Plasminogen-binding proteins as an evasion mechanism of the host’s innate immunity in infectious diseases

Abstract

Pathogens have developed particular strategies to infect and invade their hosts. Amongst these strategies’ figures the modulation of several components of the innate immune system participating in early host defenses, such as the coagulation and complement cascades, as well as the fibrinolytic system. The components of the coagulation cascade and the fibrinolytic system have been proposed to be interfered during host invasion and tissue migration of bacteria, fungi, protozoa, and more recently, helminths. One of the components that has been proposed to facilitate pathogen migration is plasminogen (Plg), a protein found in the host’s plasma, which is activated into plasmin (Plm), a serine protease that degrades fibrin networks and promotes degradation of extracellular matrix (ECM), aiding maintenance of homeostasis. However, pathogens possess Plg-binding proteins that can activate it, therefore taking advantage of the fibrin degradation to facilitate establishment in their hosts. Emergence of Plg-binding proteins appears to have occurred in diverse infectious agents along evolutionary history of host–pathogen relationships. The goal of the present review is to list, summarize, and analyze different examples of Plg-binding proteins used by infectious agents to invade and establish in their hosts. Emphasis was placed on mechanisms used by helminth parasites, particularly taeniid cestodes, where enolase has been identified as a major Plg-binding and activating protein. A new picture is starting to arise about how this glycolytic enzyme could acquire an entirely new role as modulator of the innate immune system in the context of the host–parasite relationship.

Moonlighting Proteins at the Candidal Cell Surface

“…One of the key infection-relevant mechanisms described for many pathogenic bacteria and fungi is an ability to interact with soluble human plasminogen (HPG) [ 96 , 97 ]. HPG is a precursor (zymogen) of plasmin―a serine protease that plays an essential role in fibrinolysis by breaking down fibrin clots.…”

Peptidylarginine Deiminase of Porphyromonas gingivalis Modulates the Interactions between Candida albicans Biofilm and Human Plasminogen and High-Molecular-Mass Kininogen

“…Hence, it is possible that citrullination may have an impact on the adhesion of HPG to C. albicans. Although in the case of enolase, frequently indicated as a major HPG-binding microbial protein, the identified modification of Arg333 is distant from the HPG-binding fragments located near its C-terminus containing the lysine-dependent binding site, its location in a higher-order structure may influence the enolase exposure at the fungal cell surface [53,69]. Furthermore, the effect of these modifications can be complex and depend on the interaction of many HPG-binding proteins present at the surface of the fungal cells and modified by PPAD, given that the detailed molecular bases of this phenomenon are currently not fully recognized for C. albicans proteins.…”

“…This includes the modulation of important host plasma homeostatic systems such as the coagulation and fibrinolysis systems, the complement system, and the kinin generation system (also known as the contact system) [45,46,[49][50][51][52]. One of the mechanisms that facilitates the interference by pathogens of plasma homeostatic systems is the binding of their individual components to the surfaces of microbial cells, which contributes to the local increase in their concentration and further processing by proteases, or to the insidious takeover of these components and their exclusion from the host systems [53,54]. Such abilities to entrain plasma cascades and thus evade host innate immunity were previously described for the opportunistic pathogen C. albicans [55,56].…”

Multi-omic studies on missense PLG variants in families with otitis media

“…Plasminogen has been shown to play a crucial role in other cellular processes such as wound healing, immunity, tissue remodeling, inflammation, and cell migration 12 . Interestingly, there is evidence that some bacteria possess plasminogen-binding adhesins on their cell surface to exploit the fibrinolytic system by degrading host junction proteins and initiating signaling events that facilitate bacterial uptake and invasion 11 , 13 . In previous studies, mice deficient in plasminogen spontaneously developed chronic OM by 18 weeks of age, and local injection of plasminogen led to healing of eardrum perforations 14 , 15 .…”

“…PLG (MIM 173,350) encodes plasminogen which is a secreted blood zymogen that, when activated by proteolysis, is converted to plasmin. The product plasmin is a serine protease that degrades fibrin clots and promotes degradation of the extracellular matrix 11 . Plasminogen has been shown to play a crucial role in other cellular processes such as wound healing, immunity, tissue remodeling, inflammation, and cell migration 12 .…”