The helminth product ES-62 protects against septic shock via Toll-like receptor 4–dependent autophagosomal degradation of the adaptor MyD88

Puneet, Padmam; McGrath, Mairi; Tay, Hwee Kee; Al-Riyami, Lamyaa; Rzepecka, Justyna; Moochhala, Shabbir; Pervaiz, Shazib; Harnett, Margaret M.; Harnett, William; Melendez, Alirio J.

doi:10.1038/ni.2004

Cited by 37 publications

(26 citation statements)

References 45 publications

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“…MyD88 is the canonical adaptor for inflammatory TLR signaling pathways [47]. The possible mechanism underlying the therapeutic effect of r Sj -Cys is that administration of r Sj -Cys stimulates Tregs and/or immune cells to produce regulatory cytokines such as IL-10 and TGF-β1 that inhibit the production of pro-inflammatory cytokines through suppressing TLR-MyD88 activation signal pathway as other helminth-derived proteins did [48–51]. …”

Section: Discussionmentioning

confidence: 99%

Therapeutic effect of Schistosoma japonicum cystatin on bacterial sepsis in mice

Wang

Zhan

et al. 2017

Parasites Vectors

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BackgroundSepsis is a life-threatening complication of an infection and remains one of the leading causes of mortality in surgical patients. Bacteremia induces excessive inflammatory responses that result in multiple organ damage. Chronic helminth infection and helminth-derived materials have been found to immunomodulate host immune system to reduce inflammation against some allergic or inflammatory diseases. Schistosoma japonicum cystatin (Sj-Cys) is a cysteine protease inhibitor that induces regulatory T-cells and a potential immunomodulatory. The effect of Sj-Cys on reducing sepsis inflammation and mortality was investigated.MethodsSepsis was induced in BALB/c mice using cecal ligation and puncture (CLP), followed by intraperitoneal injection of different doses (10, 25 or 50 μg) of recombinant Sj-Cys (rSj-Cys). The therapeutic effect of rSj-Cys on sepsis was evaluated by observing the survival rates of mice for 96 h after CLP and the pathological injury of liver, kidney and lung by measuring the levels of alanine transaminase (ALT), aspartate transaminase (AST), blood urea nitrogen (BUN) and creatinine (Cr) in sera and the tissue sections pathology, and the expression of MyD88 in liver, kidney and lung tissues. The immunological mechanism was investigated by examining pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and IL-10 and TGF-β1 in mice sera and in culture of macrophages stimulated by lipopolysaccharides (LPS).ResultsrSj-Cys treatment provided significant therapeutic effects on CLP-induced sepsis in mice demonstrated with increased survival rates, alleviated overall disease severity and tissue injury of liver, kidney and lung. The rSj-Cys conferred therapeutic efficacy was associated with upregualted IL-10 and TGF-β1 cytokines and reduced pro-inflammatory cytokines TNF-α, IL-6, IL-1β. MyD88 expression in liver, kidney and lung tissues of rSj-Cys-treated mice was reduced. In vitro assay with macrophages also showed that rSj-Cys inhibited the release of pro-inflammatory cytokines and mediator nitric oxide (NO) after being stimulated by lipopolysaccharide (LPS).ConclusionsThe results suggest the anti-inflammatory potential of rSj-Cys as a promising therapeutic agent on sepsis. The immunological mechanism underlying its therapeutic effect may involve the downregulation of pro-inflammatory cytokines and upregulation of IL-10 and TGF-β1 cytokines possibly via downregulation of the TLR adaptor-transducer MyD88 pathway. The findings suggest rSj-Cys is a potential therapeutic agent for sepsis and other inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

Therapeutic effect of Schistosoma japonicum cystatin on bacterial sepsis in mice

Wang

Zhan

et al. 2017

Parasites Vectors

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“…10 A helminth product, ES-62, also downregulates TLR2-and TLR4-driven inflammatory responses by enhancing MYD88-dependent autophagosome formation. 21 The mechanisms of protective effect of autophagy activation in sepsis remain to be elucidated. Further pharmacokinetic/pharmacodynamic studies of the potential therapeutic agents may reveal which organs are protected.…”

Section: Microbe-host Interactions and Autophagymentioning

confidence: 99%

“…16,17 In support of this notion, newly tested therapeutic agents in animal models have targeted modulation of the same molecular pathway-autophagy. 10,[18][19][20][21][22] In this review, we discuss the role of autophagy in sepsis.…”

Section: Introductionmentioning

confidence: 99%

Autophagy in sepsis: Degradation into exhaustion?

Wong

et al. 2016

Autophagy

113

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Autophagy is one of the innate immune defense mechanisms against microbial challenges. Previous in vitro and in vivo models of sepsis demonstrated that autophagy was activated initially in sepsis, followed by a subsequent phase of impairment. Autophagy modulation appears to be protective against multiple organ injuries in these murine sepsis models. This is achieved in part by preventing apoptosis, maintaining a balance between the productions of pro-and anti-inflammatory cytokines, and preserving mitochondrial functions. This article aims to discuss the role of autophagy in sepsis and the therapeutic potential of autophagy enhancers.

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“…81 Low doses of CO have been shown to prevent LPS-induced organ damage most likely through the ability of CO to activate autophagy, 82 and ES-62, an immunomodulator secreted by the fi larial nematode Acanthocheilonema viteae , protected mice against endotoxic and polymicrobial septic shock by Toll-like receptor 4-mediated induction of autophagy . 83 Given that the treatments for septic shock at present are inadequate, the autophagydependent mechanism of action by new and existing therapies might form the basis for urgently needed therapeutic intervention against this life-threatening condition.…”

Section: Autophagy In Respiratory Infection and Sepsismentioning

confidence: 99%