Serum Proteomics Provides Novel Biomarkers of Inflammation, Tissue Injury, and Therapeutic Response in Experimental Chagas Disease

Chagas disease remains a major public health challenge and still lacks reliable serum biomarkers capable of accurately reflecting disease progression and therapeutic response. Here, we performed a quantitative label-free serum proteomic analysis in a murine model infected with two <i>Trypanosoma cruzi</i> strains exhibiting contrasting sensitivity to benznidazole (Be-78, sensitive; VL-10, resistant), evaluated during both acute and chronic phases, in the presence or absence of treatment. Distinct proteomic signatures were observed across strains, infection stages, and experimental groups, involving pathways related to complement activation, inflammatory responses, immunoglobulins, energy metabolism, and tissue remodeling. Markers of cellular injury, including LDH-A, C1q, and C6, remained predominantly elevated in mice infected with the benznidazole-resistant strain, whereas animals infected with Be-78 showed substantial proteomic normalization following treatment. In addition, structural proteins such as dystrophin, nebulin, alpha-adducin, and myosin XVIIIb clearly distinguished strain-dependent profiles of disease aggressiveness and tissue damage. Integrated analyses revealed that benznidazole efficacy is strongly influenced by the biological characteristics of the infecting strain and is directly mirrored in the serum proteome. Collectively, these findings identify promising serum biomarkers of tissue injury and therapeutic response and underscore the importance of parasite genetic variability in disease monitoring and in the development of improved diagnostic and therapeutic strategies.