The human innate immune protein calprotectin induces iron starvation responses in Pseudomonas aeruginosa

Zygiel, Emily M.; Nelson, Cassandra E.; Brewer, Luke K.; Oglesby-Sherrouse, Amanda G.; Nolan, Elizabeth M.

doi:10.1074/jbc.ra118.006819

Cited by 63 publications

(197 citation statements)

References 65 publications

(87 reference statements)

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“…The rewiring of metabolic networks that is suggested by our proteomics study also appears to contribute to alterations in virulence factor production. We show that iron starvation downregulates several proteins in the phenazine biosynthesis proteins, consistent with reduced phenazine production upon iron starvation, as observed by Zygiel et al in a recent study performed under similar conditions (51). Previous work demonstrated the phenazines play a role in biofilm development by reducing ferric iron to ferrous iron, thereby aiding in iron acquisition (74).…”

Section: Discussionsupporting

confidence: 90%

“…6A) (50). These data are consistent with recently published work showing that phenazine metabolites are reduced upon iron starvation mediated by the host innate immune protein calprotectin (51). The amino acid sequences of the enzymes encoded by the two phz operons are 100% identical from PhzC to PhzG, so only PhzA1/A2 and PhzB1/B2 could be differentiated by proteomic analysis.…”

Section: Proteomics Reveals Broad Changes In Metabolic Proteins Upon supporting

confidence: 89%

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Proteomic Analysis of the Pseudomonas aeruginosa Iron Starvation Response Reveals PrrF Small Regulatory RNA-Dependent Iron Regulation of Twitching Motility, Amino Acid Metabolism, and Zinc Homeostasis Proteins

et al. 2019

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Iron is a critical nutrient for most microbial pathogens, and the immune system exploits this requirement by sequestering iron. The opportunistic pathogen Pseudomonas aeruginosa exhibits a high requirement for iron yet an exquisite ability to overcome iron deprivation during infection. Upon iron starvation, P. aeruginosa induces the expression of several high-affinity iron acquisition systems, as well as the PrrF small regulatory RNAs (sRNAs) that mediate an iron-sparing response. Here, we used liquid chromatography-tandem mass spectrometry to conduct proteomics of the iron starvation response of P. aeruginosa. Iron starvation increased levels of multiple proteins involved in amino acid catabolism, providing the capacity for iron-independent entry of carbons into the tricarboxylic acid (TCA) cycle. Proteins involved in sulfur assimilation and cysteine biosynthesis were reduced upon iron starvation, while proteins involved in iron-sulfur cluster biogenesis were increased, highlighting the central role of iron in P. aeruginosa metabolism. Iron starvation also resulted in changes in the expression of several zinc-responsive proteins and increased levels of twitching motility proteins. Subsequent analyses provided evidence for the regulation of many of these proteins via posttranscriptional regulatory events, some of which are dependent upon the PrrF sRNAs. Moreover, we showed that iron-regulated twitching motility is partially dependent upon the prrF locus, highlighting a novel link between the PrrF sRNAs and motility. These findings add to the known impacts of iron starvation in P. aeruginosa and outline potentially novel roles for the PrrF sRNAs in iron homeostasis and pathogenesis. IMPORTANCE Iron is central for growth and metabolism of almost all microbial pathogens, and as such, this element is sequestered by the host innate immune system to restrict microbial growth. Here, we used label-free proteomics to investigate the Pseudomonas aeruginosa iron starvation response, revealing a broad landscape of metabolic and metal homeostasis changes that have not previously been described. We further provide evidence that many of these processes, including twitching motility, are regulated through the iron-responsive PrrF small regulatory RNAs. As such, this study demonstrates the power of proteomics for defining stress responses of microbial pathogens.

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Section: Discussionsupporting

confidence: 90%

Section: Proteomics Reveals Broad Changes In Metabolic Proteins Upon supporting

confidence: 89%

Proteomic Analysis of the Pseudomonas aeruginosa Iron Starvation Response Reveals PrrF Small Regulatory RNA-Dependent Iron Regulation of Twitching Motility, Amino Acid Metabolism, and Zinc Homeostasis Proteins

et al. 2019

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“…The immune protein calprotectin has been shown to play a critical role in hampering the progress of infections associated with pathogens occupying a range of host niches, including Staphylococcus aureus, Helicobacter pylori, Candida albicans, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterococcus faecalis (32,(56)(57)(58)(59)(60). Though earlier reports suggested that calprotectin was incapable of binding Fe in the host environment, new evidence has emerged indicating that calprotectin can starve bacteria for iron in selected media as well as under certain in vivo conditions (3,32,43,(56)(57)(58)(59)(60)(61)(62). Importantly, enzymatic function of the S. mutans superoxide dismutase (SOD) is heavily dependent on Mn for protection from oxidative stresses.…”

Section: Discussionmentioning

confidence: 99%

Manganese Uptake, Mediated by SloABC and MntH, Is Essential for the Fitness of Streptococcus mutans

