Schistosome immunomodulators

Abstract

Schistosomes are long lived, intravascular parasitic platyhelminths that infect >200 million people globally. The molecular mechanisms used by these blood flukes to dampen host immune responses are described in this review. Adult worms express a collection of host-interactive tegumental ectoenzymes that can cleave host signaling molecules such as the "alarmin" ATP (cleaved by SmATPDase1), the platelet activator ADP (SmATPDase1, SmNPP5), and can convert AMP into the anti-inflammatory mediator adenosine (SmAP). SmAP can additionally cleave the lipid immunomodulator sphingosine-1-phosphate and the proinflammatory anionic polymer, polyP. In addition, the worms release a barrage of proteins (e.g., SmCB1, SjHSP70, cyclophilin A) that can impinge on immune cell function. Parasite eggs also release their own immunoregulatory proteins (e.g., IPSE/α1, omega1, SmCKBP) as do invasive cercariae (e.g., Sm16, Sj16). Some schistosome glycans (e.g., LNFPIII, LNnT) and lipids (e.g., Lyso-PS, LPC), produced by several life stages, likewise affect immune cell responses. The parasites not only produce eicosanoids (e.g., PGE2, PGD2-that can be anti-inflammatory) but can also induce host cells to release these metabolites. Finally, the worms release extracellular vesicles (EVs) containing microRNAs, and these too have been shown to skew host cell metabolism. Thus, schistosomes employ an array of biomolecules-protein, lipid, glycan, nucleic acid, and more, to bend host biochemistry to their liking. Many of the listed molecules have been individually shown capable of inducing aspects of the polarized Th2 response seen following infection (with the generation of regulatory T cells (Tregs), regulatory B cells (Bregs) and anti-inflammatory, alternatively activated (M2) macrophages). Precisely how host cells integrate the impact of these myriad parasite products following natural infection is not known. Several of the schistosome immunomodulators described here are in development as novel therapeutics against autoimmune, inflammatory, and other, nonparasitic, diseases.

Fig 1. The impact of molecules (bold text) produced by schistosome larvae (cercariae and/or schistosomula) on the host cells indicated.

An image of an S. mansoni cercaria is seen at the center. The green dashed lines indicate stimulatory effects, while red dashed lines indicate inhibitory effects. See text for details regarding the impact of individual schistosome molecules on specific cell types. DC, dendritic cell; ES, excretions/secretions; IFNγ, interferon gamma; IL-10, interleukin 10; IL-1ra, IL-1 receptor antagonist a; LPS, lipopolysaccharide; PGE2, prostaglandin E2; PGD2, prostaglandin D2 SmAF, S. mansoni apoptosis factor; SmTCTP, S. mansoni translationally controlled tumor protein.

Fig 2. The impact of molecules (bold text) derived from intravascular stage schistosomes (schistosomula and adults) on host cells and metabolites, as indicated.

The box (top left) lists S. mansoni tegumental NMEEs and, connected by dashed yellow lines, the host signaling molecules they have been shown to cleave (white text). The green dashed lines indicate stimulatory effects on immune cells, while red dashed lines indicate inhibitory effects. An image of an S. mansoni adult male is seen at center. See text for details regarding the impact of individual schistosome molecules on specific cell types. ATP, adenosine triphosphate; ADP, adenosine diphosphate; AMP, adenosine monophosphate; DC, dendritic cell; Hz, hemozoin; LNnT, lacto-N-neotetraose; LPC, lysophosphatidylcholine; NAD, nicotinamide adenine dinucleotide; NMEE, nucleotide metabolizing ectoenzyme; PGE2, prostaglandin E2; PGD2, prostaglandin D2.

Fig 3. The impact of molecules (bold text) produced by schistosome eggs on the host immune cells indicated.

The green dashed lines indicate stimulatory effects, while red dashed lines indicate inhibitory effects. An image of an S. mansoni egg is seen at center. See text for details regarding the impact of individual schistosome molecules on specific cell types. DC, dendritic cell; dsRNA, double-strand RNA; IPSE/α1, IL-4–inducing principle of schistosome eggs/alpha 1; PGE2, prostaglandin E2; PGD2, prostaglandin D2; SmCKBP, S. mansoni chemokine binding protein; SmHMGB1, S. mansoni high mobility group box 1 protein 1.

Fig 4. List of immunomodulatory schistosome proteins and their major effects.

ADP, adenosine diphosphate; AMP, adenosine monophosphate; ATP, adenosine triphosphate; Breg, regulatory B cell; DC, dendritic cell; HDM, helminth defense molecule; IL-1ra, IL-1 receptor antagonist a; LPS, lipopolysaccharide; NAD, nicotinamide adenine dinucleotide; polyP, polyphosphate; SmAF, S. mansoni apoptosis factor; SmTCTP, S. mansoni translationally controlled tumor protein; Treg, regulatory T cell.

Fig 5. List of nonprotein immunomodulatory schistosome products and their major effects.

Structural representations of some molecules are presented: For the glycans LNFPIII and LNnT, blue circles depict glucose, blue squares N-acetylglucosamine, yellow circles galactose, and the red triangle indicates fucose. Lyso-PS 20:1 and LPC 16:0 are depicted. DC, dendritic cell; EXC4, eoxin C4; LTC4, leukotriene C4; TGF-β, transforming growth factor beta; TNFα, tumor necrosis factor alpha; Treg, regulatory T cell.