ADAM proteases control disease severity and systemic outcome in pneumonia

Pneumonia caused by viral or bacterial pathogens such as Sars-CoV2 or Pseudomonas aeruginosa may result in life-threatening disease with a strong contribution of proteases’ dysregulation to disease initiation, progression, and systemic spread. Within our recent research, we observed a severity dependent increase of ADAM10 and ADAM17 activity on circulating exosomes of hospitalized bacterial pneumonia and Covid-19 patients. Mechanistic studies in preclinical models indicated a critical contribution by leukocytes to this increase in exosomal proteolytic activity. In the local environment of the lung, ADAM10 orchestrated a pro-inflammatory, M1 driven response, whereas ADAM17 seemed to dampen the initial inflammatory response protecting against oxidative distress. Most importantly, circulating exosomes had multiple influences on distinct organs and the vasculature. Thus, ADAM proteases seem to be essential control elements of bacterial and viral pneumonia with exosomes as potential cargo system mediating systemic effects. Therefore, the diagnostic, prognostic, and therapeutic value of ADAM proteases should be evaluated in further preclinical and translational studies to prevent severe pneumonia and long-term effects.