Immune competence as a factor of treatment efficacy in Trypanosoma cruzi infection. The main drawbacks for a wider application of treatment of long-term T. cruzi infections include the difficulty of assessing treatment efficacy and the potential adverse effects of these therapeutics. Likewise, treatment regimens in terms of doses and duration in chronically T. cruzi-infected subjects are still debated. Conversely, drug therapy in T. cruzi-infected children is considered to be more effective than in adult patients.
The aim of this application is to determine the association between the immunological status prior to treatment and the rate of cure following either complete treatment with benznidazole or interrupted treatment due to adverse effects. The prediction is that subjects with polyfunctional T cell responses to T. cruzi pre-therapy have higher chances to achieve cure compared with those displaying a narrower range of T cell functions. Furthermore, shortened treatment regimens are predicted to be effective in cases where immune responses are strong prior to treatment. Based on extensive preliminary data produced in the applicants' laboratories, these hypotheses will be tested by pursuing two specific aims: 1) Determine the association between the quality of T cell responses prior to drug therapy and success of treatment with benznidazole, and further validate non-conventional parameters as markers of treatment efficacy in T. cruzi-infected children; and 2) Compare treatment outcomes between complete and incomplete treatment schedules in T. cruzi-infected adults and children treated with benznidazole.
Under Aim1, pretreatment immune responses specific for T. cruzi will be determined in infected children and stratified based on the capacity of T cells to exert monofunctional or polyfunctional T cell responses as determined by ELISPOT and flow cytometric assays. Then, treatment efficacy after benznidazole administration will be assessed by the achievement of complete seronegative conversion by conventional serological tests (i.e. the accepted standard of treatment success and cure in Chagas disease) and determine if treatment success is associated with a highly functional T cell profile prior to treatment compared with patients in which treatment fails. In addition, we will follow these treated subjects (irrespective of prior quality in T cell responses) with our previously reported surrogate parameters of treatment efficacy (i.e. T cell cytokine ELISPOT technique and multiplex serological assay) to determine whether patients who achieve cure show changes in immune responses post-treatment considered to reflect parasite clearance; as well as to identify the earliest changes that can be associated with cure. An observation of such association would further validate these metrics for monitoring treatment outcomes. Under the second aim, we will assess whether an incomplete course of treatment preferentially provide cure in those individuals who had more highly functional parasite specific T cell responses prior to therapy. Changes in T and B cell responses by non-conventional measures of treatment efficacy will be also compared between patients receiving full doses of benznidazole vs. those who received incomplete treatment regimens to evaluate the usefulness of these parameters to measure efficacy in cases of interrupted treatment. The proposed study is innovative in that it represents a departure from the current therapeutic approaches, namely the notion that improving host immune responses to T. cruzi could enhance treatment efficacy. These contributions will be significant because it will expand our understanding of how drug treatment works and provide guidance on how to most effectively treat and monitor therapy outcomes in chronically infected individuals.

Public Health Relevance

Immune competence as a factor of treatment efficacy in Trypanosoma cruzi infection. Chagas disease, caused by the intracellular protozoan parasite T. cruzi, affects approximately 10 million people being the most common cause of infectious myocarditis in the world. The present proposal is expected to provide evidence that supports reconsideration of new treatment regimens with currently available drugs and offer tools to anticipate treatment outcomes. The ultimate goal of this project is to provide data supporting a broader application of specific treatment for T. cruzi infection which would significant prevent transmission through potential blood donors and women of reproductive age, and decrease the probability of developing clinical disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IDM-R (54)R)
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Wali, Tonu M
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Eva Peron Acute Interzonal Gen Hospital
Independent Hospitals
Buenos Aires
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Castro Eiro, Melisa D; Alvarez, María G; Cooley, Gretchen et al. (2017) The Significance of Discordant Serology in Chagas Disease: Enhanced T-Cell Immunity to Trypanosoma cruzi in Serodiscordant Subjects. Front Immunol 8:1141
Alvarez, María G; Bertocchi, Graciela L; Cooley, Gretchen et al. (2016) Treatment Success in Trypanosoma cruzi Infection Is Predicted by Early Changes in Serially Monitored Parasite-Specific T and B Cell Responses. PLoS Negl Trop Dis 10:e0004657