Functional characterization of alveolar macrophages during Legionella pneumophila infection

• Applicant: Professor Dr. Bastian Opitz
• Subject Area: Pneumology, Thoracic Surgery ; Clinical Infectiology and Tropical Medicine
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 558127540

Similar to several other bacterial pathogens, Legionella pneumophila uses alveolar macrophages (AMs) as a replication niche. AMs are long-lived tissue-resident macrophages that are influenced by specific milieu factors of the lung tissue, and differ ontogenetically, phenotypically and functionally from short-lived monocyte-derived "transient" macrophages. However, the vast majority of studies focusing on host cell - L. pneumophila interactions have examined monocyte-derived or bone-marrow macrophages in vitro. Comparatively little is known about how Ams respond to the bacterium and how this influences infection and antibacterial immune responses in the lungs. In preliminary experiments, we analyzed the transcriptome and proteome of Ams during lung infection with virulent L. pneumophila and an avirulent mutant in vivo. While the expression of the vast majority of immune-related molecules (e.g. chemokines and cytokines) appeared to be inhibited on a posttranscriptional level in Ams of mice infected with virulent bacteria, only a small subset of immune mediators (e.g., IL-1a, GDF15), immunoregulatory molecules (ZFP36 and TNFAIP3), and the transcription factor (ATF3) were found to be upregulated on protein level. Moreover, several molecules involved in cholesterol homeostasis were downregulated on both transcript and protein levels in Ams upon infection with virulent L. pneumophila in vivo. Based on these new and unpublished findings, we will test the hypotheses that 1) host defense pathways in the lungs are critically shaped by AM-derived GDF15 and/or ATF3, 2) the induced expression of the anti-inflammatory proteins ZFP36 and/or TNFAIP3 in Ams enables L. pneumophila to evade host defenses and to replicate intracellularly, and 3) depletion of cholesterol in Ams represents a novel cell-intrinsic antibacterial defense strategy against virulent/replicating L. pneumophila.

• DFG Programme: Research Grants