Immunobiophysics
We investigate the molecular principles of the innate immune response to lipids. Bacterial membrane components are highly effective activators of inflammation and antimicrobial effector mechanisms. Dysregulation of these immune responses can lead to severe diseases like pneumonia, acute respiratory distress syndrome, and sepsis. We analyze the mechanisms of initiation and regulation of inflammation with a special focus on the investigation of host defense peptides, proteins and lipids involved in anti-inflammatory immune regulation. The aim of these studies it to evaluate natural immune-response modifiers as candidates for therapeutic applications.
The innate immune system provides a central protective barrier of human beings against bacterial infections. Bacterial membrane components are highly effective activators of innate immune responses and trigger inflammation and antimicrobial defense mechanisms. Dysregulation of these immune responses can lead to severe diseases like sepsis, pneumonia and acute respiratory distress syndrome. We combine high-resolution 3D structure analysis and membrane biophysics with immunological expertise in macrophage biology to elucidate the structural basis and molecular mechanisms of lipid-mediated inflammatory reactions. The aim of our work is to develop new strategies for host-directed anti-inflammatory therapies. The focus is on anti-inflammatory peptides, proteins and lipids participating in endogenous immune regulation and new drugs that are largely free of free of resistance induction.
Lipids and membranes: Organization, function and role in modulating inflammation
We characterize the structural and physical prerequisites for the inflammatory activity of bacterial lipids to elucidate how lipids are recognized by the immune system as danger signals. The biological activity of lipids is based on the chemical composition and the organization of lipids in supramolecular membrane structures. We investigate natural and reconstituted membrane systems and use biophysical methods such as fluorescence and IR spectroscopy to characterize membrane properties. The elucidation of the 3D organization of lipids in solution by small angle X-ray diffraction (SAXS) at the highly brilliant electron synchrotron PETRA III at DESY is well established in the group. By characterizing the structural and physical basis for the inflammatory effect of bacterial pathogenicity factors, we obtain information on the molecular mode of action of activators and inhibitors. This knowledge is essential for the further development of lipid-based drugs as adjuvants and therapeutics.
Bacterial membrane vesicles as shuttle in pathogen-host intercation
Bacterial pathogens expose complex microbial membranes. Outer membrane vesicles (OMV) are important bacterial shuttles for virulence-associated molecules. Their relevance for pathogen-host interaction is increasingly recognized. Recent research has demonstrated a role of OMV in manipulating host cell responses and the course of infection. We investigate the basic biophysical properties, mechanisms of interaction with the host cell membrane and activation pathways of natural OMV isolates. This work is part of a consortium within the priority area of infections investigating the formation, function and composition of OMV. The pathomechanisms and significance for pathogen-host interaction will be addressed for the lung pathogens M.tuberculosis, Ps.aeruginosa, L.pneumophila and the commensal S.maltophilia.
Mechanisms of immune regulation in the lung
Pulmonary diseases caused by Gram-negative bacteria are the leading cause of mortality from infectious diseases. The difficulties associated with effective treatment of these diseases include the emergence of antibiotic-resistant pathogens, increasing numbers of elder individuals, and immunocompromised patients. An attractive target for improving clinical outcomes is the modulation of the host pulmonary immune response itself. The pulmonary immune system is specifically adapted to microbial exposition by respiration. Our aim is to elucidate the lung specific mechanisms of regulating immune responses. To this aim we investigate the molecular principles of immune regulation by surfactant proteins and surfactant lipids. Both compound classes have potential for clinical applications i.e. to improve surfactant-substitution therapies in cases of bacterial induced pneumonia or pulmonary insufficiency such as acute respiratory distress syndrome. In collaboration with colleagues from children's hospitals at the universities of Kiel and Lübeck, we investigate molecular interactions and mechanisms using reconstituted surfactant preparations, structure-function studies on surfactant, and in vitro cell culture systems. Our aim is to provide the rationales for improving surfactant preparations for therapeutic immune modulation.
Peptide-based immune regulation (host defense peptides)
Antimicrobial peptides, also referred to as host-defense peptides are effector molecules of the innate immune system instrumental in the immune response to bacterial infection. This class of defense molecules is produced in all epithelial surfaces and in the lung. Besides their potent antimicrobial activity these peptides also have the potential to control immune cell functions, a property of importance in the regulation of over shooting immune responses such as sepsis or the resolution of chronic inflammatory diseases such as in COPD. Basis of this activity is among others a direct interaction of antimicrobial peptides with host cells (macrophages). Analysis of the mechanisms underlying antimicrobial peptide-based regulation of macrophage biology is essential to a targeted development of this class of immune response modifiers.
German Research Foundation (DFG)
- DFG / EXC 306 O TP4 Exzellenzcluster „Inflammation at Interfaces“
Project “Surfactant therapy in neonatal acute respiratory distress syndrome” - DFG / EXC 306 RA3 Exzellenzcluster „Inflammation at Interfaces “
Project “Anti-inflammatory regulation of immune cells by membrane active host defense peptides”
EMBL/DESY
- Beam time grants for measurements at the German Electron Synchrotron DESY (EMBL beamline P12@PETRA III, DESY). In various projects we analyze the organization of lipid membranes and aggregates on the nanometer scale.
- Reconstituted model membranes
- Membrane interaction studies (Förster-Resonanz-Energie-Transfer (FRET) Spectroscopy)
- Biophysical characterization of membranes (Infrared-Spectroscopy)
- 3D structure analysis of membranes (Small angle X-Ray diffraction, SAXS)
- Transient gene expression and generation of stable cell lines
- Isolation, differentiation and functinal analysis of monocytes and macrophages
- ELISA, western blot
- Flow cytometry
- Molecular biology
- Protein biochemistry (purification and characterization)
- Fluorescence microscopy (CLSM)
2024
Liebold, I, Al Jawazneh, A, Casar, C, Lanzloth, C, Leyk, S, Hamley, M, Wong, MN, Kylies, D, Gräfe, SK & Edenhofer, I et al. 2024, 'Apoptotic cell identity induces distinct functional responses to IL-4 in efferocytic macrophages', Science (New York, N.Y.), Jg. 384, Nr. 6691, S. eabo7027. https://doi.org/10.1126/science.abo7027
Schromm, AB, Correa, W, Gisch, N, Steiniger, F, Richter, W, Martinez-de-Tejada, G, Brandenburg, K & von Wintzingerode, F 2024, 'Supramolecular assembly of micellar aggregates is the basis of low endotoxin recovery (LER) in a drug formulation that can be resolved by a whole blood assay', Biomedicine & pharmacotherapy, Jg. 173, S. 116286. https://doi.org/10.1016/j.biopha.2024.116286
2022
Kupsch S, Eggers LF, Spengler D, Gisch N, Goldmann T, Fehrenbach H, Stichtenoth G, Krause MF, Schwudke D, Schromm AB. Characterization of phospholipid-modified lung surfactant in vitro and in a neonatal ARDS model reveals anti-inflammatory potential and surfactant lipidome signatures. Eur J Pharm Sci. 2022 Aug 1;175:106216. https://doi.org/10.1016/j.ejps.2022.106216
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