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Scientific projects AG Bauer/Kaufmann
Research field 1: Innate immune recognition of RNA
In order to survive, all organisms have to recognize and eliminate foreign invaders, for example harmful viruses and bacteria. The innate immune system relies on the recognition of conserved microbial structures, so called pathogen associated molecular patterns. These PAMPs are unique for certain pathogens and are not expressed in a mammalian cell this way.
Since viruses depend on host metabolism for replication, they have similar carbohydrate and lipid structures like our cells. Therefore, the immune system has evolved several receptors for the detection of viral nucleic acid, which can be recognized due to unusual modifications, sequences or structures. Our group investigates further into the immunostimulatory potential of nucleic acid, especially of RNA.
Project 1: RIG-I activation by self RNA during virus infection
During an infection, viral RNA acts as a danger signal and is recognized by several cellular receptors like RIG-I and TLR7/8. Additionally, viral RNA can indirectly activate RNase L which degrades cellular RNA. In contrast to the paradigm that cellular RNA is per se non-stimulatory, these degraded self-RNA fragments get also recognized by RIG-I. This leads to an amplification of the danger signal, enhancing the immune response to a viral infection.
We identified these stimulatory RNA-fragments and investigate why these cellular RNA-fragments can be immunostimulatory.
Additionally, our results on the immunoregulatory potential of naturally occurring ribosomal RNA-methylations were currently published in PLOS ONE. We are now investigating further into the influence of different nucleoside-methylations on TLR7 and TLR8-activation.
Project 2: Role of RNA modifications in viral pathogenicity
To overcome the innate antiviral response, viruses have evolved several evasion strategies: they inhibit the IFN response, interfere with signal transduction or avoid PRR activation by modifying their 5’ RNA ends. There is evidence that also methylations like 2’O-methylations or N6-methyladenosine can be found in the viral genome and could negatively modulate the PRR-mediated RNA recognition.
Within the subproject A04 of the "Collaborative Research Centre 1021 – RNA viruses: RNA metabolism, host response and pathogenesis" we investigate whether RNA methylations are used by viruses to evade an immune recognition and want to elucidate their role for pathogenicity and infectivity of viruses like influenza.
Project 3: Cholesterol-coupled dsRNA as a new adjuvant?
Vaccination is indispensable to prevent infectious diseases. Adjuvants are essential to induce an immune response to an antigen and are therefore included in vaccines. Since Toll-like receptors (TLR) are expressed by several subtypes of immune cells and their activation induces the secretion of different cytokines, TLR-ligands possess the potential to serve as an adjuvant. To engage intracellular TLR, the TLR-ligand has to be transfected into the immune cells. But a major problem is that usage of common transfection reagents can lead to toxic side-effects. Therefore the development of non-toxic/safe and potent vaccine adjuvants becomes highly important.
In this project we investigate the capability of coupling cholesterol to dsRNA to act as a novel adjuvant delivery system without the requirement of a common, potentially harmful, transfection reagent.
Research field 2: Host defence in pneumonia
Within subprojects A1 and B3 of the Transregional Collaborative Research Center SFB-TR 84 - “Innate Immunity of the Lung: Mechanisms of Pathogen Attack and Host Defence in Pneumonia“ we are investigating on the one hand the role of innate immune receptors during pneumonia and how they control hyperinflammation and tissue repair (A1) and on the other hand the development and function of respiratory macrophages and dendritic cell subsets during bacterial pneumonia (B3).
A1
Nucleic acid sensing and type I interferon production differentially regulate the outcome of lung infection. Two molecules of the TLR/interleukin-1 receptor (TIR) family, ST2 and TIR8 (SIGIRR), which have been implicated in negative control of PRR-mediated inflammatory responses and/or promotion of repair processes, are in our focus.
We investigate the immune-regulatory function of TIR8 during pneumonia and want to elucidate whether this immune regulation depends on recognition of microbe-associated molecular patterns (MAMP) or damage-associated molecular patterns (DAMP) and whether caspase-1 regulates the transport of TIR8
B3
Since bacterial infections are a leading cause of pneumonia we are interested in the precise contribution of different subsets of dendritic cells (DC) and lung macrophages to the respiratory immune response during bacterial infection.
Here, we discovered a novel function of the RNA editing enzyme adenosine deaminase 1 acting on RNA (ADAR1) in lung DC and macrophage development and are now investigating involved signaling pathways and which ADAR1-edited target structures regulate the immune cell development.