title: The helminth product ES-62 protects against septic shock via Toll-like receptor 4-dependent autophagosomal degradation of the adaptor MyD88.
abstract: Sepsis is one of the most challenging health problems worldwide. Here we found that phagocytes from patients with sepsis had considerable upregulation of Toll-like receptor 4 (TLR4) and TLR2; however, shock-inducing inflammatory responses mediated by these TLRs were inhibited by ES-62, an immunomodulator secreted by the filarial nematode Acanthocheilonema viteae. ES-62 subverted TLR4 signaling to block TLR2- and TLR4-driven inflammatory responses via autophagosome-mediated downregulation of the TLR adaptor-transducer MyD88. In vivo, ES-62 protected mice against endotoxic and polymicrobial septic shock by TLR4-mediated induction of autophagy and was protective even when administered after the induction of sepsis. Given that the treatments for septic shock at present are inadequate, the autophagy-dependent mechanism of action by ES-62 might form the basis for urgently needed therapeutic intervention against this life-threatening condition.
authors.affiliation: Department of Physiology, National University of Singapore, Singapore.
authors.forename: Padmam
authors.initials: P
authors.lastname: Puneet
authors.forename: Mairi A
authors.initials: MA
authors.lastname: McGrath
authors.forename: Hwee Kee
authors.initials: HK
authors.lastname: Tay
authors.forename: Lamyaa
authors.initials: L
authors.lastname: Al-Riyami
authors.forename: Justyna
authors.initials: J
authors.lastname: Rzepecka
authors.forename: Shabbir M
authors.initials: SM
authors.lastname: Moochhala
authors.forename: Shazib
authors.initials: S
authors.lastname: Pervaiz
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Harnett
authors.forename: William
authors.initials: W
authors.lastname: Harnett
authors.forename: Alirio J
authors.initials: AJ
authors.lastname: Melendez
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D015801:Helminth Proteins / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism*; D010588:Phagosomes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D012772:Shock, Septic / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: C435884:ES-62 protein, Acanthocheilonema viteae; D015801:Helminth Proteins; D018836:Inflammation Mediators; D053594:Myeloid Differentiation Factor 88; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4