Beyond cuts and scrapes: plasmin in malaria and other vector-borne diseases

Abstract

Plasmodium and other vector-borne pathogens have evolved mechanisms to hijack the mammalian fibrinolytic system to facilitate infection of the human host and the invertebrate vector. Plasmin, the effector protease of fibrinolysis, maintains homeostasis in the blood vasculature by degrading the fibrin that forms blood clots. Plasmin also degrades proteins from extracellular matrices, the complement system, and immunoglobulins. Here, we review some of the mechanisms by which vector-borne pathogens interact with components of the fibrinolytic system and co-opt its functions to facilitate transmission and infection in the host and the vector. Further, we discuss innovative strategies beyond conventional therapeutics that could be developed to target the interaction of vector-borne pathogens with the fibrinolytic proteins and prevent their transmission.

Keywords: fibrinolysis; malaria; plasmin; vector-borne diseases.

Figure 1.. The fibrinolytic system and its roles in humans and pathogens.

A. Plasminogen is activated into the serine protease plasmin by the tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). Both tPA and uPA are inhibited by plasminogen activator inhibitor-1 (PAI-1). Plasmin is inhibited by α2- antiplasmin and α2-macroglobulin. B. Pathogens evade immunity by co-opting plasmin to degrade C3b and prevent the formation of the terminal complement complex (TCC). C. During coagulation, thrombin converts fibrinogen into insoluble fibrin which polymerizes to form a clot. Plasmin degrades fibrin, thus facilitating clot removal to maintain homeostasis. D. Plasmin degrades ECM proteins, like fibronectin, laminin, and proteoglycans, thus facilitating cell migration and tissue rearrangement. Pathogens co-opt plasmin to facilitate migration through fibrin networks (C) and ECM (D). Figure created with BioRender.com.

Figure 2, Key Figure.. Vector-borne pathogens co-opt the fibrinolytic system for invasion and transmission.

A. The role of the fibrinolytic proteins in malaria. A1. uPA binding on mature trophozoites is essential for merozoite egress. A2. Plasmodium gametes recruit host tPA to activate surface-bound plasminogen into plasmin. It is proposed that plasmin degrades fibrin networks in the midgut blood bolus and thus facilitate gamete migration and fertilization. A3. tPA activates plasminogen into plasmin at the sporozoite surface and plasmin facilitates sporozoite migration in the dermis and the liver by degrading ECM proteins. A4. tPA activates plasminogen to plasmin on infected RBCs. Plasmin facilitates parasite complement evasion by degrading C3b on the infected RBC surface, thereby preventing the formation of the terminal complement complex (TCC) and parasite lysis. B1. Plasminogen-deficient mice restrict the formation of leishmaniasis lesions suggesting the role of plasmin for parasite dissemination. C1. T. cruzi epimastigotes enhance plasminogen activation by tPA, which might have a role in parasite traversal and survival (*). D1. Plasmin enhances DENV infection of Ae. aegypti mosquitoes. It is proposed that plasmin on the surface of DENV facilitates the degradation of the glycocalyx matrix and enhances internalization of the virus by the midgut epithelial cells. E1. Borrelia spp. plasminogen activation by tPA and uPA facilitates systemic bacteria dissemination in mice, and dissemination from the tick gut to the salivary glands. E2. Plasmin enhances Borrelia spp. infection of the brain and heart by disrupting the tissue through the degradation of tight junction proteins. Figure created with BioRender.com.