Adjusting the base: (Epi)transcriptomic RNA modification in inflammation & host-microbiome crosstalk

Chronic inflammatory diseases impair the quality of life on an ever increasing number of patients and are a serious burden on health care systems worldwide. The incidence of inflammatory bowel diseases like Crohns disease and ulcerative colitis has increased worldwide over the last decades, particularly in western countries. These diseases are characterized by recurring inflammations of the gastrointestinal tract and are incurable to date. The underlying cause of these inflammatory diseases is only poorly understood. Current scientific knowledge assumes multifactorial genetic and environmental triggers with one important mechanism being an overreaction of the bodys immune system to the gut microbiome. Newest studies also suggest a change in the microbiome induced by western life style which itself might lead to inflammatory bowel disease. The gut microbiome and the hosts body are in a state of continuous crosstalk and adaptation. This important crosstalk utilizes different biological pathways that need to be modulated and fine-tuned at several levels. Genetic information passes through different steps on its way to building a functional protein. One essential step is the production of an RNA molecule that contains all the information for the protein sequence. Importantly, such RNA molecules can be much shorter, non-protein coding and can have direct functions on their own. One example are so-called microRNAs which can bind other protein coding RNAs and thus control different cellular functions. An important regulating mechanism is RNA editing which can change the sequence of protein-coding RNAs and microRNAs after their initial production. RNA-editing can therefore lead to changes in proteins or the function of microRNAs. RNA editing is essential for life. Mutations in the enzymes that mediate RNA editing in cells cause drastic neurological defects and trigger inflammation. These important enzymes are called ADARs (for adenosine deaminase acting on RNA). Studies in the lab of Michael Jantsch at the Medical University of Vienna show that RNA editing of one particular protein coding RNA is implicated in inflammatory bowel disease. The young independent researcher group aims to investigate and uncover medically relevant aspects and implications of RNA editing in inflammatory bowel diseases, in the host-microbiome crosstalk and in immune homeostasis. Combining the expertise of four different researchers from the Medical University of Vienna, the University of Vienna and the Vienna BioCenter Core Facilities will enable tackling these important interdisciplinary questions.

Over the past few years, our interdisciplinary consortium has been working on fundamental questions of RNA biology in the context of inflammatory bowel diseases and lung infections. We studied the interaction between the intestinal microbiome and the host (in humans and mice), as well as the influence of certain RNA modification processes ("A-to-I editing") on the course of acute colitis and COVID-19. We were able to detect a previously unknown communication route between the microbiome and the host. Specifically, certain small message RNAs (microRNAs) are produced in the intestine and "read" by a subset of bacteria in our microbiome. These little messages then impact their growth and metabolism, which in turn can contribute to a stronger inflammatory response in the gut. Furthermore, we were able to characterize previously unexplored functions of an essential RNA-modifying protein (ADAR2) in the lung. ADAR2 influences the severity and progression of bacterial and viral pneumonia in mouse models and could play a new key role in immune defense in the lungs, which could also influence the defense against, among other things, SARS-COV2. In a third study, we found that a selective change in the RNA that encodes an important protein - filamin A - has a strong influence on the expression of disease symptoms in a model of ulcerative colitis (a common inflammatory bowel disease). The other protein variant created by the RNA modification in the body cells themselves ensures a better intestinal microbiome and, more importantly, causes the immune system to act less destructively in the event of inflammation, thereby alleviating the symptoms of the disease. In both mice and humans, filamin A RNA is less modified during acute intestinal inflammation, a fact that could potentially be exploited as a marker for the severity of colitis.