Francisella tularensis uses human neutrophils as trojan horses for infection and repolarization of macrophages
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Francisella tularensis (Ft), the causative agent of tularemia, is a Gram-negative bacterium that infects neutrophils (polymorphonuclear leukocytes, PMNs) and macrophages. Previous studies by our group and others demonstrate that Ft inhibits the respiratory burst, escapes the phagosome, replicates in the cytosol, and significantly prolongs human neutrophil lifespan. Ft promotes the development of a unique metabolic landscape characterized by increased glucose uptake, glycogen storage, and glycolysis and requires P38 MAPK and PI3Kα to do so. We work to understand which p38 and PI3Kα pathways Ft utilizes to change PMN metabolism and apoptosis. Additionally, the fate of infected neutrophils with extended lifespans and their bacterial cargo are unknown. We demonstrate that Ft-infected neutrophils (iPMNs) interact more efficiently with primary human monocyte-derived macrophages (MDMs) than aged, control PMNs despite their viability and paucity of surface phosphatidylserine and identify an important role for serum and C1q in this process. Uptake by this mechanism supports bacterial growth in MDMs, indicating that iPMNs can act as Trojan horses to spread infection. iPMN uptake by MDMs elicits an atypical phenotype notable for downregulation of both pro- and anti-inflammatory polarization markers.
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Ph. D