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6. Tartrate resistant acid phosphatase 5 (TRAP5) mediates immune cell recruitment in a murine model of pulmonary bacterial infection

Author

Tanner, Lloyd, primary, Bergwik, Jesper, additional, Bhongir, Ravi K. V., additional, Puthia, Manoj, additional, Lång, Pernilla, additional, Ali, Mohamad N., additional, Welinder, Charlotte, additional, Önnerfjord, Patrik, additional, Erjefält, Jonas S., additional, Palmberg, Lena, additional, Andersson, Göran, additional, and Egesten, Arne, additional

Published
2022
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9. On dysregulated inflammation and airway host defense

Author

Bhongir, Ravi K. V.

Subjects
Aiway inflammation, Cystic Fibrosis, Respiratory Medicine and Allergy, Immunology, Pseudomonas aeruginosa, Chronic obstructive pulmonary disease (COPD), DNase I
Abstract

Acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) are characterized by dysregulated inflammation of the airways. The increased influx of immune cells and the accumulation of cytokines lead to cell death, tissue destruction and impaired pulmonary function. Intracellular proteins like histones and granule proteins of neutrophils, DNA fibers act as Danger-Associated Molecular Patterns (DAMPs), further promoting tissue damage. As a result, the lungs of such patients are at an increased risk of infection due to impaired host defense functions. During inflammation, there is an increased expression of osteopontin (OPN), a highly anionic phosphoglycoprotein, in the airways and it is involved in cell recruitment, tissue remodeling, and repair. In this thesis we show that OPN can interact with many cationic proteins and peptides present in the extracellular milieu of the inflamed airways. In the first paper included in this thesis we show that OPN bound to extracellular histones have protective function against DAMPs-induced inflammation. In the second paper, we show that OPN binds to several common innate antibiotics and abrogate their antimicrobial activities. Taken together, these data suggest that OPN can modulate the host immune functions, thereby increasing the susceptibility of the patients with airway inflammatory diseases to acquire infections.Use of anti-inflammatory drugs like roflumilast is a common treatment strategy in COPD to ameliorate severe exacerbations. In the third paper we highlight the adverse effects of roflumilast, in a murine acute airway infection model. The findings suggest that use of this drug can impair host defense functions of immune cells, thereby increasing the susceptibility of COPD patients to bacterial pathogens. DNase I is used to clear the airways of CF patients from highly viscous, high molecular weight eDNA rich sputum. In the fourth paper of this thesis, we elucidated the molecular aspects of the fragmented DNA that are important to exhibit antimicrobial properties against the common CF lung pathogen, i.e. P. aeruginosa. The findings highlight a novel aspect of host defense that could be employed treating bacteria resistant against conventional antibiotics.

Published
2017

11. NLF20 : an antimicrobial peptide with therapeutic potential against invasive Pseudomonas aeruginosa infection

Author

Papareddy, Praveen, Kasetty, Gopinath, Kalle, Martina, Bhongir, Ravi K. V., Morgelin, Matthias, Schmidtchen, Artur, Malmsten, Martin, Papareddy, Praveen, Kasetty, Gopinath, Kalle, Martina, Bhongir, Ravi K. V., Morgelin, Matthias, Schmidtchen, Artur, and Malmsten, Martin

Abstract

Objectives:Increasing resistance to antibiotics makes antimicrobial peptides interesting as novel therapeutics. Here, we report on studies of the peptide NLF20 (NLFRKLTHRLFRRNFGYTLR), corresponding to an epitope of the D helix of heparin cofactor II (HCII), a plasma protein mediating bacterial clearance. Methods: Peptide effects were evaluated by a combination of in vitro and in vivo methods, including antibacterial, anti-inflammatory and cytotoxicity assays, fluorescence and electron microscopy, and experimental models of endotoxin shock and Pseudomonas aeruginosa sepsis. Results: The results showed that NLF20 displayed potent antimicrobial effects against the Gram-negative bacteria Escherichia coli and P. aeruginosa, the Gram-positive Bacillus subtilis and Staphylococcus aureus and the fungi Candida albicans and Candida parapsilosis. Importantly, this antimicrobial effect was retained in human blood, particularly for P. aeruginosa. Fluorescence and electron microscopy studies showed that the peptide exerted membrane-breaking effects. In an animal model of P. aeruginosa sepsis, NLF20 reduced bacterial levels, resulting in improved survival. Reduced mortality was also observed in experimental animal models of endotoxin shock, which was paralleled with modulated IFN-gamma, IL-10 and coagulation responses. Conclusions: Together, these results indicate that functional epitopes of HCII may have therapeutic potential against bacterial infection.

