Chagas Disease Megaesophagus Patients Carrying Variant MRPS18B P260A Display Nitro-Oxidative Stress and Mitochondrial Dysfunction in Response to IFN-γ Stimulus

Karla Deysiree Alcântara Silva; João Paulo Silva Nunes; Pauline Andrieux; Pauline Brochet; Rafael Ribeiro Almeida; Andréia Cristina Kazue Kuramoto Takara; Natalia Bueno Pereira; Laurent Abel; Aurelie Cobat; Ricardo Costa Fernandes Zaniratto; Débora Levy; Sergio Paulo Bydlowski; Ivan Cecconello; Francisco Carlos Bernal da Costa Seguro; Jorge Kalil; Christophe Chevillard; Edecio Cunha-Neto

doi:10.3390/biomedicines10092215

Chagas Disease Megaesophagus Patients Carrying Variant MRPS18B P260A Display Nitro-Oxidative Stress and Mitochondrial Dysfunction in Response to IFN-γ Stimulus

Biomedicines. 2022 Sep 7;10(9):2215. doi: 10.3390/biomedicines10092215.

Authors

Karla Deysiree Alcântara Silva^{1

2

3}, João Paulo Silva Nunes^{1

2

3

4}, Pauline Andrieux⁴, Pauline Brochet⁴, Rafael Ribeiro Almeida^{1

3}, Andréia Cristina Kazue Kuramoto Takara^{1

3}, Natalia Bueno Pereira^{1

2}, Laurent Abel^{5

6

7}, Aurelie Cobat^{5

6

7}, Ricardo Costa Fernandes Zaniratto¹, Débora Levy¹, Sergio Paulo Bydlowski¹, Ivan Cecconello⁸, Francisco Carlos Bernal da Costa Seguro⁸, Jorge Kalil^{1

2

3}, Christophe Chevillard⁴, Edecio Cunha-Neto^{1

2

3}

Affiliations

¹ Laboratory of Immunology, Heart Institute (Incor) Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, Brazil.
² Division of Clinical Immunology and Allergy, Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-000, Brazil.
³ Institute for Investigation in Immunology/INCT, São Paulo 05403-900, Brazil.
⁴ Institut MarMaRa, INSERM, UMR_1090, Aix Marseille Université, TAGC Theories and Approaches of Genomic Complexity, 13288 Marseille, France.
⁵ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France.
⁶ Imagine Institute, University of Paris, 75015 Paris, France.
⁷ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.
⁸ Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, Brazil.

Abstract

Chagas disease (CD), caused by the protozoan parasite Trypanosoma cruzi, affects 8 million people, and around 1/3 develop chronic cardiac (CCC) or digestive disease (megaesophagus/megacolon), while the majority remain asymptomatic, in the indeterminate form of Chagas disease (ASY). Most CCC cases in families with multiple Chagas disease patients carry damaging mutations in mitochondrial genes. We searched for exonic mutations associated to chagasic megaesophagus (CME) in genes essential to mitochondrial processes. We performed whole exome sequencing of 13 CME and 45 ASY patients. We found the damaging variant MRPS18B 688C > G P230A, in five out of the 13 CME patients (one of them being homozygous; 38.4%), while the variant appeared in one out of 45 ASY patients (2.2%). We analyzed the interferon (IFN)-γ-induced nitro-oxidative stress and mitochondrial function of EBV-transformed lymphoblastoid cell lines. We found the CME carriers of the mutation displayed increased levels of nitrite and nitrated proteins; in addition, the homozygous (G/G) CME patient also showed increased mitochondrial superoxide and reduced levels of ATP production. The results suggest that pathogenic mitochondrial mutations may contribute to cytokine-induced nitro-oxidative stress and mitochondrial dysfunction. We hypothesize that, in mutation carriers, IFN-γ produced in the esophageal myenteric plexus might cause nitro-oxidative stress and mitochondrial dysfunction in neurons, contributing to megaesophagus.

Keywords: Chagas disease; MRPS18B; Trypanosoma cruzi; chagasic megaesophagus; interferon-gamma; mitochondria; mitochondrial dysfunction; mitochondrial mutation.

Grants and funding

This work received specific support from the funding body Fundação de Amparo à Pesquisa do Estado de S. Paulo (FAPESP 2019/22858-3). This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM); Aix-Marseille University (grant number: AMIDEX “International_2018” MITOMUTCHAGAS); the French Agency for Research (Agence Nationale de la Recherche—ANR) (grant numbers: “Br-Fr-Chagas”, “landscardio”); the Brazilian Council for Scientific and Technological Development (CNPq); the National Institutes of Health/USA (grant numbers: 2 P50 AI098461-02 and 2U19AI098461-06). This work was funded by the Inserm Cross-Cutting Project GOLD. This project has received funding from the Excellence Initiative of Aix-Marseille University—A*Midex a French “Investissements d’Avenir programme”—Institute MarMaRa AMX-19-IET-007. J.P.S.N. was a recipient of a MarMaRa fellowship. The funders did not play any role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.