Towards a map of the immune system manipulation network by Trypanosoma cruzi

<i>Trypanosoma cruzi</i> (<i>T. cruzi</i>), 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 <i>T. cruzi</i> immune manipulation network, integrating research on numerous parasite and host components involved. Five main cores of manipulation are proposed, including how <i>T. cruzi</i> 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 non-specific 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 <i>T. cruzi</i>.