Phagocytosis-independent antimicrobial activity of mast cells by formation of extracellular traps: cellular receptors involved and underlying molecular mechanism
It has been increasingly recognized that mast cells are critical components of host defense against pathogens. We have recently described a completely novel mechanism used by mast cells to kill bacteria such as Streptococcus pyogenes or Staphylococcus aureus. This mechanism consists on entrapping them in extracellular structures similar to the extracellular traps described for neutrophils. The mast cells extracellular traps (MCETs) are composed of DNA, histones, tryptase, and the anti-microbial peptide LL-37. Formation of MCETs is not the result of passive release of DNA and granule proteins during cellular disintegration but rather an active and controlled process in response to specific stimulation and strongly dependent on the production of reactive oxygen radicals (ROS). This type of death has been recently termed "Etosis". Etosis is neither typical apoptosis nor necrosis and it is characterized by disintegration of the nuclear membrane concomitant with cytoplasmic granule dissolution, allowing the components of the traps to mix in the cytoplasm before been released.
The goals of this grant proposal are the characterization of the mast cell receptors and bacterial factors triggering the formation of MCETs as well as the characterization of the downstream molecular mechanisms, specifically how ROS trigger mast cell death.