title: Fibronectin binding and proteolytic degradation by Leishmania and effects on macrophage activation.
abstract: Infection by vector-borne protozoa of the genus Leishmania occurs by the deposition of parasites within the skin of the mammalian host, where they eventually bind to and are phagocytized by Mphis. Our previous work supported the idea that parasites can interact with extracellular matrix and basement membrane proteins, such as fibronectin (FN), within the skin, leading to enhanced invasion. In this report, we extend these findings and show that both promastigotes and amastigotes of Leishmania species can bind directly to soluble FN and laminin (LM) and that promastigotes express a distinct surface protein of approximately 60 kDa that binds both FN and LM. Promastigotes of multiple Leishmania species can rapidly degrade FN by using surface-localized and secreted metalloprotease (leishmanolysin). FN degradation at the surfaces of amastigotes is leishmanolysin dependent, whereas both secreted leishmanolysin and cysteine protease B contribute to extracellular FN degradation. Leishmania-degraded FN decreased the production of reactive oxygen intermediates by parasite-infected macrophages and affected the accumulation of intracellular parasites. These findings show that both parasite stages of Leishmania species bind to and proteolytically degrade FN at the parasite surface and distantly through secreted proteases and that degraded forms of FN can influence the activation state of parasite-infected macrophages.
authors.affiliation: Division of Infectious Diseases and Center for Microbial Interface Biology, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Manjusha M
authors.initials: MM
authors.lastname: Kulkarni
authors.forename: Eric A
authors.initials: EA
authors.lastname: Jones
authors.forename: W Robert
authors.initials: WR
authors.lastname: McMaster
authors.forename: Bradford S
authors.initials: BS
authors.lastname: McGwire
mesh_terms: D000818:Animals; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism*; D005786:Gene Expression Regulation; D007891:Leishmania / Q000201:enzymology / Q000502:physiology*; D008262:Macrophage Activation; D008264:Macrophages / Q000502:physiology*; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D011485:Protein Binding; D015032:Zinc / Q000378:metabolism
chemical_list: D005353:Fibronectins; D003546:Cysteine Endopeptidases; D008666:Metalloendopeptidases; C055146:glycoprotein gp63, Leishmania; D015032:Zinc