Regulation of protective pulmonary immunity by innate pathways sensing bacterial viability

• Applicant: Professor Dr. Leif Erik Sander
• Subject Area: Pneumology, Thoracic Surgery
• Term: from 2012 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 224703840

Pneumonia represents a leading cause of death worldwide even after the introduction of antibiotics over 70 years ago. Increasing occurrence of multidrugresistant strains and persistently high mortality rates despite adequate antibiotic therapy, illustrate the urgent need for novel therapeutic approaches. Together with classical pathogen-centered antimicrobial strategies, concepts to improve local immunity could significantly reduce pneumonia-associated mortality by preventing and limiting infections and improving the efficiency of existing therapies. Development of these new strategies however requires a better in-depth understanding of the molecular mechanisms of protective pulmonary immunity.We could recently demonstrate that the immune system has the inherent capacity to sense bacterial viability, and hence infectivity. Immune cells can discriminate live from dead bacteria through the detection of bacterial messenger (m)RNA, which is selectively present in live but not dead bacteria. We call such molecules ‘viability-associated PAMPs’ (vita-PAMPs). Viable bacteria and vita-PAMPs activate specific signaling pathways and elicit more robust immune responses that lead to improved host protection and antibody production. In the current proposal we want to investigate the role of the identified pathways for the generation of protective pulmonary immunity. Besides activation of innate immune responses, we will characterize mechanisms that control antibody production in the lung.Given the often-observed lifelong protective immunity conferred by live vaccines and survived infections, we will investigate if ‘viability-detection’ and the identified signaling pathways can control pulmonary and B cell responses, particularly the production of pathogen-specific IgA and IgG to improve immunity.Notably, very little is known about the regulation of protective antibody responses by innate immune signals in the lung. In this project we aim to identify the microbial signals, the responding immune cells and the molecular pathways that control protective humoral immune responses in the lung. Using various mouse models of infection and vaccination, involving avirulent recombinant bacteria as modelorganisms expressing natural and modelantigens, we will decipher the central pathways, in order to transfer these findings to clinically relevant pathogens at a later stage of the project. We will especially focus on the regulation of B cell functions by innate and microbial signals and their interactions with other cells of the respiratory tract and associated lymphoid tissues. Finally we will transfer key findings to the human system by analyzing primary human immune cells and isolated lung tissue specimen. The proposed project will elucidate cellular and molecular mechanisms that control protective pulmonary immunity, which will form the basis for the development of novel treatments and vaccination strategies against bacterial infections of the respiratory tract.

• DFG Programme: Independent Junior Research Groups