Alexander Dalpke Group
Infection & Immunity, Microbiome Studies
My lab focuses on different aspects of infection & immunity. Currently three major topics are addressed:
Immunostimulation by nucleic acids
Cells of the innate immune system recognize conserved microbial structures, so called pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors. Among these receptors Toll-like receptors (TLR) 3, -7, -8, -9 and -13 recognize nucleic acids of viral, bacterial or synthetic origin. However, the exact mechanisms of nucleic acid recognition and the differentiation between foreign (dangerous) and self (usually harmless) are still only known partially. Work of our own could show that bacterial RNA represents a PAMP recognized by various immune cells. We could also show that former orphan TLR13 is a murine receptor for bacterial RNA. Posttranscriptional RNA modifications play a decisive role for self/non-self discrimination. Present work aims to further characterize the modes of bacterial RNA recognition and stimulation.
Immune functions of airway epithelium
We have shown that airway epithelial cells use TLRs for sensing infectious danger. However, TLRs are strictly regulated at mucosal surfaces to avoid overshooting reactions and to account for the specific needs of pathogen recognition in airways. We could show that bronchial epithelial cells regulate local dendritic cells and T-lymphocytes, thereby establishing a specific, tolerogenic microenvironment. We propose a concept of local immunity that is shaped by non-immune, stromal cells. We speculate that additional stressors are necessary to switch from a tolerogenic, homeostatic environment towards a reactive one upon true infection. ER stress was identified to be a kind of “second” signal that mediates this function. Recent work focuses on Pseudomonas aeruginosa and its immune-modulatory functions in Cystic Fibrosis.
Microbiome analysis in cystic fibrosis
Interactions between bacteria and their host represent a full continuum from pathogenicity to mutualism. From an evolutionary perspective, host-bacteria relationships are no longer considered a two-component ecological system but rather a complex interactive network. Cystic fibrosis (CF) is characterized by defective mucociliary clearance associated with polymicrobial chronic airway infections. Those infections, leading to persistent inflammation and periodic episodes of acute pulmonary exacerbation, contribute to an irreversible decline in CF lung function. We study CF lung microbiome aiming to answer different questions about CF microbiome resilience, antibiotic treatment effect and possible dysbiosis induced by exacerbation. Recent work focuses on interactions of commensal bacteria with Pseudomonas aeruginosa.
Future Projects and Goals
Future work aims to study the mechanisms of RNA recognition in physiological systems and to analyze whether and how the molecular mechanisms of nucleic acid self/foreign discrimination are disturbed in autoimmune diseases. Work in the lung project aims to decipher means by which airway epithelial cells can switch to an activation state and how this might affect chronic inflammatory airway diseases. In CF we try to translate findings from microbial ecology into new diagnostic procedures and treatment strategies.
Methodological and Technical Expertise
- Magnetic cell sorting
- In vivo infection models
- Microbiome analysis pipeline
- Precision cut lung slices