Please find below some information on our current projects (as of September 2020). The projects evolve constantly. Please do not hesitate to contact us for further information.
SARS-CoV-2 related projects
Infections with SARS-CoV-2 show a broad spectrum of clinical courses, from asymptomatic infections to severe pneumonia with lung failure and high mortality. In COVID-19, pre-existing severe lung damage can be associated with relative well-being for a long time, but can lead to sudden lung failure as the disease progresses. The research network PROVID of six research groups will investigate whether and to what extent established clinical and molecular parameters of lung diseases caused by other pathogens can be transferred to COVID-19. These findings are important for better predicting the course of the disease on the one hand and for initiating appropriate therapies at an early stage on the other. Based on this knowledge, recommendations for a better clinical management of COVID-19 patients will be developed. PROVID partners are six research groups at the Charité, the University of Leipzig and the CAPNETZ STIFTUNG.
Pa-COVID-19 is the central phenotyping platform and longitudinal registry study for COVID-19 patients at the Charité. It is used for harmonized clinical and molecular phenotyping of COVID-19 patients. The aim of the Pa-COVID-19 study is a rapid and comprehensive clinical and molecular characterization of COVID-19 patients to identify individual risk factors for severe disease progression as well as prognostic biomarkers and therapeutic targets in a timely manner. In the same manner CM-COVID-19 aims to follow up the chronic course of COVID-19. The third project „Organospecific stratification of COVID-19“ aims to identify SARS-CoV-2 effects on single-cell level. These three projecs are funded by the BIH.
Pneumonia and Acute Lung Injury
Our major aim in this field is the development of new preventive and therapeutic options for pneumonia and acute lung injury (ALI) on the basis of an enhanced understanding of pathophysiology. Recent and current projects examine pulmonary bacterial-host interaction, cellular and humoral mechanisms in innate immunity, as well as endothelial alterations and barrier dysfunction (e.g. in SFB-TR84). Isolated pathogenic factors, bacterial mutants are employed, and the studies are conducted on different levels. Employment of primary human cell and tissue cultures as well as specimen of human pneumonia patients strengthens the methodological approach. A particular focus lies on cardiovascular sequelae of pneumonia.
In a BMBF-funded network project, called CAPSyS, we are following a systems medicine approach to improve our understanding of the development of ARDS in pneumonia in a comprehensive way.
Furthermore, the long-term aim of the BMBF-funded Project Phage4Cure is to establish bacteriophages as drugs in the fight against bacterial infections and as such gain legal authorisation as medicinal products in a variety of dosage forms for different indications.
Pneumonia and Atherosclerosis
Ischemic heart disease, cerebrovascular disease and lower respiratory tract infections have been among the four leading causes of death globally for the past 20 years. Traditionally, coronary and cerebro-vascular diseases have been considered as independent of pneumonia. However, recent epidemiological studies suggest that lower respiratory tract infections are associated with increased short-term and long-term risk of acute cardiovascular events. One possible explanation could be an acceleration of inflammation in atherosclerosis (the leading cause of cardiovascular events), which leads to growth and instability of atherosclerotic plaques and is triggered by acute systemic inflammation during pneumonia. In the consortium SYMPATH (Systems Medicine of Pneumonia-aggravated Atherosclerosis) we join forces with the Charité’s cardiology department and the institute of physiology as well as with the insitute of medical informatics, statistics and epidemiology of Leipzig university to synergistically combine our expertise in research on pneumonia, atherosclerosis and biomathematical modeling. We aim to identify molecular mediators of pneumonia-aggravated atherosclerosis in large clinical cohorts and test these pneumonia-related pathomechanisms in preclinical experimental models, and build a comprehensive biomathematical model. Overall, we hope to unravel systemic molecular relationships between pneumonia and atherosclerosis.
Ventilator-associated pneumonia (VAP), defined as pneumonia that occurs later than 48 hours following endotracheal intubation, is characterized by high incidence and accounts for about 50% of all cases of hospital-acquired pneumonia. Approximately half of all antibiotics used in the intensive care units (ICU) are employed for VAP treatment. VAP caused by multidrug-resistant (MDR) bacterial pathogens is associated with increased mortality. A well-known drawback of conventional antimicrobial therapy is the disturbance of the host´s microbiota. This nosocomial infection is associated with a substantial disease burden, resource utilization, and long-term reduction in quality of life and cognitive impairment. Due to the lack of suitable experimental models, little is known about the underlying pathomechanisms.
