![]() Recombinant plasminogen added to depleted blood rescues oocyst development, whereas recombinant plasminogen carrying a point mutation (S741A) in the plasmin catalytic triad does not ( 18). Oocyst formation is strongly reduced when gametocytes are fed to mosquitoes in plasminogen-depleted blood ( 18). PAI-1 constitutively circulates in the blood at low levels, and its expression is strongly up-regulated during inflammation, which contributes to the tight control of plasminogen activation ( 16, 17). The serpin plasminogen activator inhibitor-1 (PAI-1) regulates plasminogen activation by specifically inhibiting the activity of both plasminogen activators but not of plasmin ( 15). In a positive feedback loop, plasmin further activates both tPA and uPA, thus accelerating and amplifying plasminogen activation. The activation of cell-associated plasminogen occurs when plasminogen and its activators bind to receptors on the cell surface, bringing the activators and plasminogen into close proximity ( 14). These two proenzymes constitutively circulate in the blood and have low intrinsic catalytic activity ( 9). Plasminogen is proteolytically activated into plasmin by plasminogen activators, namely, tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) ( 9). Surface-associated plasmin broadly facilitates cell migration via digestion of connective tissue and extracellular matrix proteins, as is the case for leukocyte infiltration of inflammatory sites ( 10), tumor growth and metastasis ( 11), embryogenesis ( 12), and pathogen invasion of host tissues ( 13). Plasmin can bind to lysine motifs of proteins exposed on the cell surface ( 9). Plasminogen is the precursor of plasmin, a potent serine protease that cleaves a broad spectrum of substrates and is the effector protease of the fibrinolytic system. The human fibrinolytic system consists of two main protein classes: serine proteases that ultimately degrade fibrin (fibrinogen-derived polymers) and dissolve clots and serpins that tightly regulate the activity of these proteases ( 9). Whereas the motile stages of the malaria parasite rely on an actomyosin-based motor (the glideosome) to generate the forces required for migration ( 8), these forces are unlikely to be sufficient to break through the intricate extracellular matrices. In the mammalian host, barriers include the extracellular matrix of the dermis, the basement lamina of blood vessels, the endothelial and Kupffer cells of the liver blood vessels, the extracellular matrix of the liver space of Disse, and the hepatocyte membranes (fig. In the mosquito, these include a compacted blood bolus, the chitin-rich peritrophic matrix, the midgut microvilli-associated network and mucins ( 4– 6), and the midgut epithelium. ![]() Throughout the Plasmodium life cycle, the parasite encounters multiple physical barriers. Infection requires sporozoites to migrate through the dermis, to find and enter a blood vessel to be carried to the liver, where they exit the circulation to invade hepatocytes and initiate a blood stage infection (fig. During probing and blood feeding, an infected mosquito deposits sporozoites into the dermis (fig. Each oocyst undergoes sporogony to form thousands of sporozoites that are released into the hemolymph, from where they specifically invade the salivary glands (fig. Ookinetes transverse the mosquito midgut epithelium and differentiate into oocysts ( 1, 2). After ingestion of an infected blood meal, Plasmodium male and female gametes mate in the mosquito midgut giving rise to zygotes, which, in turn, differentiate into motile ookinetes (fig. Plasmodium parasites are the etiological agents of malaria and are transmitted to humans by the bite of infected Anopheles mosquitoes. The fibrinolytic system is a potential target to hamper Plasmodium transmission. Surface-bound plasmin promotes sporozoite transmission by facilitating parasite migration across the extracellular matrices of the dermis and of the liver. Furthermore, we show that sporozoites, the parasite form transmitted by the mosquito to humans, also bind plasminogen and plasminogen activators on their surface, where plasminogen is activated into plasmin. We show that increased fibrinogen and fibrin in the blood bolus, which are natural substrates of plasmin, inversely correlate with parasite infectivity of the mosquito. Inhibition of plasminogen activation arrests parasite development early during sexual reproduction, before ookinete formation. We report that Plasmodium gametes recruit human plasminogen to their surface where it is processed into plasmin by corecruited plasminogen activators. ![]() Plasmin, a mammalian serine protease, degrades extracellular matrix proteins allowing cell migration through tissues. Plasmodium parasites must migrate across proteinaceous matrices to infect the mosquito and vertebrate hosts.
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