Biochemical and biophysical methodologies open the road for effective schistosomiasis therapy and vaccination

• Published in: Biochimica et biophysica acta. General subjects Vol. 1861; no. 1; pp. 3613 - 3620
• Main Authors: El Ridi, Rashika, Tallima, Hatem, Migliardo, Federica
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2017
• Subjects: adults; Animals; antibodies; antigens; antiplatyhelmintic agents; Arachidonic acid; Biochemistry - methods; Biophysics - methods; biosynthesis; bleaching; children; cholesterol; Elastic incoherent and quasi-elastic neutron scattering; excretory-secretory products; flukes; Hydrogen bond barrier; hydrogen bonding; hydrolysis; Immune Evasion; laboratory animals; lipid bilayers; Middle East; Neutral sphingomyelinase; nutrients; permeability; Schistosoma; Schistosoma - growth & development; Schistosoma - immunology; Schistosoma haematobium; Schistosoma mansoni; schistosomiasis; Schistosomiasis - immunology; Schistosomiasis - therapy; South America; Sphingomyelin; sphingomyelins; Sub-Saharan Africa; toxicity; Vaccination; vaccines; viability; Middle East; South America; Sub-Saharan Africa; nSMase; ESP; PUFA; PZQ; Neutral sphingomyelinase; Hydrogen bond barrier; EINS; Schistosoma; Arachidonic acid; Elastic incoherent and quasi-elastic neutron scattering; ARA; MBCD; SG3PDH; Sphingomyelin; SM; QENS; IF
• ISSN: 0304-4165; 1872-8006
• DOI: 10.1016/j.bbagen.2016.03.036

Schistosomiasis caused by blood-dwelling flukes, namely Schistosoma mansoni and Schistosoma haematobium is a severe debilitating disease, widespread in sub-Saharan Africa, the Middle East, and South America. Developing and adult worms are unscathed by the surrounding immune effectors and antibodies because the parasite is protected by a double lipid bilayer armor which allows access of nutrients, while binding of specific antibodies is denied. Fluorescence recovery after bleaching, extraction of surface membrane cholesterol by methyl-β-cyclodextrin, inhibition and activation of sphingomyelin biosynthesis and hydrolysis, and elastic incoherent and quasi-elastic neutron scattering approaches have helped to clarify the basic mechanism of this immune evasion, and showed that sphingomyelin (SM) molecules in the worm apical lipid bilayer form with surrounding water molecules a tight hydrogen bond barrier. Viability of the parasite and permeability of the outer shield are controlled by equilibrium between SM biosynthesis and activity of a tegument-associated neutral sphingomyelinase (nSMase). Excessive nSMase activation by polyunsaturated fatty acids (PUFA), such as arachidonic acid (ARA) leads to disruption of the SM molecules and associated hydrogen bond network, with subsequent access of host antibodies and immune effectors to the outer membrane and eventual parasite death. ARA was predicted and shown to be a potent schistosomicide in vitro and in vivo in experimental animals and in children. Additionally, it was advocated that schistosomiasis vaccine candidates should be selected uniquely among excretory–secretory products of developing worms, as contrary to cytosolic and surface membrane antigens, they are able to activate the effector functions of the host antibodies and toxic molecules. This article is part of a Special Issue entitled “Science for Life” Guest Editor: Dr. Austen Angell, Dr. Salvatore Magazù and Dr. Federica Migliardo“. [Display omitted] •Cholesterol and sphingomyelin sequester larval schistosome outer membrane antigens.•Sphingomyelin protects schistosomes via tight hydrogen bond barrier formation.•QENS and EINS measurements were performed to study schistosomes mobility and rigidity.•The measurements revealed the different diffusion and flexibility properties of larvae and adult parasites.•Activator of neutral sphingomyelinase, arachidonic acid, is a new schistosomicide.•Larval excretory-secretory products were advocated as sole vaccine candidates.