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Published on: March 16, 2018
Klebsiella pneumoniae manipulates human macrophages to acquire iron
Philipp Grubwieser1, Richard Hilbe1, Clemens Michael Gehrer1
1Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pulmonology, Medical University of Innsbruck, Innsbruck, Austria.
Background:
Klebsiella 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.
Methods:
We 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.
Results:
Viable 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.
Conclusion:
Our 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.
Insights
Klebsiella pneumoniae manipulates macrophage iron to survive inside host cells. This involves inducing transferrin receptor 1 (TFR1) via the STAT-6-IL-10 pathway, which can be targeted for new antimicrobial therapies.
Area of Science:
- Microbiology
- Immunology
- Infectious Diseases
Background:
- Klebsiella pneumoniae (KP) is a significant cause of hospital-acquired infections and a growing concern due to antimicrobial resistance.
- KP establishes intracellular infections within macrophages by altering host cell metabolism.
- Iron availability is critical for KP proliferation and influences host antimicrobial responses.
Purpose of the Study:
- To investigate the hypothesis that KP manipulates macrophage iron homeostasis for nutrient acquisition.
- To understand the mechanisms by which KP persists intracellularly within macrophages.
Main Methods:
- An in vitro model using human THP1 macrophages infected with KP.
- Quantification of intracellular bacteria and analysis of iron acquisition during infection.
- Assessment of host and pathogen gene/protein expression related to iron metabolism.
Main Results:
- KP persists within macrophages, with viable bacteria recovered from cell lysates.
- Macrophage transferrin receptor 1 (TFR1) expression is significantly induced post-KP infection.
- Iron supplementation enhances intracellular KP proliferation, while inhibiting the STAT-6-IL-10 pathway reduces bacterial survival.
Conclusions:
- KP actively manipulates macrophage iron metabolism to support intracellular proliferation and persistence.
- Microbial induction of TFR1 via the STAT-6-IL-10 axis is a key mechanism for KP iron acquisition.
- Understanding these immune-metabolic interactions offers potential for novel antimicrobial strategies.
