Hepcidin-mediated iron sequestration protects against bacterial dissemination during pneumonia

Michels, Kathryn; Zhang, Zhimin; Bettina, Alexandra M.; Cagnina, R. Elaine; Stefanova, Debora; Burdick, Marie D.; Vaulont, Sophie; Nemeth, Elizabeta; Ganz, Tomas; Mehrad, Borna

doi:10.1172/jci.insight.92002

Cited by 75 publications

(72 citation statements)

References 67 publications

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“…The molecular mechanisms that allow bacteria to sense iron-rich environments and initiate rapid growth remain to be characterized. These mechanisms may be more widespread than is generally recognized, as Klebsiella pneumoniae [39] and Escherichia coli (manuscript in preparation) also manifest greatly enhanced, iron-dependent pathogenicity in hepcidin-1 knockout mice.…”

Section: Mouse Models Of Hepcidin Deficiency Implicate Non-transferrimentioning

confidence: 99%

Iron and infection

2017

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Section: Mouse Models Of Hepcidin Deficiency Implicate Non-transferrimentioning

confidence: 99%

Iron and infection

2017

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“…S4 ). Siderophore-mediated iron uptake is often required in vivo (39, 82, 83) due to iron sequestration by host proteins (84-87), thus the in vivo settings could support these interactions. Interestingly pyoverdine, the higher affinity siderophore, was not required for the co-culture response mirroring findings that genes for the biosynthesis of pyoverdine, but not pyochelin, are commonly disrupted in chronic CF clinical isolates (44-46).…”

Section: Discussionmentioning

confidence: 99%

Intra-species signaling betweenPseudomonas aeruginosagenotypes increases production of quorum sensing controlled virulence factors

Mould

Botelho

Hogan

2020

Preprint

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1The opportunistic pathogen Pseudomonas aeruginosa damages hosts through the 2 production of diverse secreted products, many of which are regulated by quorum 3 sensing. The lasR gene, which encodes a central quorum-sensing regulator, is 4 frequently mutated, and loss of LasR function impairs the activity of downstream 5 regulators RhlR and PqsR. We found that in diverse models, the presence of P. 6 aeruginosa wild type causes LasR loss-of-function strains to hyperproduce RhlR/I-7 regulated antagonistic factors, and autoinducer production by the wild type is not 8 required for this effect. We uncovered a reciprocal interaction between isogenic wild 9 type and lasR mutant pairs wherein the iron-scavenging siderophore pyochelin, 10 specifically produced by the lasR mutant, induces citrate release and cross-feeding from 11 wild type. Citrate stimulates RhlR signaling and RhlI levels in LasR-but not in LasR+ 12 strains, and the interactions occur in diverse media. Co-culture interactions between 13 strains that differ by the function of a single transcription factor may explain worse 14 outcomes associated with mixtures of LasR+ and LasR loss-of-function strains. More 15 broadly, this report illustrates how interactions within a genotypically diverse population, 16 similar to those that frequently develop in natural settings, can promote net virulence 17 factor production. (19, 20). Further, some LasR-strains exhibit rewired regulation of quorum sensing 35 (QS)-controlled exoproducts (21) and LasR-strains can activate QS signaling in 36 response to products from other species (22) or in specific culture conditions (23, 24). 37LasR-strains are also frequently found among LasR+ P. aeruginosa strains where 38 exoproducts can be shared or signal cross-feeding can occur (13). 39 P. aeruginosa LasR participates in the regulation of QS in conjunction with two 40 transcription factors: RhlR and PqsR (MvfR). Each of these three regulators has one or 41 more autoinducer ligands: 3-oxo-C12-homoserine lactone (3OC12HSL) for LasR, C4-42 homoserine lactone (C4HSL) for RhlR, and hydroxyalkylquinolones (Pseudomonas 43Quinolone Signal (PQS) and hydroxy-heptyl quinolone (HHQ)) for PqsR (25). In the 44 regulatory networks described in the widely-used P. aeruginosa model strains, LasR is 45 an upstream regulator of RhlR and PqsR signaling, and together these regulators 46 control the expression of a suite of genes associated with virulence including redox-47 active small molecule phenazines (26-28), cyanide (29), proteases (30-33), and 48 rhamnolipid surfactants important for surface motility, biofilm dispersal, and host cell 49 damage (34)(35)(36). 50Other traits that are often heterogeneous across P. aeruginosa isolates relate to 51 strategies for iron acquisition. P. aeruginosa procures iron through the use of 52 siderophores, including pyochelin (37-39) and pyoverdine (40), from heme or through a 53 direct iron uptake system (41-43). It is common to encounter P. aeruginosa strains with 54 loss of function mutations in genes encoding ...

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“…For instance, iron acquisition is essential for bacteria to thrive (414), and host factors that limit iron availability can be protective (235). Hepcidin, which is largely driven by IL-6-dependent STAT3 activity in the liver (361), limits iron availability by controlling its absorption in the intestines (362), and this factor was recently shown to be both sufficient and necessary for promoting defense against K. pneumonia in the lungs (331). Beyond opsonophagocytosis, leukocyte activation, and metal homeostasis, additional relevant APP functions may include protease regulation, hemostasis, toxin inhibition, microbial starvation, and more.…”

Section: Livermentioning

confidence: 99%

Integrative Physiology of Pneumonia

Quinton

Walkey

Mizgerd

2018

Physiological Reviews

205

203

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Pneumonia is a type of acute lower respiratory infection that is common and severe. The outcome of lower respiratory infection is determined by the degrees to which immunity is protective and inflammation is damaging. Intercellular and interorgan signaling networks coordinate these actions to fight infection and protect the tissue. Cells residing in the lung initiate and steer these responses, with additional immunity effectors recruited from the bloodstream. Responses of extrapulmonary tissues, including the liver, bone marrow, and others, are essential to resistance and resilience. Responses in the lung and extrapulmonary organs can also be counterproductive and drive acute and chronic comorbidities after respiratory infection. This review discusses cell-specific and organ-specific roles in the integrated physiological response to acute lung infection, and the mechanisms by which intercellular and interorgan signaling contribute to host defense and healthy respiratory physiology or to acute lung injury, chronic pulmonary disease, and adverse extrapulmonary sequelae. Pneumonia should no longer be perceived as simply an acute infection of the lung. Pneumonia susceptibility reflects ongoing and poorly understood chronic conditions, and pneumonia results in diverse and often persistent deleterious consequences for multiple physiological systems.

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Hepcidin-mediated iron sequestration protects against bacterial dissemination during pneumonia

Cited by 75 publications

References 67 publications

Iron and infection

Iron and infection

Intra-species signaling betweenPseudomonas aeruginosagenotypes increases production of quorum sensing controlled virulence factors

Integrative Physiology of Pneumonia

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