Heme protects Pseudomonas aeruginosa and Staphylococcus aureus from calprotectin-induced iron starvation

Emily M Zygiel,Adunoluwa O Obisesan,Cassandra E Nelson,Amanda G Oglesby,Elizabeth M Nolan

doi:10.1074/jbc.ra120.015975

Emily M Zygiel, Adunoluwa O Obisesan + Show 3 more

Open Access

https://doi.org/10.1074/jbc.ra120.015975

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Abstract

Pseudomonas aeruginosa and Staphylococcus aureus are opportunistic bacterial pathogens that cause severe infections in immunocompromised individuals and patients with cystic fibrosis. Both P. aeruginosa and S. aureus require iron to infect the mammalian host. To obtain iron, these pathogens may rely on siderophore-mediated ferric iron uptake, ferrous iron uptake, or heme uptake at different points during infection. The preferred iron source depends on environmental conditions, including the presence of iron-sequestering host-defense proteins. Here, we investigate how the presence of heme, a highly relevant iron source during infection, affects bacterial responses to iron withholding by the innate immune protein calprotectin (CP). Prior work has shown that P. aeruginosa is starved of iron in the presence of CP. We report that P. aeruginosa upregulates expression of heme uptake machinery in response to CP. Furthermore, we show that heme protects P. aeruginosa from CP-mediated inhibition of iron uptake and iron-starvation responses. We extend our study to a second bacterial pathogen, S. aureus, and demonstrate that CP also inhibits iron uptake and induces iron-starvation responses by this pathogen. Similarly to P. aeruginosa, we show that heme protects S. aureus from CP-mediated inhibition of iron uptake and iron-starvation responses. These findings expand our understanding of microbial responses to iron sequestration by CP and highlight the importance of heme utilization for bacterial adaptation to host iron-withholding strategies.

Highlights

Pseudomonas aeruginosa and Staphylococcus aureus are two of the most prevalent nosocomial pathogens that can cause deleterious infections in part due to the emergence of multidrug-resistant strains [1]
The current work uncovers that the availability of heme as an iron source reduces the ability of CP to starve P. aeruginosa and S. aureus of iron (Figs. 9 and S8)
For P. aeruginosa, the importance of heme uptake has only recently been appreciated, and the current work indicates that when P. aeruginosa is challenged with CP, heme is an important iron source for the bacterium

Summary

Introduction

Pseudomonas aeruginosa and Staphylococcus aureus are two of the most prevalent nosocomial pathogens that can cause deleterious infections in part due to the emergence of multidrug-resistant strains [1]. Heme protects bacterial pathogens from calprotectin proteins lactoferrin and transferrin [15] These siderophores provide an important iron-acquisition strategy for S. aureus, studies have shown that S. aureus prefers heme, which accounts for 80% of the iron in the host, as an iron source [5, 16]. In response to bacterial infection, the host uses ironsequestering host-defense proteins, which are capable of limiting Fe(III), Fe(II), and heme at infection sites These proteins include lactoferrin, lipocalin-2, haptoglobin, hemopexin, and calprotectin (CP) and serve to starve invading bacterial pathogens of iron as part of the metalwithholding innate immune response [12, 18,19,20,21]. From the standpoint of iron in infection and immunity, CP is the only known Fe(II)-sequestering host-defense protein [20,21,22]

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