Mem Inst Oswaldo Cruz, Rio de Janeiro, VOLUME 121 | 2026
Research Articles

Therapeutic potential of hookworm proteins in promoting regulatory immune responses to modulate Trypanosoma cruzi induced liver inflammation and oxidative stress

Maria Jose Villar1,2, Cristina Poveda1,2,3, Bin Zhan1,2,3, Maya Gonsoulin1, Kathryn M Jones1,2,3,+

1Baylor College of Medicine, National School of Tropical Medicine, Department of Pediatrics, Houston, TX, United States
2Texas Children’s Hospital Center for Vaccine Development, Houston, TX, United States
3Baylor College of Medicine, Department of Molecular Virology and Microbiology, Houston, TX, United States

DOI: 10.1590/0074-02760250123
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ABSTRACT

BACKGROUND Chronic Trypanosoma cruzi infection causes significant liver pathology, and current antiparasitic treatments often worsen hepatic damage. Hookworm-derived proteins have shown immunomodulatory effects in inflammatory diseases, including T. cruzi-induced myocarditis.
OBJECTIVE This study evaluates recombinant hookworm proteins AIP-1 and AIP-2 for treating liver inflammation in a murine model of chronic Chagas disease (CD).
METHODS Female BALB/c mice infected with T. cruzi were treated with AIP-1 or AIP-2 (1 mg/kg) for seven days. Controls were untreated or received aspirin (25 mg/kg) for 14 days. Liver tissues were analyzed for parasite burden (quantitative polymerase chain reaction - qPCR), histopathology (H&E, Picrosirius Red), and cytokines (multiplex assay). Splenocytes were assessed by flow cytometry, and serum was tested for liver enzyme levels.
FINDINGS AIP-1 and AIP-2 increased hepatic interferon gamma (IFN-γ) and interleukin 10 (IL-10), decreased Nfκ-B and Stat-1, and elevated Arg1 and Nos2 expression. AIP-1 uniquely upregulated Mmp9 and Btg2. Increased splenic CD11b⁺CD11c⁺ and CD11b⁺Ly6GloLy6C⁺ cells were observed. Despite increased immune cell infiltration, parasite load and fibrosis remained unchanged, and liver enzyme levels were stable.
MAIN CONCLUSION AIP-1 and AIP-2 reduce hepatic inflammation and promote a balanced TH1/TH2 response, likely mediated by regulatory dendritic and myeloid-derived suppressor cells, supporting their potential as immunotherapeutic for T. cruzi-induced liver pathology.

key words: immunomodulation hookworm Trypanosoma cruzi liver
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Financial support: This work was funded by a Pilot Award from the Baylor College of Medicine Cardiovascular Research Institute and NIH R01AI168038 grant (KMJ). This project was supported by the Human Tissue Acquisition and Pathology core with funding from the Comprehensive Cancer Center grant (P30 CA125123), by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the CPRIT Core Facility Support Award (CPRIT-RP180672), the NIH (CA125123 and RR024574) and the assistance of Joel M Sederstrom, and the Center for Comparative Medicine Research Services Laboratory at Baylor College of Medicine.
+ Corresponding author: kathrynj@bcm.edu | ORCID https://orcid.org/0000-0001-8745-1987
Received 15 May 2025
Accepted 13 October 2025

HOW TO CITE
Villar MJ, Poveda C, Zhan B, Gonsoulin M, Jones KM. Therapeutic potential of hookworm proteins in promoting regulatory immune responses to modulate Trypanosoma cruzi induced liver inflammation and oxidative stress. Mem Inst Oswaldo Cruz. 2025; 120: e250123.

HANDLING EDITOR
Adeilton Alves Brandão | ORCID https://orcid.org/0000-0001-5877-607X

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