[S4-6] Efferocytosis of macrophage-entrapped bacteria shelters S. Typhimurium from neutrophil killing
Intracellular pathogens commonly reside within macrophages to find shelter from defenses that target extracellular bacteria, such as neutrophils. However, little is known about how intracellular pathogens avoid neutrophil-mediated killing when macrophage cell death exposes them to the extracellular milieu. Here we show that during macrophage cell death, the intracellular pathogen Salmonella enterica serovar (S.) Typhimurium uses a type III secretion system encoded by Salmonella pathogenicity island 2 (T3SS-2) to perforate the membrane of the Salmonella containing vacuole, thereby allowing complement deposition on the surface of bacteria entrapped in the cellular debris of the deceased host cell. In turn, complement activation by bacteria within the pore-induced intracellular traps (PITs) attracts neutrophils that use efferocytosis to internalize macrophage cellular debris containing viable bacteria. However, unlike extracellular bacteria, bacteria entrapped in PITs are sheltered from the neutrophil respiratory burst generated during efferocytosis, thereby enabling S. Typhimurium to evade neutrophil-mediated killing in a T3SS-2-dependent fashion. Collectively, this work identifies T3SS-2-induced perforation of the Salmonella-containing vacuole of macrophages as a new virulence strategy to subvert neutrophil-mediated host defenses.