A major risk factor for the development of VAP is prolonged mechanical ventilation. We investigate how ventilator-induced inflammation can further exacerbate the preexisting lung injury, attenuating the lung barrier function, contributing to increased risk of pulmonary infections among patients who are already colonized with pathogenic bacteria. Furthermore, we aim to develop approaches to prevent translocation of pulmonary inflammatory mediators and bacteria to extra-pulmonary organs to attenuate multi-organ dysfunction and reduce VAP mortality.
In the joint French-German project MAPVAP (Pre-clinical mechanistic assessment of two bacteriophage cocktails targeting multidrug-resistant Pseudomonas aeruginosa and Escherichia coli for the treatment of ventilator-associated pneumonia), we will synergistically combine our extensive and complementary expertise and resources to strengthen phage therapy in France and Germany and significantly improve its transition towards human treatments. MAPVAP will provide the necessary pre-clinical information on two established cocktails of phages targeting MDR P. aeruginosa and E. coli, regarding biology, efficacy and impact on microbiota and immunity to support a future Phase II clinical trial on severe MDR pneumonia in VAP patients.
Immunization is the most important prophylactic strategy used worldwide to prevent invasive bacterial diseases. However, existing polysaccharide vaccines are subject to several limitations. An innovative chemical method recently established by our collaborator now enables the rapid synthesis of structurally defined oligosaccharide antigens with optimized immunogenic properties based on the binding specificities and structural features of protective antibodies (Seeberger PH et al. Curr Opin Chem Biol 2009). Together with our collaborators, we are currently evaluating highly promising vaccine candidates for their immunostimulatory and -protective capacity in preclinical in vitro and in vivo studies.
Ventilator induced lung injury
In acute respiratory failure, mechanical ventilation (MV) is a life saving treatment without alternatives. One third of all patients in intensive care units worldwide are receiving MV. However, particularly in preinjured lungs even minimal MV-associated physical stress is translated into biological signals of inflammation, evoking ventilator-induced lung injury (VILI). VILI is characterized by liberation of cytokines, recruitment of leukocytes to the lung and increased lung permeability, consecutively resulting in lung edema, surfactant dysfunction, impaired lung compliance and deterioration of pulmonary gas exchange. As the necessity to guarantee sufficient gas exchange limits a further substantial reduction of tidal volumes, new adjuvant pharmacological therapies in addition to lung-protective ventilation are needed to prevent VILI. Thus, we aim to enhance the understanding of pathomechanisms underlying VILI in order to develop new therapeutic strategies to limit VILI.
Work by our group showed that infusion of the endogenous peptide Adrenomedullin or treatment with simvastatin attenuates VILI in mice (Thorax 2010; Crit Care 2010; PloS One 2012; Crit Care 2014). Another approach is to explore the mechanisms by which the circadian rhythm influences innate immune response to MV.
We established the first mouse video-bronchoscope worldwide (Am J Resp Cell Mol Biol 2014) to enable for localized allergen challenge and repetitive analysis, and to reduce animal numbers. Our specific interest lies in the development of novel therapies by investigating different models of acute and chronic airway inflammation. Recently, we found that inhibition of spleen tyrosine kinase improved the main hallmarks of asthma, namely airway (hyper-) responsiveness, allergic airway inflammation and airway remodeling (Allergy 2017). Another goal is to optimize the long-term effects of allergen-specific immunotherapy e.g. by vitamin D supplementation (J Immunol 2014).
Together with our collaborators, we recently uncovered central mechanisms of hypoxic pulmonary vasoconstriction (Eur Respir J 2017; Proc Natl Acad Sci U S A 2015; J Clin Invest 2012) and established the role of functional autoantibodies in pulmonary arterial hypertension associated with systemic sclerosis (Am J Resp Crit Care Med 2014). Further, we described the development of pulmonary vascular hyperresponsiveness and remodeling due to pulmonary Th2 inflammation (FASEB J 2011; J Allergy Clin Immunol 2009; Eur Resp J 2006). Current research is also focusing on spleen tyrosine kinase as a novel therapeutic target in PH (Am J Respir Crit Care Med 2017;195:A2272).