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Necroptosis of infiltrated macrophages drives Yersinia pestis dispersal within buboes
Mohammad Arifuzzaman, … , Ashley L. St. John, Soman N. Abraham
Mohammad Arifuzzaman, … , Ashley L. St. John, Soman N. Abraham
Published September 20, 2018
Citation Information: JCI Insight. 2018;3(18):e122188. https://doi.org/10.1172/jci.insight.122188.
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Research Article Immunology Microbiology

Necroptosis of infiltrated macrophages drives Yersinia pestis dispersal within buboes

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Abstract

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.

Authors

Mohammad Arifuzzaman, W.X. Gladys Ang, Hae Woong Choi, Matthew L. Nilles, Ashley L. St. John, Soman N. Abraham

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Figure 1

YopJ is a critical virulence factor promoting bacterial dispersal.

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YopJ is a critical virulence factor promoting bacterial dispersal.
(A) S...
(A) Survival of mice challenged with bacteria instilled into a single rear footpad. Data are combined from 2 independent experiments, n = 9–10. (B) Bacterial numbers (CFU) in the blood, 48 hours after footpad infection with Kim5 or ΔyopJ strain (n = 5). (C) Bacterial numbers in spleen, 72 hours after infection (h.p.i.) (n = 8–9). (D and E) Bacterial numbers in iliac nodes (INs) (D) and popliteal nodes (PNs) (E) 24 h.p.i. (n = 5–7). Data are representative of 3 independent experiments. (F) Immunofluorescence staining of PN cross-sections 24 hours after footpad infection with OFP-labeled Kim5 or ΔyopJ bacteria. The images are representative of 2 independent experiments. Scale bar: 25 μm. The graph shows bacteria-containing pockets counted in 4 fields (n = 4) (G) Quantification of OFP+ cells in PNs 24 h.p.i. by flow cytometry. Data are combined from 2 independent experiments (distinguished by open and closed symbols), each with 4 mice per group. Significance for Kaplan-Meier curves was determined by the log-rank test. Other data were analyzed via unpaired 2-tailed Student’s t test. *P < 0.05, **P < 0.01, ***P < 0.001.

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