Vaccine-linked chemotherapy improves cardiac structure and function in a mouse model of chronic Chagas disease

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dc.citation.articleNumber1106315en_US
dc.citation.journalTitleFrontiers in Cellular and Infection Microbiologyen_US
dc.citation.volumeNumber13en_US
dc.contributor.authorJones, Kathryn M.en_US
dc.contributor.authorMangin, Elise N.en_US
dc.contributor.authorReynolds, Corey L.en_US
dc.contributor.authorVillanueva, Liliana E.en_US
dc.contributor.authorCruz, Julio Vladimiren_US
dc.contributor.authorVersteeg, Leroyen_US
dc.contributor.authorKeegan, Brianen_US
dc.contributor.authorKendricks, Aprilen_US
dc.contributor.authorPollet, Jeroenen_US
dc.contributor.authorGusovsky, Fabianen_US
dc.contributor.authorBottazzi, Maria Elenaen_US
dc.contributor.authorHotez, Peter J.en_US
dc.contributor.orgJames A. Baker III Institute for Public Policyen_US
dc.date.accessioned2023-03-10T19:04:14Zen_US
dc.date.available2023-03-10T19:04:14Zen_US
dc.date.issued2023en_US
dc.description.abstractIntroduction: Chagas disease, caused by chronic infection with the protozoan parasite Trypanosoma cruzi, affects 6-7 million people worldwide. The major clinical manifestation of Chagas disease is chronic Chagasic cardiomyopathy (CCC), which encompasses a spectrum of symptoms including arrhythmias, hypertrophy, dilated cardiomyopathy, heart failure, and sudden death. Current treatment is limited to two antiparasitic drugs, benznidazole (BNZ) and nifurtimox, but both have limited efficacy to halt the progression of CCC. We developed a vaccine-linked chemotherapy strategy using our vaccine consisting of recombinant Tc24-C4 protein and a TLR-4 agonist adjuvant in a stable squalene emulsion, in combination with low dose benznidazole treatment. We previously demonstrated in acute infection models that this strategy parasite specific immune responses, and reduced parasite burdens and cardiac pathology. Here, we tested our vaccine-linked chemotherapy strategy in a mouse model of chronic T. cruzi infection to evaluate the effect on cardiac function.Methods: Female BALB/c mice infected with 500 blood form T. cruzi H1 strain trypomastigotes were treated beginning 70 days after infection with a low dose of BNZ and either low or high dose of vaccine, in both sequential and concurrent treatments streams. Control mice were untreated, or administered only one treatment. Cardiac health was monitored throughout the course of treatment by echocardiography and electrocardiograms. Approximately 8 months after infection, endpoint histopathology was performed to measure cardiac fibrosis and cellular infiltration.ResultsVaccine-linked chemotherapy improved cardiac function as evidenced by amelioration of altered left ventricular wall thickness, left ventricular diameter, as well as ejection fraction and fractional shortening by approximately 4 months of infection, corresponding to two months after treatment was initiated. At study endpoint, vaccine-linked chemotherapy reduced cardiac cellular infiltration, and induced significantly increased antigen specific IFN-γ and IL-10 release from splenocytes, as well as a trend toward increased IL-17A.Discussion: These data suggest that vaccine-linked chemotherapy ameliorates changes in cardiac structure and function induced by infection with T. cruzi. Importantly, similar to our acute model, the vaccine-linked chemotherapy strategy induced durable antigen specific immune responses, suggesting the potential for a long lasting protective effect. Future studies will evaluate additional treatments that can further improve cardiac function during chronic infection.en_US
dc.identifier.citationJones, Kathryn M., Mangin, Elise N., Reynolds, Corey L., et al.. "Vaccine-linked chemotherapy improves cardiac structure and function in a mouse model of chronic Chagas disease." <i>Frontiers in Cellular and Infection Microbiology,</i> 13, (2023) Frontiers: https://doi.org/10.3389/fcimb.2023.1106315.en_US
dc.identifier.digitalfcimb-13-1106315en_US
dc.identifier.doihttps://doi.org/10.3389/fcimb.2023.1106315en_US
dc.identifier.urihttps://hdl.handle.net/1911/114502en_US
dc.language.isoengen_US
dc.publisherFrontiersen_US
dc.rightsThis 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) and the copyright owner(s) 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.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titleVaccine-linked chemotherapy improves cardiac structure and function in a mouse model of chronic Chagas diseaseen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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