Schistosome immunomodulators

Sreemoyee Acharya

doi:10.1371/journal.ppat.1010064

Schistosome immunomodulators

2021-12-30

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DOI：10.1371/journal.ppat.1010064

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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/alpha 1, 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. Author summarySchistosomes, or blood flukes, are long lived, parasitic worms that are found in the bloodstreams of >200 million people around the world. How the worms manage to survive in the face of attack by the mammalian host's elaborate immune system is the subject of this review. The adult worms express a collection of enzymes on their surface that cleave important immune signaling molecules in the blood, and this could impede the ability of such molecules to awaken antiparasite immune cells. The worms also release a barrage of other proteins that directly interact with host cells to blunt their activation. The worms have nonprotein mediators too, including lipids, glycans, and nucleic acids (e.g., in the form of microRNAs) that can each affect immune cell responses. All of these metabolites may be used by the worms to bend host biochemistry to their liking and so ensure their survival. Several of the schistosome immunomodulators described in this work are in development as novel therapeutics against autoimmune, inflammatory, and other, nonparasitic, diseases.

Keyword:

SKIN-STAGE SCHISTOSOMULA

MANSONI EGGS

PROTEOMIC ANALYSIS

MOLECULAR CHARACTERIZATION

DENDRITIC CELLS

IMMUNE-RESPONSES

TH2 POLARIZATION

INTERLEUKIN-4-INDUCING PRINCIPLE

EXCRETORY/SECRETORY PROTEOME

ALTERNATIVE ACTIVATION

Schistosome immunomodulators

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