sphingosine-1-phosphate and Plague

When draining lymph nodes become infected by Yersinia pestis (Y. pestis), a massive influx of phagocytic cells occurs, resulting in distended and necrotic structures known as buboes. The bubonic stage of the Y. pestis life cycle precedes septicemia, which is facilitated by trafficking of infected mononuclear phagocytes through these buboes. However, how Y. pestis convert these immunocytes recruited by host to contain the pathogen into vehicles for bacterial dispersal and the role of immune cell death in this context are unknown. We show that the lymphatic spread requires Yersinia outer protein J (YopJ), which triggers death of infected macrophages by downregulating a suppressor of receptor-interacting protein kinase 1-mediated (RIPK1-mediated) cell death programs. The YopJ-triggered cell death was identified as necroptotic, which released intracellular bacteria, allowing them to infect new neighboring cell targets. Dying macrophages also produced chemotactic sphingosine 1-phosphate, enhancing cell-to-cell contact, further promoting infection. This necroptosis-driven expansion of infected macrophages in buboes maximized the number of bacteria-bearing macrophages reaching secondary lymph nodes, leading to sepsis. In support, necrostatins confined bacteria within macrophages and protected mice from lethal infection. These findings define necrotization of buboes as a mechanism for bacterial spread and a potential target for therapeutic intervention.

Topics: Animals; Apoptosis; Bacterial Proteins; Cell Death; Cell Line; Disease Models, Animal; Lysophospholipids; Macrophages; Mice; Mice, Inbred C57BL; Plague; Receptor-Interacting Protein Serine-Threonine Kinases; Sphingosine; Virulence Factors; Yersinia pestis

The hallmark of bubonic plague is the presence of grotesquely swollen lymph nodes, called buboes. This frenzied inflammatory response to Yersinia pestis is poorly understood. In this issue of Immunity, St. John et al. (2014) explore the mechanism by which Y. pestis spreads and thus leads to this striking lymphadenopathy.

Topics: Animals; Female; Lymph Nodes; Lysophospholipids; Plague; Receptors, Lysosphingolipid; Sphingosine; Yersinia pestis

Pathologically swollen lymph nodes (LNs), or buboes, characterize Yersinia pestis infection, yet how they form and function is unknown. We report that colonization of the draining LN (dLN) occurred due to trafficking of infected dendritic cells and monocytes in temporally distinct waves in response to redundant chemotactic signals, including through CCR7, CCR2, and sphingosine-1-phospate (S1P) receptors. Retention of multiple subsets of phagocytes within peripheral LNs using the S1P receptor agonist FTY720 or S1P1-specific agonist SEW2871 increased survival, reduced colonization of downstream LNs, and limited progression to transmission-associated septicemic or pneumonic disease states. Conditional deletion of S1P1 in mononuclear phagocytes abolished node-to-node trafficking of infected cells. Thus, Y. pestis-orchestrated LN remodeling promoted its dissemination via host cells through the lymphatic system but can be blocked by prevention of leukocyte egress from DLNs. These findings define a novel trafficking route of mononuclear phagocytes and identify S1P as a therapeutic target during infection.

Topics: Animals; CD11 Antigens; CD11b Antigen; Cell Movement; Chemokine CCL21; Dendritic Cells; Female; Fingolimod Hydrochloride; Integrin alpha Chains; Lymph Nodes; Lysophospholipids; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Oxadiazoles; Phagocytes; Plague; Propylene Glycols; Receptors, CCR2; Receptors, CCR7; Receptors, Lysosphingolipid; Sphingosine; Thiophenes; Yersinia pestis