Fibrinolysis-unrelated functions of the plasminogen/plasmin system: A gateway to successful parasitism?

Parasites have evolved remarkable mechanisms to exploit host resources by subverting key physiological pathways to facilitate their survival and transmission. A paradigmatic example of this is the ability of some of these organisms to interact with the plasminogen (PLG)/plasmin system of their definitive hosts, which facilitates parasite survival and dissemination through mammalian tissues. The PLG/plasmin system has been historically referred to as the fibrinolytic system owing to its major role in degrading fibrin clots, which depends on the conversion of the PLG zymogen into the catalytically active protease plasmin by the tissue-type and urokinase-type PLG activators (t-PA and u-PA, respectively). Beyond this canonical role, the multiplicity of plasmin substrates and the broad cellular expression of u-PA, the main extravascular PLG activator, engage the PLG/plasmin system in a myriad of functions that are unrelated to fibrin clot removal, including brain function, cell adhesion, wound healing, angiogenesis, inflammation/immunity, and cell migration. Intriguingly, these processes are generally modified in parasitised hosts compared to healthy individuals, suggesting that their manipulation may provide survival advantages to parasites. In the present review, we explore the link between clinically relevant endoparasites and the PLG/plasmin system with a particular emphasis on how these organisms exploit its fibrinolysis-unrelated functions to modulate host physiology and facilitate tissue invasion, immune evasion, and persistence within the mammalian organism. Finally, we also discuss the involvement of this host-parasite interaction in host pathogenesis, its potential for informing novel antiparasitic control strategies, and its broader significance as a fundamental aspect of successful parasitism.