Transregional Collaborative Research Center SFB-TR 84 - “Innate Immunity of the Lung: Mechanisms of Pathogen Attack and Host Defence in Pneumonia“

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A2-Subproject

The role of enolase-1 and extracellular nucleic acids in lung infection and their contribution to innate immune responses and bacterial tropism (Wygrecka / Preissner)

 

Upon bacterial infection, vascular injury or tissue damage, intracellular material like nucleic acids, histones and other macromolecules become exposed to the extracellular milieu where they may serve as endogenous alarming factors and affect various host defence processes, associated with innate immunity. Moreover, extracellular nucleic acids may influence the bacteria-host cell interactions and the microbial tropism in the lung. One prominent mechanism in this regard upon lung infection is the generation of alveolar- and tissue-NET (“Neutrophil extracellular traps”), expelled from activated neutrophils and composed of nucleosomes/DNA in complex with histones and antimicrobial peptides. These extracellular NET are able to kill bacteria and, together with neutrophil-mediated phagocytosis, provide another key antimicrobial mechanism of neutrophils. Yet, the interplay between both processes, especially in the course of lung infection, remains elusive.

A second process is based upon our recent data that demonstrate an association of host-derived nucleic acids with the surface of pneumococci and other bacteria, thereby facilitating their binding to lung epithelial and endothelial cells and possible bacterial uptake. In this regard, extracellular eukaryotic and prokaryotic enolase were both found to interact with host-derived nucleic acids and may thus promote microbial binding, uptake and subsequent signaling processes, associated with innate immune responses.

To address the molecular and cellular mechanisms underlying the extracellular nucleic acid-dependent bacterial tropism during lung infection, the following issues will be addressed:

(a) Our recent data demonstrate a cooperative effect between phagocytosis and NETosis (usually occurring within some hours) upon neutrophil activation, which leads to a significant acceleration of NET formation (within a few minutes). Apparently, this cooperative action is substantial to improve the efficacy of both phagocytosis and NETosis in combating the rapidly disseminating bacteria or other microbes. In order to define the lung-specific conditions for the connection between these two neutrophil-derived killing mechanisms, the kinetics and outcome of fast NETosis will be characterized in relation to the severity and course of pneumonia in mice. Here, bacterial toxins and mutated pneumococci will be investigated as well to characterize the nature of fast NETosis. Besides its antimicrobial potential, we found that the histone component of NET may trigger alveolar epithelial cell death leading to lung tissue destruction. Since strategies based on the neutralisation of histone-mediated cytotoxicity may be of potential benefit in the treatment of pneumonia, we aim to characterize the molecular mechanism of histone-provoked cell death in vitro and apply respective interventional strategies upon pneumonia in mice models.

(b) As eukaryotic enolase, associated with the surface of host cells, provides the ability to bind nucleic acids as docking sites for bacterial adherence, the mechanisms of enolase export from the cytosol, its binding mode to nucleic acids and the consequences for bacterial tropism will be characterized. Since enolase was also shown by us to serve as cell membrane-associated cofactor for inflammatory cell invasion in the lung, the respective mechanistic relations to nucleic acid binding and outcome of pneumonia as well as possible anti-enolase approaches as new interventions will be investigated. Our project will provide new mechanistic insights into the role of host-derived nucleic acids and their interacting partners in bacterial infection and inflammation in the lung.