Project A06

Pulmonary Aspergillus infection progression determined by alveolar macrophages as initial responders

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Prof. Dr. Dr. Andreas Beilhack & Prof. Dr. Jürgen Löffler

 

Opportunistic lung infections remain a clinical challenge. It is remarkable that healthy individuals can maintain lung homeostasis while daily inhaling hundreds to thousands of pathogenic fungal spores, which would – if not rapidly eliminated – form invasively growing hyphae within hours. The mechanisms determining whether an airborne pathogen such as Aspergillus fumigatus that has reached the lower respiratory tract can be contained or will invade alveolar epithelia to cause infection remain poorly understood. Here we will investigate the earliest decision points in alveolar macrophages (AMs) upon encounter with the pathogenic fungus A. fumigatus and interrogate the impact of previous exposures to other pathogens that appear to decisively alter lung immune surveillance. Tissue-resident AMs engage together with alveolar epithelial cells (AEC) as sentinels to eliminate airborne viral, bacterial, and fungal pathogens. We and others have observed different functional states of sessile versus patrolling AMs. Yet, molecular decision points in these two distinct AM functional states remain unknown, e.g., whether AMs silently contain a pathogen or rather orchestrate a multi-tiered immune response in concert with other immune cell populations. Whereas pulmonary clearance of fungal pathogens appears strikingly efficient in healthy individuals, co-infections with viral pathogens such as cytomegalovirus (CMV) or influenza viruses (IAV) increase morbidity and mortality in affected individuals. Pre-exposure to or concomitant infection can either enhance antimicrobial fitness or increase vulnerability towards infections as stimulation of innate immune cells with specific microbial antigens can induce long-lasting epigenetic and metabolic re-programming or even AM replacement. Consequently, this can alter AM capacity to efficiently eliminate pathogens or, conversely, suppress effector programmes leading to pathogen persistence or even trigger disease dissemination. Our aim is to pinpoint cellular and molecular determinants resulting in an effective control of A. fumigatus in the alveolar space environment either by close AM-AEC interactions or through recruitment of other immune cells such as neutrophilic granulocytes (PMN), monocytes and dendritic cells (DCs).