In vivo growth of Staphylococcus lugdunensis is facilitated by the concerted function of heme and non-heme iron acquisition mechanisms

Ronald S Flannagan,Jeremy R Brozyna,Brijesh Kumar,Lea A Adolf,Jeffrey John Power,Simon Heilbronner,David E Heinrichs

doi:10.1016/j.jbc.2022.101823

Ronald S Flannagan, Jeremy R Brozyna + Show 5 more

Open Access

https://doi.org/10.1016/j.jbc.2022.101823

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Abstract

Staphylococcus lugdunensis has increasingly been recognized as a pathogen that can cause serious infection indicating this bacterium overcomes host nutritional immunity. Despite this, there exists a significant knowledge gap regarding the iron acquisition mechanisms employed by S. lugdunensis, especially during infection of the mammalian host. Here we show that S. lugdunensis can usurp hydroxamate siderophores and staphyloferrin A and B from Staphylococcus aureus. These transport activities all required a functional FhuC ATPase. Moreover, we show that the acquisition of catechol siderophores and catecholamine stress hormones by S. lugdunensis required the presence of the sst-1 transporter-encoding locus, but not the sst-2 locus. Iron-dependent growth in acidic culture conditions necessitated the ferrous iron transport system encoded by feoAB. Heme iron was acquired via expression of the iron-regulated surface determinant (isd) locus. During systemic infection of mice, we demonstrated that while S. lugdunensis does not cause overt illness, it does colonize and proliferate to high numbers in the kidneys. By combining mutations in the various iron acquisition loci (isd, fhuC, sst-1, and feo), we demonstrate that only a strain deficient for all of these systems was attenuated in its ability to proliferate to high numbers in the murine kidney. We propose the concerted action of heme and non-heme iron acquisition systems also enable S. lugdunensis to cause human infection.

Highlights

Iron (Fe) is an essential nutrient for most forms of life, and despite its importance and abundance on earth, it primarily exists, at neutral pH, in an insoluble, ferric iron (Fe3+) state
Given that the ability to acquire iron from the host is essential for bacteria to cause infection, we speculated that S. lugdunensis and S. aureus may display similar capacity for iron acquisition
Using bacterial two-hybrid analyses, we demonstrated that IsdL, and not FhuC, interacted with the IsdF membrane permease (Fig. S4B), providing further proof that the iron-regulated surface determinant (Isd) heme acquisition system has a dedicated ATPase to power heme uptake, and that FhuC does not function in heme acquisition, rather it operates with the siderophore transporters in S. lugdunensis

Summary

Introduction

Iron (Fe) is an essential nutrient for most forms of life, and despite its importance and abundance on earth, it primarily exists, at neutral pH, in an insoluble, ferric iron (Fe3+) state. These data reveal that S. lugdunensis HKU09-01 is reliant on the fhuC gene to utilize SA and SB, in addition to hydroxamate type siderophores, for growth under iron limited conditions.

Results

Conclusion