Reviewed by Ronald Sherman, M.D.
Laan LC, Williams AR, Stavenhagen K, Giera M, Kooij G, Vlasakov I, Kalay H, Kringel H, Nejsum P, Thamsborg SM, Wuhrer M, Dijkstra CD, Cummings RD, van Die I. The whipworm (Trichuris suis) secretes prostaglandin E2 to suppress proinflammatory properties in human dendritic cells. FASEB J. 2016. pii: fj.201600841R.
Clinical trials have shown that administration of the nematode Trichuris suis can be beneficial in treating various immune disorders. To provide insight in the mechanisms by which this worm suppresses inflammatory responses, an active component was purified from T. suis-soluble products (TsSPs) that suppress TNF and IL-12 secretion from LPS-activated human dendritic cells (DCs). Analysis by liquid chromatography tandem mass spectrometry identified this compound as prostaglandin (PG)E2. The purified compound showed similar properties compared with TsSPs and commercial PGE2 in modulating LPS-induced expression of many cytokines and chemokines and in modulating Rab7B and P2RX7 expression in human DCs. Furthermore, the TsSP-induced reduction of TNF secretion from DCs is reversed by receptor antagonists for EP2 and EP4, indicating PGE2 action. T. suis secretes extremely high amounts of PGE2 (45-90 ng/mg protein) within their excretory/secretory products but few related lipid mediators as established by metabololipidomic analysis. Culture of T. suis with several cyclooxygenase (COX) inhibitors that inhibit mammalian prostaglandin synthesis affected the worm’s motility but did not inhibit PGE2 secretion, suggesting that the worms can synthesize PGE2 via a COX-independent pathway. We conclude that T. suis secretes PGE2 to suppress proinflammatory responses in human DCs, thereby modulating the host’s immune response.
Helminthic therapy is based on the observation that some helminth (round worms) infections are associated with decreased inflammation and symptomatic disease in people with a variety of autoimmune and other immune-mediated illnesses. As the authors point out, this should not really be a surprise, since many parasitic worms spend much of their energy resources suppressing the host immune system in an attempt to evade detection and/or death.
The authors further propose that, if the biochemistry of that immunosuppression could be worked out and reproduced, then it should be possible to administer those chemicals as drugs, without the need to administer the live helminths. This idea is not without some basis, since previous research has already shown that T. suis extracts can reduce symptoms of multiple sclerosis in a murine model.
In pursuit of that proposal, they set out to identify the major immunomodulatory components of Trichuris suis (the pig whipworm), a helminth already demonstrated to confer significant benefits in several helminthic therapy studies. The authors had already shown that soluble components in T. suis extracts reduce the secretion of pro-inflammatory mediators from human dendritic cells (dendritic cells are immune cells that are essential for determining the type of immune responses).
T. suis secretory products were prepared by infecting pigs with the whipworm, harvesting worms from the pig’s gut, rinsing the worms several times, and then allowing the worms to secrete/excrete into fresh media. T. suis-soluble products (TsSPs) were extracted from frozen T. suis by homogenation, extraction, and chromatographic separation. The fraction which was active in suppressing TNF and IL-12 secretion from LPS-activated human dendritic cells was confirmed to be prostaglandin E2 (PGE2), based on liquid chromatography tandem mass spectrometry.
TsSP, PGE2 and purified active extracts all had similar immunomodulatory effects in the dendritic cell (DC) assay, further confirming a major active component to be PGE2. Secretion of this PGE2 by T. suis into the environment was confirmed by finding large amounts in the media into which the worms were allowed to excrete/secrete.
PGE2 production by T. suis does not appear to be constant throughout its life. Secretion was higher in the young stages than in the older stages. PGE2 was also quantitatively measured in Ascaris suum fourth-stage larvae and Schistosoma mansoni soluble egg antigen. Neither of these samples were found to contain as high concentrations of PGE2 as did the T. suis extracts.
Finally, PGE2 synthesis was not impaired by a variety of COX inhibitors, indicating that the synthesis by the worms is accomplished by a COX-independent pathway.
This research extends the team’s effort to explain the mechanisms by which T. suis interacts with host immunity, and thereby helps to explain the immunomodulatory or therapeutic effect of helminthic therapy. The authors “conclude that T. suis secretes PGE2 to suppress proinflammatory responses in human DCs, thereby modulating the host’s immune response.”
This work is detailed and elegant. The authors even propose some theories as to why helminthic therapy sometimes shows no benefits. They suggest that the production of PGE2 from medicinal grade T. suis should be intact. After all, laboratory-produced helminths should be healthy and they should not die in the human before they are already at their PGE2-producing prime (by day 18). Therefore, they speculate that the non-responders may themselves differ from responders. Such host-variability might take the form of non-reacting to PGE2, or the immunomodulatory response may be inadequate to alter the symptomatology of the underlying illness being treated. Then again, the illnesses that we sometimes lump together as being the same disease are sometimes very different diseases in terms of the pathophysiology that leads to similar or identical manifestations. In other words, we may not yet be able to distinguish between similar but physiologically and/or genetically different disturbances, and therefore cannot yet separate out which patients will respond and which ones will not.
Perhaps, in a twist of fate, studies like this – studies which identify specific mechanisms of action – will eventually help us differentiate between similar diseases that are not yet distinguishable, by forcing us to look at individual differences to explain the occasional treatment failures, rather than always blaming the inconsistent results on the treatment itself.
Of course, another potential benefit of this work could be the ability to treat immune dysfunction with the worms’ products (i.e., TsSP or PGE2) rather than the worms themselves. . . if only physiological manipulation might be that simple.
To view other articles reviewed in this and other issues of the Biotherapy Journal Review, visit http://www.bterfoundation.org/jforum.