Proteomic identification of IPSE/alpha-1 as a major Hepatotoxin secreted by Schistosoma mansoni eggs

Background: eggs deposited in the liver of the mammalian host by the blood fluke parasite,schistosoma mansoni,normally drive a t-helper-2 (th2)-mediated granulomatous response in immune-competent mice. by contrast,in mice deprived of t-cells and incapable of producing granulomata,egg-secreted proteins (esp) induce acute hepatic injury and death. previous work has shown that one such esp,the t2 ribonuclease known as omega-1,is hepatotoxic in vivo in that specific antisera to omega-1 prevent hepatocyte damage. methodology/principal findings: using an in vitro culture system employing mouse primary hepatocytes and alanine transaminase (alt) activity as a marker of heptocyte injury,we demonstrated that s. mansoni eggs,egg-secreted proteins (esp),soluble-egg antigen (sea),and omega-1 are directly hepatotoxic and in a dose-dependent manner. depletion of omega-1 using a monoclonal antibody abolished the toxicity of pure omega-1 and diminished the toxicity in esp and sea by 47 and 33%,respectively. anion exchange chromatography of esp yielded one predominant hepatotoxic fraction. proteomics of that fraction identified the presence of ipse/alpha-1 (il-4 inducing principle from s. mansoni eggs),a known activator of basophils and inducer of th2-type responses. pure recombinant ipse/alpha-1 also displayed a dose-dependent hepatotoxicity in vitro. monoclonal antibody depletion of ipse/alpha-1 abolished the latter's toxicity and diminished the total toxicity of esp and sea by 32 and 35%,respectively. combined depletion of omega-1 and ipse/alpha-1 diminished hepatotoxicity of esp and sea by 60 and 58% respectively. conclusions: we identified ipse/alpha-1 as a novel hepatotoxin and conclude that both ipse/alpha-1 and omega-1 account for the majority of the hepatotoxicity secreted by s. mansoni eggs. © 2011 abdulla et al.