title: Changes in Proteome Profile of Peripheral Blood Mononuclear Cells in Chronic Chagas Disease.
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.
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, Texas, United States of America.|Department of Pathology, UTMB, Galveston, Texas, United States of America.|Faculty of the Institute for Human Infections and Immunity, and Sealy Center for Vaccine Development, UTMB, Galveston, Texas, United States of America.
authors.forename: Nisha Jain
authors.initials: NJ
authors.lastname: Garg
authors.affiliation: Department of Biochemistry and Molecular Biology, and the Sealy Center for Molecular Medicine, UTMB, Galveston, Texas, United States of America.
authors.forename: Kizhake V
authors.initials: KV
authors.lastname: Soman
authors.affiliation: Instituto de Patología Experimental, CONICET-UNSa, Salta, Argentina.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Zago
authors.affiliation: Department of Pathology, UTMB, Galveston, Texas, United States of America.
authors.forename: Sue-Jie
authors.initials: SJ
authors.lastname: Koo
authors.affiliation: Department of Preventive Medicine and Community Health, UTMB, Galveston, Texas, United States of America.|Institute for Translational Sciences, UTMB, Galveston, Texas, United States of America.
authors.forename: Heidi
authors.initials: H
authors.lastname: Spratt
authors.affiliation: Department of Biochemistry and Molecular Biology, and the Sealy Center for Molecular Medicine, UTMB, Galveston, Texas, United States of America.
authors.forename: Susan
authors.initials: S
authors.lastname: Stafford
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, Texas, United States of America.
authors.forename: Zinzi N
authors.initials: ZN
authors.lastname: Blell
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, Texas, United States of America.
authors.forename: Shivali
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Servicio de Cardiología, Hospital San Bernardo, Salta, Argentina.
authors.forename: Julio
authors.initials: J
authors.lastname: Nuñez Burgos
authors.affiliation: Servicio de Cardiología, Hospital San Bernardo, Salta, Argentina.
authors.forename: Natalia
authors.initials: N
authors.lastname: Barrientos
authors.affiliation: Institute for Translational Sciences, UTMB, Galveston, Texas, United States of America.|Department of Internal Medicine, UTMB, Galveston, Texas, United States of America.
authors.forename: Allan R
authors.initials: AR
authors.lastname: Brasier
authors.affiliation: Department of Biochemistry and Molecular Biology, and the Sealy Center for Molecular Medicine, UTMB, Galveston, Texas, United States of America.|Institute for Translational Sciences, UTMB, Galveston, Texas, United States of America.
authors.forename: John E
authors.initials: JE
authors.lastname: Wiktorowicz
mesh_terms: D002598:Chagas Cardiomyopathy / Q000378:metabolism* / Q000469:parasitology; D002908:Chronic Disease; D015180:Electrophoresis, Gel, Two-Dimensional; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000737:chemistry* / Q000378:metabolism / Q000469:parasitology; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D020543:Proteome / Q000737:chemistry* / Q000378:metabolism; D040901:Proteomics; D014349:Trypanosoma cruzi / Q000502:physiology
chemical_list: D011506:Proteins; D020543:Proteome