Surface-Associated Plasminogen Binding of Cryptococcus neoformans Promotes Extracellular Matrix Invasion

Abstract

BackgroundThe fungal pathogen Cryptococcus neoformans is a leading cause of illness and death in persons with predisposing factors, including: malignancies, solid organ transplants, and corticosteroid use. C. neoformans is ubiquitous in the environment and enters into the lungs via inhalation, where it can disseminate through the bloodstream and penetrate the central nervous system (CNS), resulting in a difficult to treat and often-fatal infection of the brain, called meningoencephalitis. Plasminogen is a highly abundant protein found in the plasma component of blood and is necessary for the degradation of fibrin, collagen, and other structural components of tissues. This fibrinolytic system is utilized by cancer cells during metastasis and several pathogenic species of bacteria have been found to manipulate the host plasminogen system to facilitate invasion of tissues during infection by modifying the activation of this process through the binding of plasminogen at their surface.MethodologyThe invasion of the brain and the central nervous system by penetration of the protective blood-brain barrier is a prerequisite to the establishment of meningoencephalitis by the opportunistic fungal pathogen C. neoformans. In this study, we examined the ability of C. neoformans to subvert the host plasminogen system to facilitate tissue barrier invasion. Through a combination of biochemical, cell biology, and proteomic approaches, we have shown that C. neoformans utilizes the host plasminogen system to cross tissue barriers, providing support for the hypothesis that plasminogen-binding may contribute to the invasion of the blood-brain barrier by penetration of the brain endothelial cells and underlying matrix. In addition, we have identified the cell wall-associated proteins that serve as plasminogen receptors and characterized both the plasminogen-binding and plasmin-activation potential for this significant human pathogen.ConclusionsThe results of this study provide evidence for the cooperative role of multiple virulence determinants in C. neoformans pathogenesis and suggest new avenues for the development of anti-infective agents in the prevention of fungal tissue invasion.

Paracoccidioides brasiliensis Enolase Is a Surface Protein That Binds Plasminogen and Mediates Interaction of Yeast Forms with Host Cells

“…Previous work has shown that enolase binds to hPlg through lysine residues (33,47). We thus examined if binding of rPbEno was lysine dependent by using competitive antagonism with the lysine analog ε-ACA.…”

“…After adherence, the next step must be to overcome the barriers imposed by epithelial tissues and ECM. The proteolytic activity achieved by subversion of host proteases by pathogens, such as plasmin, has been shown to be important during the process of many types of infections (47,51).…”

“…The importance of plasminogen in infectious diseases is supported by the fact that many pathogens manifest the ability to bind plaminogen (47,13). Plasminogen is a single-chain glycoprotein with a molecular mass of 92 kDa.…”

“…Plasmin is involved in fibrinolysis homeostasis and degradation of the extracellular matrix and basement membrane. The mammalian plasminogen-plasmin proteolytic system plays a crucial role in extracellular matrix degradation which is exploited by invasive pathogens, including fungi (25,47). Microbe-derived plasminogen conversion to plasmin may promote dissemination of the pathogen within the host (1).…”

Interaction of Leptospira interrogans with Human Proteolytic Systems Enhances Dissemination through Endothelial Cells and Protease Levels

“…Indeed, the PLG/PLA binding has been described to facilitate the keratinocyte invasion by Streptococcus pyogenes (32). Furthermore, it has been reported that the fungal pathogen Cryptococcus neoformans coated with PLG promotes extracellular matrix (ECM) invasion (33). Surprisingly, the cellular transmigration efficiency of leptospires treated only with PLG and lacking uPA was higher than that in the untreated control.…”