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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Novel pathways of alveolar epithelial cell injury in influenza virus pneumonia: cellular cross-talks and virus-host interactions
(Herold / Pleschka / Wolff)


Influenza virus (IV) pneumonia is characterized by severe alveolar epithelial cell (AEC) damage, progression to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) whereby the extent of tissue injury is determined by the quality and quantity of the (dysbalanced) innate immune response and by viral pathogenicity factors. One of the hallmarks of IV-induced ALI is the structural and functional impairment of the alveolar epithelium, due to epithelial cell death with loss of barrier integrity and accumulation of protein-rich edema fluid in the alveolar compartment of the lung, resulting in hypoxia and multi-organ failure. We and others have previously demonstrated that mononuclear phagocytes, and, in particular, M1-polarized alveolar macrophages which accumulate in the alveolar airspaces to large amounts following IV infection, significantly contribute to AEC injury by release of inflammatory mediators. Damage of the alveolar epithelium comprises both loss of structural integrity and polarity, and severe impairment of important AEC functions. Of particular importance for the survival of the patient following severe lung injury is the coordinated transport of edema fluid across AEC and out of the airspaces which is actively mediated by the basolateral Na,K-ATPase, and fluid clearance is negatively affected after IV infection in vivo. However, the key molecular steps of these injury processes and, in particular, the roles of distinct IV gene products and their variants in modulating and exploiting important AEC pathways and functions remain unclear. We therefore aim to elucidate (i) the signaling pathways and central effector molecules involved in breakdown of the alveolar epithelial barrier structure and function in vitro in the context of multiple cellular interaction partners within the inflamed alveolus after IV infection, (ii) which lung macrophage subsets or polarization phenotypes are involved in these processes and which molecular interactions underlie this detrimental cellular cross-talk, and (iii) how IV exploit intracellular signal transduction pathways for effective replication in AEC and thereby compromise structural epithelial cell integrity and (edema clearance) function and which molecular interactions at the virus-host interface are involved. We will furthermore determine whether therapeutic targeting of such pathways or interactions can be explored to attenuate severe lung damage or to drive edema clearance in severe IV-induced lung injury in vivo. Experiments will be performed on different complexity levels, including in vitro (primary murine and human AEC cultures as well as primary macrophage-AEC co-cultures), ex vivo (human lung [HuLu] organ culture model) and in vivo approaches using wild-type and epithelial cell specific constitutive or inducible loss of function mouse models combined with adoptive cell transfer strategies and bone marrow chimeric mice. For in vitro, ex vivo, and in vivo infection experiments we will use different IV strains with known pathogenicity in humans/mice or with different levels of adaptation to the mammalian host, and reassortant/mutated IV in comparison to their isogenic wild-type strains. Our project is expected to provide new cellular and molecular targets for future intervention strategies to dampen lung injury, reduce viral replication in the distal airways and foster clearance of alveolar edema in severe IV pneumonia.