title: Parasite cysteine proteinase interactions with alpha 2-macroglobulin or kininogens: differential pathways modulating inflammation and innate immunity in infection by pathogenic trypanosomatids.
abstract: Plasma extravasation is a common endothelium response to tissue injury provoked by pathogens. Herein I will review studies showing that host proteinase inhibitors (e.g., alpha2-macroglobulin (alpha2M) or kininogens) interact with protozoan cysteine proteinases (CPs) in extravascular infection sites, linking inflammation to innate immunity by different mechanisms. Using human monocytes as antigen presenting cells, we first demonstrated that alpha2M entrapment of cruzipain, a Trypanosoma cruzi CP, reduced the activation threshold of cruzipain-specific CD4 T cells due to facilitated uptake of alpha2M-cruzipain complexes by the multiscavenger receptor (CD91). More recently, studies of the mechanisms underlying inflammation elicited by T. cruzi revealed that kininogens, once bound to glycosaminoglycans, are not able to efficiently inactivate cruzipain via their inhibitory cystatin-like domains. Instead, we found that cruzipain readily processes surface-bound kininogens, liberating bioactive kinins. Acting as paracrine hormones, kinins vigorously activate host cells through bradykinin (BK) receptors, thus stimulating endocytic uptake of the pathogen. Rather than unilaterally enhancing parasite infectivity, the liberated kinins activate innate immunity by potently stimulating dendritic cell maturation via the BK B2 receptor. The discovery of chagasin, a novel family of endogenous inhibitors expressed by trypanosomatids, is likely another regulatory player involved in the dynamics of the inflammatory response.
authors.affiliation: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, C.C.S., Ilha do Fundão, Rio de Janeiro 21949-900, RJ, Brazil. scharf@biof.ufrj.br
authors.forename: Julio
authors.initials: J
authors.lastname: Scharfstein
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000201:enzymology* / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism* / Q000502:physiology; D007704:Kininogens / Q000378:metabolism* / Q000502:physiology; D015800:Protozoan Proteins / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D014349:Trypanosoma cruzi / Q000201:enzymology* / Q000254:growth & development / Q000276:immunology / Q000472:pathogenicity; D000511:alpha-Macroglobulins / Q000378:metabolism* / Q000502:physiology
chemical_list: D018836:Inflammation Mediators; D007704:Kininogens; D015800:Protozoan Proteins; D000511:alpha-Macroglobulins; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi