Sequential Inhalational Tobramycin-Colistin-Combination in CF-Patients with Chronic P. Aeruginosa Colonization - an Observational Study

Riethmüller, Joachim; Herrmann, Gloria; Graepler-Mainka, Ute; Hellwig, D.; Heuer, Hans-Eberhard; Heyder, S.; Köster, H.; Kinder, Birte; Kröger, Kristina; Paul, Klaus; Poplawska, Krystyna; Melichar, Volker O.; Smaczny, Christina; Mellies, Uwe

doi:10.1159/000447821

Cited by 17 publications

(9 citation statements)

References 18 publications

(25 reference statements)

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“…This modification is highly relevant in the clinical setting as aminoarabinose modification of lipid A is commonly observed in polymyxin-tolerant P. aeruginosa isolates ( 70 , 71 ). Nebulized colistin is commonly used to reduce P. aeruginosa burdens in the lungs of CF patients ( 72 – 74 ). Our results suggest that CP released during the inflammatory response in the CF lung may promote P. aeruginosa to tolerate this treatment.…”

Section: Discussionmentioning

confidence: 99%

The Human Innate Immune Protein Calprotectin Elicits a Multimetal Starvation Response in Pseudomonas aeruginosa

et al. 2021

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Transition metal nutrients are critical for growth and infection by all pathogens, and the innate immune system withholds these metals from pathogens to limit their growth in a strategy termed “nutritional immunity.” While multimetal depletion by the host is appreciated, the majority of studies have focused on individual metals. Here, we use the innate immune protein calprotectin (CP), which complexes with several metals, including iron (Fe), zinc (Zn), and manganese (Mn), and the opportunistic pathogen Pseudomonas aeruginosa to investigate multimetal starvation.

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Section: Discussionmentioning

confidence: 99%

The Human Innate Immune Protein Calprotectin Elicits a Multimetal Starvation Response in Pseudomonas aeruginosa

et al. 2021

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“…While we did not address the mechanism in this study, the observed upregulation of ArnA and ArnB suggests that the increased resistance occurs through the addition of aminoarabinose to lipid A (62, 64) This modification is highly relevant in the clinical setting as aminoarabinose modification of lipid A is commonly observed in polymyxin-resistant P. aeruginosa isolates (72, 73). Nebulized colistin is commonly used to reduce P. aeruginosa burdens in the lungs of CF patients (74–76). Our results suggest that CP released during the inflammatory response in the CF lung may promote P. aeruginosa to resist this treatment.…”

Section: Discussionmentioning

confidence: 99%

The human innate immune protein calprotectin elicits a multi-metal starvation response inPseudomonas aeruginosa

Nelson¹,

Huang²,

Zygiel

et al. 2021

Preprint

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To combat infections, the mammalian host limits availability of essential transition metals such as iron (Fe), zinc (Zn), and manganese (Mn) in a strategy termed “nutritional immunity”. The innate immune protein calprotectin (CP) contributes to nutritional immunity by sequestering these metals to exert antimicrobial activity against a broad range of microbial pathogens. One such pathogen is Pseudomonas aeruginosa, which causes opportunistic infections in vulnerable populations including individuals with cystic fibrosis. CP was previously shown to withhold Fe(II) and Zn(II) from P. aeruginosa and induce Fe- and Zn-starvation responses in this pathogen. In this work, we performed quantitative, label-free proteomics to further elucidate how CP impacts metal homeostasis pathways in P. aeruginosa. We report that CP induces an incomplete Fe-starvation response, as many Fe-containing proteins that are repressed by Fe limitation are not affected by CP treatment. The Zn-starvation response elicited by CP seems to be more complete than the Fe-starvation response and includes increases in Zn transporters and Zn-independent proteins. CP also induces the expression of membrane-modifying proteins, and metal-depletion studies indicate this response results from the sequestration of multiple metals. Moreover, the increased expression of membrane-modifying enzymes upon CP treatment correlates with increased resistance to polymyxin B. Thus, response of P. aeruginosa to CP treatment includes both single and multi-metal starvation responses and includes many factors related to virulence potential, broadening our understanding of this pathogen’s interaction with the host.ImportanceTransition metals are critical for growth and infection by all pathogens, and the innate immune system withholds these metals from pathogens to limit their growth in a strategy termed “nutritional immunity”. While multi-metal depletion by the host is appreciated, the majority of metal depletion studies have focused on individual metald. Here we use the innate immune protein calprotectin (CP), which complexes with several metals including iron (Fe), zinc (Zn), and manganese (Mn), and the opportunistic pathogen Pseudomonas aeruginosa to investigate multi-metal starvation. Using an unbiased label-free proteomics response, we demonstrate that multi-metal withholding by CP induces a regulatory response that is not merely additive of individual metal starvation responses, including the induction of Lipid A modification enzymes.

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“…Given that ceramide also plays a very critical role in cystic fibrosis and normalization of ceramide levels by blockers of the acid sphingomyelinase has been shown to prevent infection and inflammation in cystic fibrosis patients [42][43][44], we hypothesize that a therapy that combines normalization of ceramide levels with inhalation of glucosylceramide and/ or sphingosine [17,37] might be the most promising way preventing or treating existing bacterial infection in CF patients in the future. Since other drugs, like antibiotics, can also be applied via an inhalation therapy in CF [45], this way of application offers the benefits of a local administration with minimal adverse systemic effects. It has to be proved if administration of GBA2 inhibitors can also be applied via inhalation and if a combination therapy of ceramide reducing and GlcCer stabilizing/generating strategy is more promising than application of one drug alone.…”

Section: Discussionmentioning

confidence: 99%

Glucosylceramide Critically Contributes to the Host Defense of Cystic Fibrosis Lungs

Kovacic

Sehl

Wilker

et al. 2017

Cell Physiol Biochem

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Background: Cystic fibrosis (CF) is the most common autosomal-recessive disorder in western countries. Previous studies have demonstrated an important role of sphingolipids in the pathophysiology of cystic fibrosis. It has been shown that ceramide has a central role in various pulmonary infections, including those with Pseudomonas aeruginosa (P. aeruginosa). Ceramide is accumulated in the airways of CF mice and patients. However, little is known about a potential role of glucosylceramide in cystic fibrosis. Methods: We investigated the expression of glucosylceramide and lactosylceramide in the respiratory tract of murine and human CF samples by immunohistochemistry and analyzed effects of glucosylceramide on P. aeruginosa in vitro. We performed pulmonary infections with P. aeruginosa and tested inhalation with glucosylceramide. Results: We demonstrate that glucosylceramide is down-regulated on the apical surface of bronchial and tracheal epithelial cells in cystic fibrosis mice. Although glucosylceramide did not have a direct bactericidal effect on Pseudomonas aeruginosa in vitro, inhalation of CF mice with glucosylceramide protected these mice from infection with P. aeruginosa, while non-inhaled CF mice developed severe pneumonia. Conclusion: Our data suggest that glucosylceramide acts in vivo in concert with ceramide and sphingosine to determine the pulmonary defense against P. aeruginosa.

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Sequential Inhalational Tobramycin-Colistin-Combination in CF-Patients with Chronic P. Aeruginosa Colonization - an Observational Study

Cited by 17 publications

References 18 publications

The Human Innate Immune Protein Calprotectin Elicits a Multimetal Starvation Response in Pseudomonas aeruginosa

The Human Innate Immune Protein Calprotectin Elicits a Multimetal Starvation Response in Pseudomonas aeruginosa

The human innate immune protein calprotectin elicits a multi-metal starvation response inPseudomonas aeruginosa

Glucosylceramide Critically Contributes to the Host Defense of Cystic Fibrosis Lungs

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