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Sci. Signal., 29 March 2011
Vol. 4, Issue 166, p. ec89
[DOI: 10.1126/scisignal.4166ec89]

EDITORS' CHOICE

Host-Pathogen Interactions Degraded for Shock Value

Wei Wong

Science Signaling, AAAS, Washington, DC 20005, USA

Sepsis is a systemic inflammatory response to microbial infection that can be fatal. A common trigger for sepsis is the bacterial product lipopolysaccharide (LPS), which binds to Toll-like receptor 4 (TLR4) and activates inflammatory signaling pathways. Puneet et al. (see also Smith and Maizels) found that the glycoprotein ES-62, which is secreted by the parasitic nematode Acanthocheilonema viteae, induced the internalization of TLR4. Macrophages from healthy individuals that were preincubated with ES-62 showed a decreased inflammatory response to LPS, as indicated by reductions in the activation of the transcription factor nuclear factor {kappa}B (NF-{kappa}B) and in the release of proinflammatory effectors, such as tumor necrosis factor (TNF), interleukin-1β (IL-1β), and IL-6. In addition, ES-62–treated macrophages showed a decreased inflammatory response to the TLR2 agonist BLP, although the surface abundance of TLR2 was not altered. The abundance of MyD88 (myeloid differentiation marker 88), which functions as an adaptor protein in TLR signaling, was decreased in ES-62–treated macrophages. In neutrophils and macrophages from individuals with sepsis, ES-62 decreased the surface abundance of TLR4 and the total abundance of MyD88 and reduced the release of various inflammatory mediators in response to LPS or BLP. In ES-62–treated human macrophages, TLR4 and MyD88 colocalized with the lysosomal marker LAMP-1 and with vesicles containing the autophagosome marker LC3, suggesting that TLR4 and MyD88 were degraded in autophagosomes. Indeed, the ES-62–induced decrease in MyD88 abundance was attenuated by various manipulations that decrease autophagy. ES-62 pretreatment enabled mice to survive LPS-induced endotoxemia as well as cecal ligation and puncture (CLP), which induces polymicrobial sepsis, a model for human sepsis. In the latter model, ES-62–treated mice showed decreased inflammatory damage to lungs and liver and reduced release of inflammatory mediators but unaltered ability to fight bacterial infection. The protective effect of ES-62 pretreatment in polymicrobial sepsis was lost in mice deficient in TLR4 or two proteins involved in autophagosome formation, ATG5 or ATG7. Mice survived CLP-induced polymicrobial sepsis when treated with ES-62 1 hour after CLP, and survival rates were improved when ES-62 was administered at longer time points (6 and 8 hours) after CLP. Mortality at 6 hours after CLP was eliminated when ES-62 was administered with amoxicillin and clavulanic acid, an antibiotic combination that is given to septic individuals. Thus, ES-62 inhibits TLR4 signaling by redirecting TLR4 and MyD88 to autophagosomes and could be developed as a treatment for sepsis.

P. Puneet, M. A. McGrath, H. K. Tay, L. Al-Riyami, J. Rzepecka, S. M. Moochhala, S. Pervaiz, M. M. Harnett, W. Harnett, A. J. Melendez, The helminth product ES-62 protects against septic shock via Toll-like receptor 4–dependent autophagosomal degradation of the adaptor MyD88. Nat. Immunol. 12, 344–351 (2011). [PubMed]

K. A. Smith, R. M. Maizels, Defeating sepsis by misleading MyD88. Nat. Immunol. 12, 284–286 (2011). [PubMed]

Citation: W. Wong, Degraded for Shock Value. Sci. Signal. 4, ec89 (2011).



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