Dendritic Cell Education by Mucosal Epithelial Cells

Vaccines that are administered via non-mucosal routes are often poorly protective against mucosal pathogens. As most pathogens enter our body through mucosal surfaces, mucosal vaccines are most desirable. However, only few mucosal vaccines are currently in clinical use because the propagation of mucosal immunity is not well understood. In this study we propose to study the mucosal immune response against Chlamydia trachomatis (Ct), a model mucosal pathogen. I could recently show that mucosal exposure of inactivated Ct (UV-Ct) results in exacerbated bacterial burden upon subsequent Ct infection. By contrast, mucosal immunization with UV-Ct complexed with charge-switching synthetic adjuvant particles (cSAP) does not exert the tolerogenic effect of UV-Ct alone but, instead, elicits long-lived protection against genital Ct infection. This differential effect of UV-Ct-cSAP versus UV-Ct is due to a different behavior of two subsets of professional antigen-presenting cells, namely dendritic cells (DCs). In this project we hypothesize that epithelial cells (ECs) might differentially orchestrate antigen-uptake by DCs, thereby shaping the quality of the mucosal immune response. My approach will focus on detailed characterization of EC DC interactions in the mucosa of mice and humans in three subaims. The human relevance of the results obtained in aim 1 and 2 will be addressed in aim 3, which will be setting stage for further studies in humans to ultimately translate our approach to vaccination in patients. This project will allow us to draw firm conclusions on the role of DCs and ECs in the induction of a protective or tolerogenic mucosal immune response. Overall, this work will give insights into new targets for vaccine design and specific immunological interventions against mucosal pathogens. By understanding the mechanisms of the induction of mucosal immunity and tolerance, the project also impacts the development of anti-cancer vaccines in the context of tumors affecting mucosal organs and strategies against allergic diseases.

The project "Dendritic Cell Education by Epithelial Cells upon Immunogenic and Tolerogenic Conditions" investigated over five years how specialized immune cells (dendritic cells) and epithelial cells in mucosal tissues collaborate to either amplify or suppress immune responses. The findings offer valuable insights into combating infections and inflammation and introduce innovative treatment approaches. Key Findings: 1. New Drugs Against Chlamydia The drug Pentamidine was identified as effective against Chlamydia through a compound screen. Laboratory and animal studies demonstrated its ability to reduce bacterial load in the uterus and even prevent infections when applied locally. Pentamidine modifies host cell metabolism to inhibit Chlamydia growth and proved more durable than antibiotics. It also exhibited direct effects against Gonorrhea bacteria, addressing common co-infections. 2. Innovative Human Studies In collaboration with the Medical University of Vienna, tissue samples from patients with cervical changes were analyzed. These studies focused on immune cell responses to Chlamydia, providing a foundation for future research into mucosal infections. Additionally, a drug study on sarcoidosis-a chronic granulomatous disease-showed that most patients responded positively to an mTOR inhibitor, paving the way for new treatments. 3. Microbiome Analysis Research on the skin microbiome revealed specific changes in patients who underwent stem cell transplants. These findings enhance understanding of how natural bacterial flora influence immune responses and may guide therapeutic approaches through microbiome modulation. 4. Immune Responses in Skin and Mucosa Further investigations illustrated how immune cells within tissues respond to different stimuli, advancing knowledge about infectious and inflammatory skin conditions. Societal Impact: This project opens new avenues for treating bacterial infections, especially through non-antibiotic approaches like Pentamidine, a critical step in combating resistant pathogens. The findings also provide deeper insights into immune defense and inflammation relevant not only to infections but also to autoimmune and inflammatory skin diseases. The project demonstrates how basic research can lead to practical solutions for health challenges, contributing to the development of innovative treatment strategies for patients.