Abstract
Trypanosoma cruzi (Tc) infection causes chagasic cardiomyopathy; however, why 30–40% of the patients develop clinical disease is not known. To discover the pathomechanisms in disease progression, we obtained the proteome signature of peripheral blood mononuclear cells (PBMCs) of normal healthy controls (N/H, n = 30) and subjects that were seropositive for Tc-specific antibodies, but were clinically asymptomatic (C/A, n = 25) or clinically symptomatic (C/S, n = 28) with cardiac involvement and left ventricular dysfunction. Protein samples were labeled with BODIPY FL-maleimide (dynamic range: > 4 orders of magnitude, detection limit: 5 f-mol) and resolved by two-dimensional gel electrophoresis (2D-GE). After normalizing the gel images, protein spots that exhibited differential abundance in any of the two groups were analyzed by mass spectrometry, and searched against UniProt human database for protein identification. We found 213 and 199 protein spots (fold change: |≥ 1.5|, p< 0.05) were differentially abundant in C/A and C/S individuals, respectively, with respect to N/H controls. Ingenuity Pathway Analysis (IPA) of PBMCs proteome dataset identified an increase in disorganization of cytoskeletal assembly and recruitment/activation and migration of immune cells in all chagasic subjects, though the invasion capacity of cells was decreased in C/S individuals. IPA predicted with high probability a decline in cell survival and free radical scavenging capacity in C/S (but not C/A) subjects. The MYC/SP1 transcription factors that regulate hypoxia and oxidative/inflammatory stress were predicted to be key targets in the context of control of Chagas disease severity. Further, MARS-modeling identified a panel of proteins that had >93% prediction success in classifying infected individuals with no disease and those with cardiac involvement and LV dysfunction. In conclusion, we have identified molecular pathways and a panel of proteins that could aid in detecting seropositive individuals at risk of developing cardiomyopathy.
Highlights
Chagasic cardiomyopathy is caused by Trypanosoma cruzi
Chagasic cardiomyopathy is elicited by Trypanosoma cruzi infection
We have employed a highly sensitive approach of protein labeling, developed a detailed proteomic map from all samples, performed comparative analysis of gel images, and identified a panel of proteins that were changed in abundance in clinically asymptomatic (C/A) and clinically symptomatic (C/S) chagasic individuals with respect to healthy controls
Summary
According to the World Health Organization report released in 2010, ~16 million individuals are infected with T. cruzi, and >25 million people are at risk of infection in Latin America and Mexico [1]. The Centers for Disease Control reports that >300,000 individuals infected with T. cruzi are currently living in the United States [8]. No vaccine is available for the prevention of infection [10] and the available drugs, benznidazole and nifurtimox, have exhibited no significant effects in arresting the progression of chronic cardiomyopathy [11]. Tools to assess the effectiveness of new drugs against T. cruzi infection and Chagas disease are currently not available
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