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.

Differential excretory/secretory proteome of the adult female and male stages of the human blood fluke,Schistosoma mansoni

“…may not yet be fully characterized or deciphered, e.g., (Acharya et al, 2021). An early study of adults stage S. japonicum ESPs showed the presence of canonical proteins such as metabolic enzymes, heat shock proteins (HSPs), detoxification proteins, and peptidases (Liu et al, 2009).…”

“…Whereas the schistosome egg is responsible for the disease manifestations of chronic schistosomiasis, as well as orchestrating the hallmark immunological transition from a Th1 to Th2 response (Pearce and MacDonald, 2002;Schwartz and Fallon, 2018;Acharya et al, 2021), the long lived, adult female and male stages also release mediators that facilitate their long-lived intra-vascular existence in a hostile niche where they are bathed in immune cells and effector molecules. These mediators, also known as excretory/secretory products (ESPs), are secreted (or released) from the esophageal gland, the gut epithelium and from the tegument of schistosomes, making it a highly diverse mixture of molecules.…”

“…These mediators, also known as excretory/secretory products (ESPs), are secreted (or released) from the esophageal gland, the gut epithelium and from the tegument of schistosomes, making it a highly diverse mixture of molecules. ESPs from several developmental stages and species of schistosomes have been described in depth, e.g., (Liu et al, 2009;Mathieson and Wilson, 2010;Hall et al, 2011;Dvořák et al, 2016;Sotillo et al, 2016;Floudas et al, 2017;De Marco Verissimo et al, 2019;Sotillo et al, 2019;Kifle et al, 2020;Neves et al, 2020;Chen et al, 2022), although the diversity, role, and packaging of these secreted and excreted antigens, including as cargo within extracellular vesicles, may not yet be fully characterized or deciphered, e.g., (Acharya et al, 2021). An early study of adults stage S. japonicum ESPs showed the presence of canonical proteins such as metabolic enzymes, heat shock proteins (HSPs), detoxification proteins, and peptidases (Liu et al, 2009).…”

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“…Whereas the schistosome egg is responsible for the disease manifestations of chronic schistosomiasis, as well as orchestrating the hallmark immunological transition from a Th1 to Th2 response (Pearce and Macdonald, 2002;Schwartz and Fallon, 2018;Acharya et al, 2021), the long lived, adult female and male stages also release mediators that facilitate their intra-vascular existence in a hostile niche where they are bathed in immune cells and effector molecules. These mediators, also known as excretory/secretory products (ESPs), are secreted (or released) from the esophageal gland, the gut epithelium and from the tegument of schistosomes, making it a highly diverse mixture of molecules.…”

“…These mediators, also known as excretory/secretory products (ESPs), are secreted (or released) from the esophageal gland, the gut epithelium and from the tegument of schistosomes, making it a highly diverse mixture of molecules. The protein composition of the ESPs from several developmental stages and species of schistosomes has been described in depth (Liu et al, 2009;Mathieson and Wilson, 2010;Hall et al, 2011;Dvorak et al, 2016;Sotillo et al, 2016Sotillo et al, , 2019Floudas et al, 2017;De Marco Verissimo et al, 2019;Kifle et al, 2020;Neves et al, 2020;Chen et al, 2022), although the diversity, role, and packaging of these secreted and excreted antigens, including as cargo within extracellular vesicles, may not yet be fully characterized or deciphered (Acharya et al, 2021). An early study of adult stage S. japonicum ESPs showed the presence of conserved proteins such as metabolic enzymes, heat shock proteins (HSPs), detoxification proteins, and peptidases (Liu et al, 2009).…”