Parasitic helminths: a pharmacopeia of anti-inflammatory molecules

Abstract

Infection with parasitic helminths takes a heavy toll on the health and well-being of humans and their domestic livestock, concomitantly resulting in major economic losses. Analyses have consistently revealed bioactive molecules in extracts of helminths or in their excretory/secretory products that modulate the immune response of the host. It is our view that parasitic helminths are an untapped source of immunomodulatory substances that, in pure form, could become new drugs (or models for drug design) to treat disease. Here, we illustrate the range of immunomodulatory molecules in selected parasitic trematodes, cestodes and nematodes, their impact on the immune cells in the host and how the host may recognize these molecules. There are many examples of the partial characterization of helminth-derived immunomodulatory molecules, but these have not yet translated into new drugs, reflecting the difficulty of isolating and fully characterizing proteins, glycoproteins and lipid-based molecules from small amounts of parasite material. However, this should not deter the investigator, since analytical techniques are now being used to accrue considerable structural information on parasite-derived molecules, even when only minute quantities of tissue are available. With the introduction of methodologies to purify and structurally-characterize molecules from small amounts of tissue and the application of high throughput immunological assays, one would predict that an assessment of parasitic helminths will yield a variety of novel drug candidates in the coming years.

Extracts of the Rat Tapeworm,Hymenolepis diminuta, Suppress Macrophage ActivationIn Vitroand Alleviate Chemically Induced Colitis in Mice

“…The active immunosuppressive activity of the HdHMW is due, at least partially, to a mannosidase-and neuraminidaseinsensitive glycoprotein. We conclude that H. diminuta, and parasitic helminths in general, are an untapped source of immunomodulatory drugs (or molecules that can serve as blueprints for novel drugs [14,19]) and support this postulate with data showing that systemic delivery of HdHMW to mice protects them against DNBS-induced colitis. ) were stimulated with ConA (2 g/ml) for 48 h. The HdHMW preparations in these experiments had substantial anticolitic effects, although some inflammatory disease was still apparent.…”

“…A plethora of studies have shown that many immunosuppressive molecules from helminths are glycoproteins (19,29,33,44) and, to a lesser extent, lipid-based molecules (19). We confirmed the presence of multiple glycoproteins in H. diminuta and, in addition, (i) we found GalNAc-containing glycoproteins in homogenized adults, but not in the ES products, suggesting that these glycoproteins are not secreted, and, in contrast to Schmidt (39), (ii) we detected GlcNAc glycoproteins in somatic extracts from adult worms in which the scolex had been removed.…”

Hookworm Excretory/Secretory Products Induce Interleukin-4 (IL-4)+IL-10+CD4+T Cell Responses and Suppress Pathology in a Mouse Model of Colitis

“…Helminths secrete proteins that modulate and/or skew immune responses (17,18), suggesting that "helminth therapy" for autoimmunity could take the form of soluble molecules derived from helminths rather than an active infection (19).…”

Parasitic infection as a potential therapeutic tool against rheumatoid arthritis

“…of RA (9)(10)(11)(12). Moreover, the systemic inflammation caused by RA is an important independent risk factor for cardiovascular disease, and the cardiovascular risk components also increase the inflammatory burden of RA (13,14).…”

“…Both the stimulation and modulation of the host immune system by parasites are determined by DC populations. Depletion of DCs ablates the Th2 immune response to infection, whereas isolated DCs pulsed with parasitic antigens readily induce Th2 responsiveness (12). Therefore, DCs are exciting therapeutic targets for autoimmune rheumatic disease (29).…”