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  • Introduction Taenia solium is the causative agent of human


    Introduction Taenia solium is the causative agent of human taeniasis/cysticercosis and porcine cysticercosis, a major health problem and a veterinary economic challenge in developing countries of Latin America, Africa, and Asia. In Mexico, approximately 500 human neurocysticercosis cases were reported in neurological centers between 1994 and 2004 (Sciutto et al., 2000; Fleury et al., 2011, Fleury et al., 2012). Little is known about the molecular mechanisms underlying the early infection events that lead to cysticercus establishment in the host tissues. While pigs are obligate intermediate hosts in the life Topiroxostat of T. solium when they are infected with the larval stage of the worm (cysticerci), humans can also be infected by cysticerci; after being ingested by the host, eggs are activated and hatch in the intestine, releasing an hexacanth embryo (oncosphere); the latter crosses the intestinal wall and migrates to several tissues, where it evolves into the larval form (cysticercus) (Flisser, 2013). Like many other pathogens, cysticerci developed strategies to favor their establishment and permanence in the host tissues, such as coating its tegument surface with host immunoglobulins (Willms and Arcos, 1997) or modulating host inflammatory and immune responses through various parasite-secreted factors (Damian, 1997; Alvarez et al., 2008; Bobes et al., 2014); furthermore, a host-parasite molecular crosstalk mediated by signaling molecules has been described (Tedford and McConkey, 2017; Singh and Chitnis, 2017; Brehm and Koziol, 2017). Recent reports indicated an extensive uptake of host proteins by T. solium cysticerci; these host proteins could play some role in the worm physiology, and this role could be analogous to the one they play in host tissues (Navarrete-Perea et al., 2014). Binding and activation of plasminogen (Plg) has been proposed as a strategy to favor the migration and establishment of several pathogens (Sanderson-Smith et al., 2012; Verhamme et al., 2015; Figuera et al., 2013). Plasmin (the activated form of Plg) is an enzyme whose primary function is to degrade fibrin clots produced by the coagulation system (fibrinolysis) to maintain vascular permeability (Lähteenmäki et al., 2001). Plasmin has also been involved in extracellular matrix (EMC) degradation, immune response modulation (Barthel et al., 2012), and its direct participation during invasion in several parasite infections has been proposed (Jolodar et al., 2003; Ghosh and Jacobs-Lorena, 2011; Figuera et al., 2013). Enolase is a dimeric, multifunctional glycolytic enzyme that catalyzes the interconversion of 2-phospho-d-glycerate and phosphoenolpyruvate in the cell. In some vertebrates, enolases are usually coded by four genes: Eno1, Topiroxostat Eno2, Eno3, and Eno4, resulting in different isoenzymes through combinations of α, β, and γ subunits (Pearce et al., 1976; Schmechel et al., 1978; Ueta et al., 2004). In humans, four tissue-specific enolase isozymes have been reported: non-neuronal enolase (αα or Eno1), muscle-specific enolase (ββ or Eno3), neuron-specific enolase (γγ or Eno2), and sperm-specific enolase (Eno4) (Edwards and Grootegoed, 1983; Nakamura et al., 2013). Enolases have received less attention in invertebrates (Tracy and Hedges, 2000), but they have been found in helminth parasites such as Onchocerca volvulus (Jolodar et al., 2003), Fasciola hepatica (Bernal et al., 2004), Echinostoma caproni (Marcilla et al., 2007), Schistosoma bovis (De la Torre-Escudero et al., 2010), and more recently in Taenia multiceps (Li et al., 2015) and T. pisiformis (Zhang et al., 2015). The existence of isoforms in flatworms is still debated. Enolases are members of a group of proteins that have been involved in other entirely distinct functions, known as moonlighting proteins (Pancholi, 2001). For instance, enolase has been reported to play a role as plasminogen receptor on the surface of several pathogenic bacteria (Xolalpa et al., 2007; Sanderson-Smith et al., 2012), fungi (Verhamme et al., 2015), and protozoa (Vanegas et al., 2007; Ghosh et al., 2011). Enolases have raised interest as inducers of protective immunity and are considered as potential vaccine candidates in two tapeworm infections (Yang et al., 2010; Chen et al., 2012). The initial goal of this study was to evaluate whether enolase from T. solium binds and activates Plg. Our results demonstrated that at least seven T. solium proteins, including enolase, are able to bind Plg. An exhaustive analysis in silico of the genome database of T. solium and other Taeniids showed at least four enolase genes. After a detailed phylogenetic analysis, herein we propose to designate the tapeworm protein isoforms as EnoA, EnoB, EnoC, and Eno4, to emphasize that they are not orthologous to their mammalian counterparts. EnoA was cloned, characterized and expressed in bacteria (rTsEnoA). This recombinant enolase showed a strong Plg binding and activating activity in vitro. The potential role of enolases in the host-parasite relation in cysticercosis is discussed.