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Potential Utility of Protein Targets of Cysteine-S-Nitrosylation in Identifying Clinical Disease Status in Human
Maria Paola Zago1, John E Wiktorowicz2,3, Heidi Spratt4
1Instituto de Patología Experimental, CONICET-UNSa, Salta, Argentina.
Insights
Chagas disease (ChD) involves protein S-nitrosylation (SNO) changes. This study identified SNO biomarkers in peripheral blood mononuclear cells (PBMC) to predict ChD severity in patients infected with Trypanosoma cruzi (Tc).
Area of Science:
- Biochemistry and Molecular Biology
- Immunology
- Cardiovascular Research
Background:
- Trypanosoma cruzi (Tc) infection causes Chagas disease (ChD), leading to dilated cardiomyopathy and heart failure.
- Oxidative and nitrosative stress during infection can alter host protein cysteine S-nitrosylation (SNO), impacting cellular function and disease progression.
Purpose of the Study:
- To identify host proteins with altered SNO levels in Chagas disease patients.
- To establish SNO modification profiles as potential biomarkers for Chagas disease severity.
Main Methods:
- Peripheral blood mononuclear cells (PBMC) from healthy controls and Chagas disease patients (asymptomatic and symptomatic) were analyzed.
- Proteins were labeled with a thiol-reactive dye after ascorbate treatment to assess SNO levels.
- Two-dimensional electrophoresis, mass spectrometry (MALDI-TOF/TOF MS, OrbiTrap LC-MS/MS), and multivariate adaptive regression splines (MARS) modeling were employed for protein identification and biomarker discovery.
Main Results:
- Differential SNO levels and protein abundance were observed between healthy controls and Chagas disease patients.
- MARS modeling identified specific SNO biomarkers (e.g., KRT1, TPM3, PNP, ALB, ACTB) with over 90% accuracy in classifying Chagas disease severity.
- Pathway analysis indicated that proteins involved in cell death and immune cell migration signaling networks were significantly affected in Chagas disease.
Conclusions:
- S-nitrosylation (SNO) of specific proteins serves as a potential hallmark for Chagas disease.
- The identified SNO biomarkers can accurately differentiate between asymptomatic and symptomatic Chagas disease patients.
- These findings suggest SNO modification profiles can aid in assessing Chagas disease severity in infected individuals.
Abstract:
Trypanosoma cruzi (Tc) infection causes Chagas disease (ChD) presented by dilated cardiomyopathy and heart failure. During infection, oxidative and nitrosative stresses are elicited by the immune cells for control the pathogen; however, excess nitric oxide and superoxide production can result in cysteine S-nitrosylation (SNO) of host proteins that affects cellular homeostasis and may contribute to disease development. To identify the proteins with changes in SNO modification levels as a hallmark of ChD, we obtained peripheral blood mononuclear cells (PBMC) from seronegative, normal healthy (NH, n = 30) subjects, and from seropositive clinically asymptomatic (ChD CA, n = 25) or clinically symptomatic (ChD CS, n = 28) ChD patients. All samples were treated (Asc+) or not-treated (Asc-) with ascorbate (reduces nitrosylated thiols), labeled with the thiol-labeling BODIPY FL-maleimide dye, resolved by two-dimensional electrophoresis (total 166 gels), and the protein spots that yielded significant differences in abundance or SNO level at p-value of ≤ 0.05 were identified by MALDI-TOF/TOF MS or OrbiTrap LC-MS/MS. Targeted analysis of a new cohort of PBMC samples (n = 10-14/group) was conducted to verify the differential abundance/SNO levels of two of the proteins in ChD (vs. NH) subjects. The multivariate adaptive regression splines (MARS) modeling, comparing differences in relative SNO level (Asc-/Asc+ ratio) of the protein spots between any two groups yielded SNO biomarkers that exhibited ≥90% prediction success in classifying ChD CA (582-KRT1 and 884-TPM3) and ChD CS (426-PNP, 582-KRT1, 486-ALB, 662-ACTB) patients from NH controls. Ingenuity Pathway Analysis (IPA) of the SNO proteome dataset normalized to changes in protein abundance suggested the proteins belonging to the signaling networks of cell death and the recruitment and migration of immune cells were most affected in ChD CA and ChD CS (vs. NH) subjects. We propose that SNO modification of the select panel of proteins identified in this study have the potential to identify ChD severity in seropositive individuals exposed to Tc infection.
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