Apoptotic signaling clears engineeredSalmonellain an organ-specific manner

Abstract

Pyroptosis and apoptosis are two forms of regulated cell death that can defend against intracellular infection. Although pyroptosis and apoptosis have distinct signaling pathways, when a cell fails to complete pyroptosis, backup pathways will initiate apoptosis. Here, we investigated the utility of apoptosis compared to pyroptosis in defense against an intracellular bacterial infection. We previously engineeredSalmonella entericaserovar Typhimurium to persistently express flagellin, and thereby activate NLRC4 during systemic infection in mice. The resulting pyroptosis clears this flagellin-engineered strain. We now show that infection of caspase-1 or gasdermin D deficient macrophages by this flagellin-engineeredS.Typhimurium induces apoptosis in vitro. Additionally, we also now engineerS.Typhimurium to translocate the pro-apoptotic BH3 domain of BID, which also triggers apoptosis in macrophages in vitro. In both engineered strains, apoptosis occurred somewhat slower than pyroptosis. During mouse infection, the apoptotic pathway successfully cleared these engineeredS.Typhimurium from the intestinal niche, but failed to clear the bacteria in the myeloid niche in the spleen or lymph nodes. In contrast, the pyroptotic pathway was beneficial in defense of both niches. In order to clear an infection, distinct cell types may have specific tasks (bucket lists) that they must complete before they die. In some cells, either apoptotic or pyroptotic signaling may initiate the same bucket list, whereas in other cell types these modes of cell death may lead to different bucket lists that may not be identical in defense against infection.