Glycocalyx-Driven Immunomodulation in Trypanosoma cruzi: Structures, Host Responses, Diagnostic and Therapeutic Targeting.

Chagas disease, caused by Trypanosoma cruzi, remains an important neglected infection due to underdiagnosis, global spread resulting from increased migration of people infected with T. cruzi and concomitant organ transplantation and blood transfusion, and limited availability of chemotherapy. The parasite's surface is covered by a dense glycocalyx enriched in GPI-anchored mucins, trans-sialidases, and glycoinositolphospholipids (GIPLs), which collectively shape host-parasite interactions. Here we synthesize structural and biosynthetic features of key glycoconjugates and discuss how they modulate innate and adaptive immunity through pattern-recognition receptors (e.g., TLR2/6 and TLR4), inhibitory lectins (e.g., Siglec-E), extracellular vesicle signalling, and complement evasion mediated by TS-like regulators (T-DAF, TcCRP) and factor H recruitment. We highlight how strain- and stage-specific glycan variation, including α-Galp- and β-Galf-containing epitopes, influences immune recognition, pathogenesis, and persistence. Finally, we evaluate translational opportunities: parasite-selective targeting of sugar-nucleotide metabolism and glycosyltransferases, and development of defined glycoepitopes (glycotopes) as improved biomarkers for diagnosis and post-treatment monitoring. Together, these insights position the T. cruzi glycocalyx as a central driver of immunomodulation and a promising source of therapeutic, vaccine and diagnostic targets.