A Two-Step Activation Mechanism Enables Mast Cells to Differentiate their Response between Extracellular and Invasive Enterobacterial Infection

Abstract

Abstract Mast cells (MCs) localize to mucosal tissues and contribute to innate immune defenses against infection. How MCs sense, differentiate between, and respond to bacterial pathogens remains a topic of ongoing debate. Using the prototype enteropathogen Salmonella Typhimurium ( S .Tm) and other closely related enterobacteria, we here demonstrate that MCs can regulate their cytokine secretion response to distinguish between extracellular and invasive bacterial infection. Tissue-invasive S .Tm and MCs colocalize in the Salmonella -infected mouse gut. Toll-like Receptor 4 (TLR4) sensing of extracellular S .Tm, or pure LPS, causes a slow and modest induction of MC cytokine transcripts and proteins, including IL-6, IL-13, and TNF. By contrast, type-III-secretion-system-1 (TTSS-1)-dependent S .Tm invasion of both mouse and human MCs triggers rapid and potent inflammatory gene expression and >100-fold elevated cytokine secretion. The S .Tm TTSS-1 effectors SopB, SopE, and SopE2 here elicit a second activation signal, including Akt phosphorylation downstream of effector translocation, which combines with TLR activation to promote the full-blown MC response. Supernatants from S .Tm-infected MCs boost macrophage survival and maturation from bone-marrow progenitors. Taken together, this study shows that MCs can differentiate between extracellular and host-cell invasive enterobacteria via a two-step activation mechanism and tune their inflammatory output accordingly.