Mitochondria within neutrophils sense bacterial lactate in the phagosome and drive NET formation

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Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B600
Abstract ID: 4913

Presenting Author:
Bailey E Holder , Graduate Student at Univ. of Tennessee

Abstract:

Neutrophil extracellular trap (NET) formation is a unique cell death process (NETosis) where neutrophils form weblike structures studded with antimicrobial peptides/proteins. We previously demonstrated that mitochondrial superoxide production is necessary to induce NETosis. To identify factors driving NETosis, we used the bacterial pathogen Staphylococcus aureus, which is a strong inducer of NET release. By screening over 1,900 genes in S. aureus, we identified that staphylococcal lactate triggers neutrophils to generate mitochondrial superoxide and undergo NETosis. Following internalization, S. aureus produces lactate in the phagosome, where accumulating lactate is transported to the mitochondria of the neutrophil via monocarboxylate transporters. Subsequently, staphylococcal lactate is converted into pyruvate and shuttled into the tricarboxylic acid cycle resulting in the generation of excess superoxide and causing NETosis. These findings demonstrate that accumulation of lactate within the phagosome acts as a metabolic danger signal indicative of intracellular bacterial replication. Rather than acting as the ‘powerhouse of the cell', mitochondria within neutrophils have adapted to become sensory organelles that are capable of detecting metabolic activity in the phagosome and triggering NETosis as a productive form of cell death that removes replicating pathogens from their intracellular niche.