Exploring global and specific pathogenic mechanisms in Chronic Chagas Cardiomyopathy through multi-omics integration

Chagas disease is a neglected disease from South America caused by a parasite, Trypanosoma cruzi . While most of infected people remains asymptomatic, around 30% develop Chronic Chagas Cardiomyopathy (CCC), a very lethal cardiomyopathy characterized by an exacerbate inflammatory response. The last few years, our team has set up multiple omics analysis. Briefly, we have pointed the over-expression of many genes involved in the Th1 lymphocyte response, as well as some epigenetic features potentially involved in their regulation, including miRNA, lncRNA and methylation site. Moreover, some mitochondria mutation seems to predispose to the development of CCC. In order to understand and characterize the impact of genetic and epigenetic elements on the pathogenic process associated to CCC, we have performed here a multi-omics integration, combining transcriptomic, methylomic, miRNomic and mitochondria sequencing. We have identified two distinct pathogenic pathways that vary among patients with chronic Chagas cardiomyopathy (CCC). One pathway is primarily influenced by IRF4, a transcription factor known for its involvement in the development of both B and T cells, while the other is driven by TLR signaling. Notably, genes related to B cells play a role in both of these processes. Additionally, we have detected certain similarities in the B cell receptors of all CCC patients, which may potentially contribute to autoimmunity. While further analysis is necessary to validate these findings, they collectively enhance our understanding of the pathogenic mechanisms associated with CCC. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Institut National de la Sante et de la Recherche Medicale (INSERM); the Aix-Marseille University (grant number: AMIDEX Internation-al_2018 MITOMUTCHAGAS); the French Agency for Research (Agence Nationale de la Recherche-ANR (grant numbers: Br-Fr-Chagas, landscardio). This work was founded by the Inserm Cross-Cutting Project GOLD. This project has received funding from the Excellence Initiative of Aix-Marseille University - AMidex a French Investissements d Avenir programme- Institute MarMaRa AMX-19-IET-007. This work was supported by FAPESP (Sao Paulo State Research Funding Agency Brazil) (grant 2022/00758-0). Brazilian National Research Council (CNPq) provided a Productivity Award for ECN and JK. This work is supported by the CAPES-COFECUB program (Me987/23). CC is supported by the Inserm PRI/IRP 2022 program (Me987/23). The funders did not play any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The protocol was approved by the institutional review boards of the University of Sao Paulo School of Medicine and INSERM (French National Institute of Health and Medical Research). Written informed consent was obtained from all patients. All experimental methods comply with the Helsinki Declaration. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors