RNA modifications shape innate immunity and cellular adaptation during bacterial respiratory infection

Gram-negative bacteria are clinically significant pathogens responsible for life-threatening infections, including respiratory infections. These can be acute or persistent and can exacerbate existing chronic diseases, such as cystic fibrosis, COPD and lung cancer. In this review, we use Pseudomonas aeruginosa as a model organism that demonstrates the molecular complexity of host-pathogen interactions during lower airway infection. Specifically, we focus on RNA modifications and show that they, on the one hand, regulate bacterial fitness and pathogenicity, and on the other control the execution of an effective host innate immune response. Furthermore, we examine the role of epigenetic and epitranscriptomic modifications in the immune dysregulation observed in sepsis, with an emphasis on sepsis-induced lung injury. Innate immune memory - a cellular adaptation mechanism to primary microbial stimulation - results in training or tolerization of host cells towards secondary immune challenges. While fundamentally grounded in epigenetic and metabolic reprogramming, we propose that it can crosstalk with epitranscriptomic regulation. To overcome limitations imposed by animal models when investigating microbe-induced epitranscriptomic dynamics, we highlight physiologically-relevant in vitro tissue models that can complement work performed in vivo . Ultimately, a detailed understanding of the RNA modification landscape regulating host-pathogen interactions will help us identify new therapeutic targets and molecular pathways to better manage the clinical symptoms of bacterial respiratory infections and address the growing challenge of antimicrobial resistance.