Laboratory of Molecular Immunology

       "The axis Toli-Bradykinin: a path of integration between the microvascular system and innate immunity in Chagas infection." Centered in the investigation of the mechanisms of immunopathogenesis in Chagas Disease, surveys conducted by the team aim to clarify the contribution of Kinin System (KS) in the delicate balance of the host-parasite relationship.

    The interest in studying the involvement of vasoactive kinins in the parasite's interaction with vascular endothelium was awakened by biochemical findings obtained at the end of the last decade, giving the cysteine proteinase majority (cruzipain) function to "liberate" the nonapeptide lysyl-bradykinin, a potent mediator of inflammation, an internal segment of its precursor protein, the Kininogens.

    In subsequent studies, we demonstrated that the contact between the parasite and the target cell favors the action of cruzipain processor, resulting in the release of kinins in the areas of juxtaposition of the plasma membranes. This process seems to be relevant to the persistence of parasítlsmo in inflamed tissue, considering that the Kininogen High Molecular Weight (HK) may be retained on the surface of mammalian cells, through interactions with various glycosaminoglycans ¬ glycans.

    Consistent with this proposal, the analysis of the mechanisms of cell invasion (primary culture of human endothelial cells (HUVECs) and cardlorníócítos rat) revealed that cells become more susceptible to infection by bipomastigotas, 2 + as a consequence of strong transient Ca that trigger intracellular parasites through receptors constituent (82) and / or armatures (81) kinin (KRS).

    In addition to characterize agonists and receptors involved in cell invasion, these studies also demonstrated that the infectivity of the parasite is critically modulated by the activity of certain metallopeptidases, (eg. angiotensia converting enzyme (ACE) and carboxypeptidase M / N), both involved catab6lica degradation of kinins.

    More recently, an analysis of the time course of the edematous response trypomastigotes induce in mice revealed that the receivers 82 and 81 are sequenoíalmente activated kinin the first 24 hours of infection. The analysis of this process also suggests that the activation of kinin reoeptores by parasites (mediated by cruzipain) is preceded by the diffusion of the substrate plasma source, the Kininogens, the sites of infection. The analysis of the initial stage of this process depends on activation indicates that initial tolyl-type receptors (TL2), presumably due to stimulation of proinflamat6rio anchors glicosítfosfatídilínosítol (tGPI-mucin) expressed by trypomastigotes.

    In conclusion, our studies suggest that TLR2-mediated pathway KRS is an axis of convergence between microvascular responses and mechanisms of activation of innate immunity. Ongoing studies will clarify whether these processes influence the profile of the adaptive immune response and the pathogenesis of Chagas disease, as well as other infectious and parasitic diseases.

Staff

Julio Scharfstein - Head of laboratory

Master Students

Larissa Nogueira de Almeida

Aline Miranda Scovino

Programa: 
Imunobiology
Chefe do laboratório: