Large-Scale Investigation of Leishmania Interaction Networks with Host Extracellular Matrix by Surface Plasmon Resonance Imaging

Abstract

We have set up an assay to study the interactions of live pathogens with their hosts by using protein and glycosaminoglycan arrays probed by surface plasmon resonance imaging. We have used this assay to characterize the interactions of Leishmania promastigotes with ϳ70 mammalian host biomolecules (extracellular proteins, glycosaminoglycans, growth factors, cell surface receptors). We have identified, in total, 27 new partners (23 proteins, 4 glycosaminoglycans) of procyclic promastigotes of six Leishmania species and 18 partners (15 proteins, 3 glycosaminoglycans) of three species of stationary-phase promastigotes for all the strains tested. The diversity of the interaction repertoires of Leishmania parasites reflects their dynamic and complex interplay with their mammalian hosts, which depends mostly on the species and strains of Leishmania. Stationary-phase Leishmania parasites target extracellular matrix proteins and glycosaminoglycans, which are highly connected in the extracellular interaction network. Heparin and heparan sulfate bind to most Leishmania strains tested, and 6-O-sulfate groups play a crucial role in these interactions. Numerous Leishmania strains bind to tropoelastin, and some strains are even able to degrade it. Several strains interact with collagen VI, which is expressed by macrophages. Most Leishmania promastigotes interact with several regulators of angiogenesis, including antiangiogenic factors (endostatin, anastellin) and proangiogenic factors (ECM-1, VEGF, and TEM8 [also known as anthrax toxin receptor 1]), which are regulated by hypoxia. Since hypoxia modulates the infection of macrophages by the parasites, these interactions might influence the infection of host cells by Leishmania.

The site of the bite: Leishmania interaction with macrophages, neutrophils and the extracellular matrix in the dermis

“…In contrast, a higher content of collagen III during leishmaniasis can induce the presence of a softer skin matrix, by which parasites would have an easier path for migration and tissue invasion. Promastigotes also bind to collagen VI, which is normally secreted by macrophages [ 23 ].…”

“…They are present in the skin and can influence a variety of events during tissue repair, such as avoiding water lost, preventing tissue compression and regulating cell migration and survival [ 41 ]. Leishmania promastigotes bind to heparan sulfate, heparin and hyaluran [ 23 ], present at the dermal epithelial junction and the dermis. A heparin-binding protein, which mediates parasite – proteoglycan binding has been described and implicated in parasite virulence and host cell invasion, since Leishmania parasites were unable to invade cells without heparin on the surface.…”

Detection and characterization of plasminogen receptors on clinical isolates ofTrichosporon asahii

“…Recently, Leishmania interaction networks with the host extracellular matrix were investigated using SPR imaging. Interestingly, of six Leishmania species , 27 new partners (23 proteins, 4 glycosaminoglycans) of procyclic promastigotes and 18 (15 proteins, 3 glycosaminoglycans) of three species of stationary phase promastigotes containing heparin and plasminogen were identified (Fatoux‐Ardore et al ., ). Of the molecules with which Leishmania interacted, several regulators of angiogenesis, including antiangiogenic (endostatin and anastellin) and pro‐angiogenic factors (ECM‐1, VEGF, TEM8, also known as anthrax toxin receptor 1), are regulated by hypoxia.…”

“…To investigate the pathogenicity, we focused on the interactions between surface molecules of T. asahii and host biomolecules. Microbial pathogens express molecules that interact with host proteins and carbohydrates (Henderson & Martin, ; Fatoux‐Ardore et al ., ), leading to invasion and colonization. Some pathogenic microorganisms express proteins that bind to and enhance plasminogen activity (Furuya & Ikeda, ; Bhattacharya et al ., ; Sanderson‐Smith et al ., ; Fulde et al ., ; Godier & Hunt, ; Magalhaes et al ., ).…”

Glycosaminoglycans and infection

“…, HSV, MCV) (54, 55), bacterial ( e.g. , Group A Streptococci, S. aureus ) (56, 57), parasitic ( e.g., Leishmania ) (58) and fungal pathogens ( e.g., Candida ) (59), have been shown to bind to GAGs. For example, Merkel cell polyoma virus (MCV) primarily binds to cell surface HS, and to a lesser extent CS, for its initial attachment to host cells (55).…”