Bacterial Responses to Iron Withholding by Calprotectin

Obisesan, Adunoluwa O.; Zygiel, Emily M.; Nolan, Elizabeth M.

doi:10.1021/acs.biochem.1c00572

Cited by 10 publications

(10 citation statements)

References 92 publications

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“…We show here that the Δ mtsA mutant strain is more susceptible to chelation by calprotectin than WT GBS, and while supplementation of extracellular Mn 2+ rescues growth of calprotectin-treated WT GBS, the Δ mtsA mutant strain remains susceptible to chelation despite Mn 2+ supplementation. While our work has focused on the role of MtsA in Mn 2+ homeostasis, in light of previous work showing the ability of calprotectin to also induce iron stress ( 61 – 63 ) and knowledge that expression of the GBS mtsABC locus is induced under both Mn 2+ and iron limitation ( 64 ), it will be of interest to examine whether the mtsABC locus is also involved in iron uptake and how this might contribute to GBS colonization of the FRT.…”

Section: Discussionmentioning

confidence: 99%

Genomic Analyses Identify Manganese Homeostasis as a Driver of Group B Streptococcal Vaginal Colonization

Burcham

Akbari

Alhajjar

et al. 2022

mBio

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Section: Discussionmentioning

confidence: 99%

Genomic Analyses Identify Manganese Homeostasis as a Driver of Group B Streptococcal Vaginal Colonization

Burcham

Akbari

Alhajjar

et al. 2022

mBio

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“…A large body of literature has demonstrated that A . baumannii is transcriptionally responsive to nutrient metal sequestration by host metalloproteins such as calprotectin [ 23 – 26 , 57 – 59 ], as well as to iron and copper stress, both in vitro and in vivo [ 79 – 92 ]. We therefore hypothesized that nutritional immunity may play an essential role in the innate immune response to this pathogen and sought to further investigate these processes during infection.…”

Section: Resultsmentioning

confidence: 99%

Lipocalin-2 is an essential component of the innate immune response to Acinetobacter baumannii infection

et al. 2022

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Acinetobacter baumannii is an opportunistic pathogen and an emerging global health threat. Within healthcare settings, major presentations of A. baumannii include bloodstream infections and ventilator-associated pneumonia. The increased prevalence of ventilated patients during the COVID-19 pandemic has led to a rise in secondary bacterial pneumonia caused by multidrug resistant (MDR) A. baumannii. Additionally, due to its MDR status and the lack of antimicrobial drugs in the development pipeline, the World Health Organization has designated carbapenem-resistant A. baumannii to be its priority critical pathogen for the development of novel therapeutics. To better inform the design of new treatment options, a comprehensive understanding of how the host contains A. baumannii infection is required. Here, we investigate the innate immune response to A. baumannii by assessing the impact of infection on host gene expression using NanoString technology. The transcriptional profile observed in the A. baumannii infected host is characteristic of Gram-negative bacteremia and reveals expression patterns consistent with the induction of nutritional immunity, a process by which the host exploits the availability of essential nutrient metals to curtail bacterial proliferation. The gene encoding for lipocalin-2 (Lcn2), a siderophore sequestering protein, was the most highly upregulated during A. baumannii bacteremia, of the targets assessed, and corresponds to robust LCN2 expression in tissues. Lcn2-/- mice exhibited distinct organ-specific gene expression changes including increased transcription of genes involved in metal sequestration, such as S100A8 and S100A9, suggesting a potential compensatory mechanism to perturbed metal homeostasis. In vitro, LCN2 inhibits the iron-dependent growth of A. baumannii and induces iron-regulated gene expression. To elucidate the role of LCN2 in infection, WT and Lcn2-/- mice were infected with A. baumannii using both bacteremia and pneumonia models. LCN2 was not required to control bacterial growth during bacteremia but was protective against mortality. In contrast, during pneumonia Lcn2-/- mice had increased bacterial burdens in all organs evaluated, suggesting that LCN2 plays an important role in inhibiting the survival and dissemination of A. baumannii. The control of A. baumannii infection by LCN2 is likely multifactorial, and our results suggest that impairment of iron acquisition by the pathogen is a contributing factor. Modulation of LCN2 expression or modifying the structure of LCN2 to expand upon its ability to sequester siderophores may thus represent feasible avenues for therapeutic development against this pathogen.

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“…Calprotectin (CP) was originally identified to be involved in Mn 2+ limitation by the host, but was more recently found to bind Fe 2+ efficiently in the presence of Ca 2+ ( Nakashige et al, 2015 ). It has been demonstrated that CP induces Fe starvation in S. aureus cultures ( Obisesan, Zygiel, and Nolan 2021 ; Zygiel et al, 2021 ). The ability of S. aureus to efficiently incorporate heme affords protection against CP induced Fe starvation ( Zygiel et al, 2021 ).…”

Section: Overcoming Reduced Iron Availabilitymentioning

confidence: 99%

The Role of Iron in Staphylococcus aureus Infection and Human Disease: A Metal Tug of War at the Host—Microbe Interface

Dijk

Kruijff

Hagedoorn

2022

Front. Cell Dev. Biol.

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Iron deficiency anemia can be treated with oral or intravenous Fe supplementation. Such supplementation has considerable effects on the human microbiome, and on opportunistic pathogenic micro-organisms. Molecular understanding of the control and regulation of Fe availability at the host-microbe interface is crucial to interpreting the side effects of Fe supplementation. Here, we provide a concise overview of the regulation of Fe by the opportunistic pathogen Staphylococcus aureus. Ferric uptake regulator (Fur) plays a central role in controlling Fe uptake, utilization and storage in order to maintain a required value. The micro-organism has a strong preference for heme iron as an Fe source, which is enabled by the Iron-regulated surface determinant (Isd) system. The strategies it employs to overcome Fe restriction imposed by the host include: hijacking host proteins, replacing metal cofactors, and replacing functions by non-metal dependent enzymes. We propose that integrated omics approaches, which include metalloproteomics, are necessary to provide a comprehensive understanding of the metal tug of war at the host-microbe interface down to the molecular level.

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Bacterial Responses to Iron Withholding by Calprotectin

Cited by 10 publications

References 92 publications

Genomic Analyses Identify Manganese Homeostasis as a Driver of Group B Streptococcal Vaginal Colonization

Genomic Analyses Identify Manganese Homeostasis as a Driver of Group B Streptococcal Vaginal Colonization

Lipocalin-2 is an essential component of the innate immune response to Acinetobacter baumannii infection

The Role of Iron in Staphylococcus aureus Infection and Human Disease: A Metal Tug of War at the Host—Microbe Interface

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