Kajfasz

Katrak

Ganguly

et al. 2020

mSphere

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Early epidemiological studies implicated manganese (Mn) as a possible caries-promoting agent, while laboratory studies have indicated that manganese stimulates the expression of virulence-related factors in the dental pathogen Streptococcus mutans. To better understand the importance of manganese homeostasis to S. mutans pathophysiology, we first used RNA sequencing to obtain the global transcriptional profile of S. mutans UA159 grown under Mn-restricted conditions. Among the most highly expressed genes were those of the entire sloABC operon, encoding a dual iron/manganese transporter, and an uncharacterized gene, here mntH, that codes for a protein bearing strong similarity to Nramp-type transporters. While inactivation of sloC, which encodes the lipoprotein receptor of the SloABC system, or of mntH alone had no major consequence for the overall fitness of S. mutans, simultaneous inactivation of sloC and mntH (ΔsloC ΔmntH) impaired growth and survival under Mn-restricted conditions, including in human saliva or in the presence of calprotectin. Further, disruption of Mn transport resulted in diminished stress tolerance and reduced biofilm formation in the presence of sucrose. These phenotypes were markedly improved when cells were provided with excess Mn. Metal quantifications revealed that the single mutant strains contained intracellular levels of Mn similar to those seen with the parent strain, whereas Mn was nearly undetectable in the ΔsloC ΔmntH strain. Collectively, these results reveal that SloABC and MntH work independently and cooperatively to promote cell growth under Mn-restricted conditions and that maintenance of Mn homeostasis is essential for the expression of major virulence attributes in S. mutans. IMPORTANCE As transition biometals such as manganese (Mn) are essential for all forms of life, the ability to scavenge biometals in the metal-restricted host environment is an important trait of successful cariogenic pathobionts. Here, we showed that the caries pathogen Streptococcus mutans utilizes two Mn transport systems, namely, SloABC and MntH, to acquire Mn from the environment and that the ability to maintain the cellular levels of Mn is important for the manifestation of characteristics that associate S. mutans with dental caries. Our results indicate that the development of strategies to deprive S. mutans of Mn hold promise in the combat against this important bacterial pathogen.

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“…Additionally, bacterial relationships are also shaped by the presence of other host proteins involved in the immune response. Calprotectin, a protein released from neutrophils or other phagocytes, sequesters essential nutrients including iron, zinc, and manganese away from bacteria in order to inhibit their growth (Zygiel et al, 2019). Iron-, zinc-, and manganese-limited environments in turn repress the production of anti-staphylococcal factors in P. aeruginosa, promoting increased levels of P. aeruginosa and S. aureus cocolonization in vitro and in vivo (Wakeman et al, 2016).…”

Section: Enhanced Tolerancementioning

confidence: 99%

Bacterial Community Interactions During Chronic Respiratory Disease

Welp

Bomberger

2020

Front. Cell. Infect. Microbiol.

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Chronic respiratory diseases including chronic rhinosinusitis, otitis media, asthma, cystic fibrosis, non-CF bronchiectasis, and chronic obstructive pulmonary disease are a major public health burden. Patients suffering from chronic respiratory disease are prone to persistent, debilitating respiratory infections due to the decreased ability to clear pathogens from the respiratory tract. Such infections often develop into chronic, lifelong complications that are difficult to treat with antibiotics due to the formation of recalcitrant biofilms. The microbial communities present in the upper and lower respiratory tracts change as these respiratory diseases progress, often becoming less diverse and dysbiotic, correlating with worsening patient morbidity. Those with chronic respiratory disease are commonly infected with a shared group of respiratory pathogens including Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, and Moraxella catarrhalis, among others. In order to understand the microbial landscape of the respiratory tract during chronic disease, we review the known inter-species interactions among these organisms and other common respiratory flora. We consider both the balance between cooperative and competitive interactions in relation to microbial community structure. By reviewing the major causes of chronic respiratory disease, we identify common features across disease states and signals that might contribute to community shifts. As microbiome shifts have been associated with respiratory disease progression, worsening morbidity, and increased mortality, these underlying community interactions likely have an impact on respiratory disease state.

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The human innate immune protein calprotectin induces iron starvation responses in Pseudomonas aeruginosa

Cited by 63 publications

References 65 publications

Proteomic Analysis of the Pseudomonas aeruginosa Iron Starvation Response Reveals PrrF Small Regulatory RNA-Dependent Iron Regulation of Twitching Motility, Amino Acid Metabolism, and Zinc Homeostasis Proteins

Proteomic Analysis of the Pseudomonas aeruginosa Iron Starvation Response Reveals PrrF Small Regulatory RNA-Dependent Iron Regulation of Twitching Motility, Amino Acid Metabolism, and Zinc Homeostasis Proteins

Manganese Uptake, Mediated by SloABC and MntH, Is Essential for the Fitness of Streptococcus mutans

Bacterial Community Interactions During Chronic Respiratory Disease

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