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pulmonology, Medical University of Innsbruck, Innsbruck, Austria;Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria;

关键词: macrophages;    Klebsiella pneumoniae;    immune metabolism;    iron;    transferrin;    transferrin receptor;    interleukin-10;   

DOI  :  10.3389/fmicb.2023.1223113

 received in 2023-05-15, accepted in 2023-07-17,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundKlebsiella pneumoniae (KP) is a major cause of hospital-acquired infections, such as pneumonia. Moreover, it is classified as a pathogen of concern due to sprawling anti-microbial resistance. During infection, the gram-negative pathogen is capable of establishing an intracellular niche in macrophages by altering cellular metabolism. One factor critically affecting the host-pathogen interaction is the availability of essential nutrients, like iron, which is required for KP to proliferate but which also modulates anti-microbial immune effector pathways. We hypothesized, that KP manipulates macrophage iron homeostasis to acquire this crucial nutrient for sustained proliferation.MethodsWe applied an in-vitro infection model, in which human macrophage-like PMA-differentiated THP1 cells were infected with KP (strain ATCC 43816). During a 24-h course of infection, we quantified the number of intracellular bacteria via serial plating of cell lysates and evaluated the effects of different stimuli on intracellular bacterial numbers and iron acquisition. Furthermore, we analyzed host and pathogen specific gene and protein expression of key iron metabolism molecules.ResultsViable bacteria are recovered from macrophage cell lysates during the course of infection, indicative of persistence of bacteria within host cells and inefficient pathogen clearing by macrophages. Strikingly, following KP infection macrophages strongly induce the expression of the main cellular iron importer transferrin-receptor-1 (TFR1). Accordingly, intracellular KP proliferation is further augmented by the addition of iron loaded transferrin. The induction of TFR1 is mediated via the STAT-6-IL-10 axis, and pharmacological inhibition of this pathway reduces macrophage iron uptake, elicits bacterial iron starvation, and decreases bacterial survival.ConclusionOur results suggest, that KP manipulates macrophage iron metabolism to acquire iron once confined inside the host cell and enforces intracellular bacterial persistence. This is facilitated by microbial mediated induction of TFR1 via the STAT-6-IL-10 axis. Mechanistic insights into immune metabolism will provide opportunities for the development of novel antimicrobial therapies.

【 授权许可】

Unknown   
Copyright © 2023 Grubwieser, Hilbe, Gehrer, Grander, Brigo, Hoffmann, Seifert, Berger, Theurl, Nairz and Weiss.