ARMADA - childhood Asthma: micRobioMe And Dna-methylations in trAined immunity to reset asthma

• Applicant: Professor Dr. Markus Weckmann
• Subject Area: Pediatric and Adolescent Medicine
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545525634

The intricate relationship between early respiratory infections in the context of pediatric asthma development has long been recognized. Whilst the epidemiological association has been univocally established, the underlying mechanisms remain incompletely understood. The German lab’s previously published work clearly identifies early childhood viral infections are driver of epigenetic modifications and lung remodeling (i.e. collagen), and are linked to suboptimal interferon responses eventuating in persistent symptoms and progressively worsening asthma trajectories. Similarly, microbial colonization, as shown by the French lab, particularly Moraxella species, has also been linked to recurrent wheezing. Conversely, exposure to certain microbial environments, such as cow shed dust is protective, underscoring the dual nature of microbial influence. Therefore, defining the exposome, encompassing pathogens and environmental stimuli and it’s mechanistic pathways is crucial in understanding asthma pathogenesis. Here, we focus on the concept of trained immunity, a long-term reprogramming of innate immune (i.e. respiratory epithelial) cells modulated by exposome-induced epigenetic modifications. These intrinsic alterations, as evidenced in our preliminary data, enrich for immunological pathway activation (e.g. IFNs) in bronchial epithelial cells from children vs. adults. Remarkably, our research suggests these differences can be virus-induced, causing differentially methylated pathways affecting mucosal focal adhesion, cytokine signaling (i.e. interleukin 6), and extracellular matrix (collagen) production. We provide the first evidence of a persistence of these exposome-associated, epigenetically augmented hallmark features of asthma development and progression in preschool children. Therefore, we aim to unravel causal mechanisms and pathways that connect microbiotic signatures and aberrant epigenetic training to asthma pathogenesis. We will demonstrate the causative links between aberrant epigenetic training, disease activity, and microbiotic signatures by combining four unique bronchoscopic pediatric cohorts (n=340). These cohorts capture clinical populations including children with infections-associated wheeze and asthma and respective controls, which are extended by an established, decade-spanning, epigenetically and clinically deep-phenotyed All-Age-Asthma cohort (n=220). Combining this unique and versatile resource with our advanced primary tissue culture models will yield direct evidence of exposome-induced modulation and persistence of epigenetic training. As such, our findings will open new avenues to characterize at-risk pediatric populations for asthma persistence, potentially advancing personalized intervention.

• DFG Programme: Research Grants
• International Connection: France
• Partner Organisation: Agence Nationale de la Recherche / The French National Research Agency
• Cooperation Partner: Professor Dr. Patrick Berger