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Necroptosis of infiltrated macrophages drives Yersinia pestis dispersal within buboes.

Publication ,  Journal Article
Arifuzzaman, M; Ang, WXG; Choi, HW; Nilles, ML; St John, AL; Abraham, SN
Published in: JCI Insight
September 20, 2018

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.

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Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

September 20, 2018

Volume

3

Issue

18

Location

United States

Related Subject Headings

  • Yersinia pestis
  • Virulence Factors
  • Sphingosine
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Plague
  • Mice, Inbred C57BL
  • Mice
  • Macrophages
  • Lysophospholipids
  • Disease Models, Animal
 

Citation

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Arifuzzaman, M., Ang, W. X. G., Choi, H. W., Nilles, M. L., St John, A. L., & Abraham, S. N. (2018). Necroptosis of infiltrated macrophages drives Yersinia pestis dispersal within buboes. JCI Insight, 3(18). https://doi.org/10.1172/jci.insight.122188
Arifuzzaman, Mohammad, WX Gladys Ang, Hae Woong Choi, Matthew L. Nilles, Ashley L. St John, and Soman N. Abraham. “Necroptosis of infiltrated macrophages drives Yersinia pestis dispersal within buboes.JCI Insight 3, no. 18 (September 20, 2018). https://doi.org/10.1172/jci.insight.122188.
Arifuzzaman M, Ang WXG, Choi HW, Nilles ML, St John AL, Abraham SN. Necroptosis of infiltrated macrophages drives Yersinia pestis dispersal within buboes. JCI Insight. 2018 Sep 20;3(18).
Arifuzzaman, Mohammad, et al. “Necroptosis of infiltrated macrophages drives Yersinia pestis dispersal within buboes.JCI Insight, vol. 3, no. 18, Sept. 2018. Pubmed, doi:10.1172/jci.insight.122188.
Arifuzzaman M, Ang WXG, Choi HW, Nilles ML, St John AL, Abraham SN. Necroptosis of infiltrated macrophages drives Yersinia pestis dispersal within buboes. JCI Insight. 2018 Sep 20;3(18).

Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

September 20, 2018

Volume

3

Issue

18

Location

United States

Related Subject Headings

  • Yersinia pestis
  • Virulence Factors
  • Sphingosine
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Plague
  • Mice, Inbred C57BL
  • Mice
  • Macrophages
  • Lysophospholipids
  • Disease Models, Animal