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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Role of mitochondria for innate immune activation in pneumonia
(Hocke / Hippenstiel)


Mitochondria are indispensable ATP-producing organelles in eukaryotic cells. However, next to their role in cellular homeostasis they act as molecular hubs for the regulation of cellular fate or central innate immune signalling pathways. For that purpose a molecular group denominated as danger-associated molecular patterns [mtDAMPs, e.g. mitochondrial DNA (mtDNA), reactive oxygen species (ROS), or cytochrome c etc.] can be released upon inflammatory stimulation. We hypothesize that the outcome of severe infections by two important pneumonia-causing pathogens, Streptococcus pneumoniae (S.p.) and influenza A virus (IAV), is decisively codetermined by a threshold dependent level of mitochondrial affection which accounts for the pattern and amount of released mtDAMPs.

By using innovative methods, including Life-Cell-Imaging (LCI) of cells and human lung tissue, our unpublished results disclose that infected cells show differentially affected mitochondrial functions such as disturbed ATP concentrations, reduced motility, mtDAMP release or cell death activation. We postulate that moderate affections of the organelles will significantly contribute to an adequate immune activation. This is supported by data showing that even initiated cell death can be reverted at moderate stages by a cellular hibernation mode. In contrast, strong mitochondrial disturbances are assumed to foster massive mtDAMP release and subsequent cellular damage and organ failure. Interestingly, the effects of mtDAMPs such as mtDNA might be additionally influenced by pathogen virulence factors. For example, our results evidence that S.p. degrades extracellular mtDNA most probably leading to subversion of host immune signals.

With help of advanced imaging methods as well as biochemical and molecular-biological approaches we will first characterize the interrelation of mitochondrial dysfunction and disintegration induced by lung infection. Secondly, the kind and level of mtDAMPs release associated with mitochondrial affections will be addressed. Finally, the contribution of mitochondrial affection to hibernation/survival or cell death will be assessed and related to the activation of innate immune pathways as well as the induction of alveolar damage.