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REVIEW article

Front. Cell. Infect. Microbiol.

Sec. Clinical and Diagnostic Microbiology and Immunology

This article is part of the Research TopicThe regulatory immune system as a target to improve adjuvants and novel vaccines – Volume IIView all articles

Towards a Map of the Immune System Manipulation Network by Trypanosoma cruzi

Provisionally accepted
Juan Cruz GambaJuan Cruz Gamba1,2Ana Rosa PérezAna Rosa Pérez3,4Carolina Verónica PonciniCarolina Verónica Poncini5Cristina PovedaCristina Poveda6Iván Sergio MarciparIván Sergio Marcipar1Gabriel CabreraGabriel Cabrera1*
  • 1Laboratorio de Tecnología Inmunológica, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina
  • 2Instituto de Investigación en Señales, Sistemas e Inteligencia Computacional (CONICET‐UNL), Facultad de Ingeniería y Ciencias Hídricas, Santa Fe, Argentina., Santa Fe, Argentina
  • 3Instituto de Inmunología Clínica y Experimental de Rosario (IDICER-CONICET), and Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Santa Fe, Argentina, Santa Fe, Argentina
  • 4Centro de Investigación y Producción de Reactivos Biológicos (CIPReB), Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Santa Fe, Argentina, Santa Fe, Argentina
  • 5Laboratorio de Inmunología Celular e Inmunopatología de Infecciones, IMPaM UBA-CONICET, Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
  • 6Department of Pediatrics, National School of Tropical Medicine, Baylor College of Medicine, Houston, TX, United States., Texas, United States

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Trypanosoma cruzi (T. cruzi), the protozoan parasite that causes Chagas disease, remains a major public health challenge, with more than six million people infected worldwide. Despite more than a century of research and extensive evaluation of different strategies, no vaccine has progressed to late-phase clinical trials. This failure highlights the need to better understand host– parasite interactions, with special emphasis on the immunoregulatory pathways exploited by the parasite. In this review, we propose an initial comprehensive map of the T. cruzi immune manipulation network, integrating research on numerous parasite and host components involved. Five main cores of manipulation are proposed, including how T. cruzi skews macrophage polarization toward regulatory profiles, the impairment of dendritic cell maturation and Th1 induction, resistance to and subversion of complement pathways, expansion of myeloid-derived suppressor cells (MDSCs), and suppression and delay of adaptive immunity by driving nonspecific B-cell activation, thymic atrophy, and T-cell dysfunction. Mapping these mechanisms may reveal how parasite molecules such as trans-sialidases, cruzipain, proline racemase, mucin-associated surface proteins, complement regulatory proteins, and others interact in a complex network of manipulated immune pathways. A deeper understanding of these interactions could have significant implications for immunotherapeutic strategies. Future vaccine designs may benefit from rationally selected combinations that maximize targeted effector responses while minimizing the manipulation of the immune network by T. cruzi.

Keywords: Chagas Disease, evasion, Immune System, Manipulation, Subversion, Trypanosoma cruzi

Received: 23 Sep 2025; Accepted: 03 Dec 2025.

Copyright: © 2025 Gamba, Pérez, Poncini, Poveda, Marcipar and Cabrera. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Gabriel Cabrera

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Supplementary Material