Date Published: January 8, 2016
Publisher: Public Library of Science
Author(s): Paola Rosa Luz, Márcia I. Miyazaki, Nelson Chiminacio Neto, Marcela C. Padeski, Ana Cláudia M. Barros, Angelica B. W. Boldt, Iara J. Messias-Reason, Herbert B. Tanowitz. http://doi.org/10.1371/journal.pntd.0004257
Abstract: Chagas disease (CD) is caused by Trypanosoma cruzi, whose sugar moieties are recognized by mannan binding lectin (MBL), a soluble pattern-recognition molecule that activates the lectin pathway of complement. MBL levels and protein activity are affected by polymorphisms in the MBL2 gene. We sequenced the MBL2 promoter and exon 1 in 196 chronic CD patients and 202 controls. The MBL2*C allele, which causes MBL deficiency, was associated with protection against CD (P = 0.007, OR = 0.32). Compared with controls, genotypes with this allele were completely absent in patients with the cardiac form of the disease (P = 0.003). Furthermore, cardiac patients with genotypes causing MBL deficiency presented less heart damage (P = 0.003, OR = 0.23), compared with cardiac patients having the XA haplotype causing low MBL levels, but fully capable of activating complement (P = 0.005, OR = 7.07). Among the patients, those with alleles causing MBL deficiency presented lower levels of cytokines and chemokines possibly implicated in symptom development (IL9, p = 0.013; PDGFB, p = 0.036 and RANTES, p = 0.031). These findings suggest a protective effect of genetically determined MBL deficiency against the development and progression of chronic CD cardiomyopathy.
Partial Text: Chagas disease (CD) is considered the most important neglected tropical disease worldwide, affecting approximately ten million people in Latin America [1,2,3]. The disease is caused by Trypanosoma cruzi, a flagellated protozoan parasite transmitted to humans mainly by blood-sucking triatomine bugs or by blood transfusion . Approximately 50% of the individuals infected by T. cruzi remain in the indeterminate or asymptomatic clinical form of CD for their whole lives. Although asymptomatic patients present in general a good prognosis, each year about 2–5% of them progress to symptomatic forms of the disease, developing cardiac, digestive and/or neurological clinical manifestations . About 30–40% of the patients develop chronic chagasic cardiomyopathy (CCC), characterized by progressive and multifocal inflammation, fibrosis and subsequent cardiac insufficiency (CI). In advanced stages, there is a marked increase in the heart in an attempt to compensate loss of function, with thromboembolic events, important arrhythmias and heart failure. Sudden death is a constant risk at any clinical stage, occurring in one to two thirds of patients who die due to CD. Although most of these patients presented prior CI, about one third to one fifth of sudden deaths occur in asymptomatic CD patients [6,7].
The process of opsonization and phagocytosis of parasites and its destruction or survival within phagocytic cells is crucial for the establishment of most infectious diseases. It is known that MBL plays a central role in the initial interaction between pathogens and phagocytes, mediating opsonization and phagocytosis, either directly or by activating the antibody-independent lectin pathway of the complement system . Importantly, complement is one of the first lines of immune defense to interact with infective forms of T. cruzi, long before the development of antibodies. In fact, MBL is able to bind to infective forms of T. cruzi , acting directly in the control of parasitemia . The major surface glycoprotein of T. cruzi amastigotes, named SA85-1, is a ligand for human MBL and adhesion of amastigotes to macrophages is facilitated by mannose receptor [38,39]. In addition, mannose receptors on cardiomyocytes where shown to be involved in the binding and internalization of T. cruzi [40,41]. Recently, a role for MBL in the regulation of host resistance on myocardial inflammation has been described in T. cruzi experimental infection .