Published
2016
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14. Antimicrobial Effects of Helix D-derived Peptides of Human Antithrombin III

Author

Papareddy, Praveen, Kalle, Martina, Bhongir, Ravi K. V., Moergelin, Matthias, Malmsten, Martin, Schmidtchen, Artur, Papareddy, Praveen, Kalle, Martina, Bhongir, Ravi K. V., Moergelin, Matthias, Malmsten, Martin, and Schmidtchen, Artur

Abstract

Background: Antithrombin III (ATIII), an antiproteinase-inhibiting coagulation, was investigated for roles in host defense. Results: Extensive proteolysis of ATIII by endogenous and bacterial enzymes generated antimicrobial activity, mapped to helix D of the molecule. Conclusion: ATIII harbor cryptic host defense epitopes released during proteolysis. Significance: The results explain previously observed antimicrobial and anti-inflammatory effects of ATIII supplementation during infection. Antithrombin III (ATIII) is a key antiproteinase involved in blood coagulation. Previous investigations have shown that ATIII is degraded by Staphylococcus aureus V8 protease, leading to release of heparin binding fragments derived from its D helix. As heparin binding and antimicrobial activity of peptides frequently overlap, we here set out to explore possible antibacterial effects of intact and degraded ATIII. In contrast to intact ATIII, the results showed that extensive degradation of the molecule yielded fragments with antimicrobial activity. Correspondingly, the heparin-binding, helix d-derived, peptide FFFAKLNCRLYRKANKSSKLV (FFF21) of human ATIII, was found to be antimicrobial against particularly the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa. Fluorescence microscopy and electron microscopy studies demonstrated that FFF21 binds to and permeabilizes bacterial membranes. Analogously, FFF21 was found to induce membrane leakage of model anionic liposomes. In vivo, FFF21 significantly reduced P. aeruginosa infection in mice. Additionally, FFF21 displayed anti-endotoxic effects in vitro. Taken together, our results suggest novel roles for ATIII-derived peptide fragments in host defense.

Published
2014
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16. The Nonantibiotic Macrolide EM703 Improves Survival in a Model of Quinolone-Treated Pseudomonas aeruginosaAirway Infection

Author

Kasetty, Gopinath, Bhongir, Ravi K. V., Papareddy, Praveen, Herwald, Heiko, and Egesten, Arne

Abstract

ABSTRACTMacrolide antibiotics are used as anti-inflammatory agents, e.g., for prevention of exacerbations in chronic obstructive pulmonary disease and cystic fibrosis. Several studies have shown improved outcomes after the addition of macrolides to β-lactam antibiotics for treatment of severe community-acquired pneumonia. However, a beneficial effect of macrolides in treating Gram-negative bacterial airway infections, e.g., those caused by Pseudomonas aeruginosa, remains to be shown. Macrolide antibiotics have significant side effects, in particular, motility-stimulating activity in the gastrointestinal tract and promotion of bacterial resistance. In this study, EM703, a modified macrolide lacking antibiotic and motility-stimulating activities but with retained anti-inflammatory properties, was used as an adjunct treatment for experimental P. aeruginosalung infection, in combination with a conventional antibiotic. Airway infections in BALB/cJRj mice were induced by nasal instillation of P. aeruginosa; this was followed by treatment with the quinolone levofloxacin in the absence or presence of EM703. Survival, inflammatory responses, and cellular influx to the airways were monitored. Both pretreatment and simultaneous administration of EM703 dramatically improved survival in levofloxacin-treated mice with P. aeruginosaairway infections. In addition, EM703 reduced the levels of proinflammatory cytokines, increased the numbers of leukocytes in bronchoalveolar lavage fluid, and reduced the numbers of neutrophils present in lung tissue. In summary, the findings of this study show that the immunomodulatory properties of the modified macrolide EM703 can be important when treating Gram-negative pneumonia, as exemplified by P. aeruginosainfection in this study.

Published
2017
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17. Roflumilast Increases Bacterial Load and Dissemination in a Model of Pseudomononas Aeruginosa Airway Infection.

Author

Kasetty G, Papareddy P, Bhongir RK, and Egesten A

Subjects
Animals, Bronchoalveolar Lavage Fluid cytology, Chemokines metabolism, Colony Count, Microbial, Cyclopropanes pharmacology, Cytokines metabolism, Female, Leukocyte Count, Lung pathology, Mice, Mice, Inbred BALB C, Neutrophils, Pseudomonas Infections pathology, Respiratory Tract Infections pathology, Aminopyridines pharmacology, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Bacterial Load drug effects, Benzamides pharmacology, Pseudomonas Infections microbiology, Pulmonary Disease, Chronic Obstructive microbiology, Respiratory Tract Infections microbiology
Abstract

Exacerbations present a major clinical problem in many patients suffering from chronic obstructive pulmonary disease (COPD). Roflumilast, an inhibitor of phosphodiesterase 4, has shown beneficial effects in several clinical trials and is currently widely used to prevent exacerbations in severe COPD. Roflumilast has anti-inflammatory properties that may interfere with potentially important host defense functions, including cytotoxic properties of neutrophils at sites of inflammation. Since chronic bacterial infection is prevalent in severe COPD, Pseudomonas aeruginosa being a major pathogen, we hypothesized that this drug could impair host defense against P. aeruginosa. In this study, mice were pretreated with vehicle alone or roflumilast at doses of 5 mg/kg or 10 mg/kg, followed by instillation of P. aeruginosa in the airways. Bacterial load and dissemination, as well as inflammatory markers and immune cells, present in the airways were monitored. Roflumilast increased mortality, bacterial load, and dissemination in mice infected with P. aeruginosa. In addition, roflumilast-treated mice had significantly lower numbers of neutrophils in the bronchi, but not in the lung tissue airways, compared with untreated mice. Several proinflammatory cytokines decreased in roflumilast-treated mice but in neither the neutrophil-recruiting chemokine KC nor IL-6. These findings show that roflumilast treatment impairs host defense against P. aeruginosa in the airways, which may indicate that patients suffering from chronic bacterial infection of the airways could benefit from withholding of treatment with roflumilast., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)

Published
2016
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