RESPIMMUN - Immune Modulation in Respiratory Diseases

Respiratory diseases such as lung cancer, COPD, lung fibrosis, and asthma, are a potential threat to health, life and affect several-hundred million people worldwide. Thus, respiratory diseases rank second only to cardiovascular diseases in terms of morbidity and social-economic burden. Very often, inflammation is an underlying problem and an altered, excessive immune-reaction can be observed, which seems to play an important role in pathogenesis as well as disease progression. However, to date these underlying mechanisms to several chronic lung diseases remain dramatically understudied, therapeutic options narrow and outcome poor. RESPImmun Immune Modulation in Respiratory Diseases, a new interdisciplinary PhD program starting in autumn 2021 at the Medical University of Graz, is the very first program in Austria and perhaps even within Europe, that will focus exactly on this interface between respiratory diseases, inflammation and immune modulation. By applying multidisciplinary and translational science, new therapeutic and diagnostic concepts will be developed. The gained knowledge will help to better combat infectious diseases like SARS-CoV-2 in future. Additional novel and unique aspects of RESPImmun are the inclusion of junior PIs to promote and nurture next generation researchers side- by-side to the early-stage scientists on PhD-student level, the focus on patient empowerment, and close collaboration with industrial partners to enable quick translation of generated concepts into possible therapeutic options. RESPImmun will bring about sustainable and outstanding lung research and training in Austria, fostering an internationally renowned center of excellence of lung research and patient care.

Over the past four years, the PhD Programme, RESPImmun, has generated new insights into the diagnosis, prevention and treatment of chronic lung diseases. Researchers working on the 19 associated projects have identified pathological molecular signals, mapped protective microbes, and explored directed, next-generation therapeutic strategies. The following highlights several key-findings. Using machine-learning applied to immune and clinical datasets, we identified an unrecognised COPD subtype termed the 'emphysema inflammatory subgroup'. We also demonstrated that blocking specific immune signalling pathways (TYK2/JAK1) in COPD can reduce harmful inflammation. In experimental studies, the drug brepocitinib reduced excessive immune responses and signs of tissue damage, suggesting a potential new treatment approach for severe COPD. Additionally, high sTfR1 levels were associated with poorer COPD outcomes and, when combined with low haemoglobin levels, could indicate severe pulmonary hypertension in patients. In lung cancer, we demonstrated that macrophages, which are prevalent in the tumour microenvironment, can transition to an alternative metabolic state that enables their function in nutrient-deprived conditions Eosinophils are key drivers of allergic inflammation such as bronchial asthma. We developed small, HDL-like 'nanodiscs' designed to target eosinophil function. These nanostructures prevented eosinophils from entering the lungs, thereby reducing inflammatory responses. This strategy represents a promising therapeutic concept for allergic airway diseases and other eosinophilic diseases. We created the first global atlas of the human respiratory microbiome from healthy individuals and patients with pneumonia, COVID-19, and cystic fibrosis. In health, microbes form a spatially organized, connected ecosystem from the nose to the lungs. In disease, this structure breaks down and key beneficial species are consistently lost. This atlas provides a reference framework to improve diagnostics, guide personalized therapies, and better predict and prevent respiratory disease. Pulmonary fibrosis (PF) is a severe scarring disease causing irreversible lung damage; we demonstrated that the intermediary metabolic molecule succinate exerts strong pro-fibrotic effects on fibroblasts derived from PF patients. In an experimental model of lung fibrosis, succinate levels were significantly increased, and the further addition of exogenous succinate exacerbated fibrosis. Findings related to this project have been patented. Additionally, we discovered that the breakdown of fat (lipolysis) in key lung epithelial cells helps to fuel mitochondria, produce surfactant and repair damage. PF patients exhibit reduced lipolysis and impaired mitochondrial function in their epithelial cells, but a specific drug can restore both. Therefore, boosting lipolysis could help to regenerate fibrotic lungs. Research on systemic sclerosis, another fibrotic disease affecting the lung, further indicated that male hormones may exert protective effects in lung fibrosis, suggesting the possibility of sex-specific therapeutic strategies. Taken together, the research conducted within the RESPImmun programme identified new drug targets and therapeutic strategies, representing important steps toward improving the diagnosis and treatment of lung diseases, and ultimately enhancing patient well-being.