# Effective immunity against Trypanosoma cruzi infection induced by immunization

> **NIH NIH R21** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $208,750

## Abstract

Chagas disease caused by Trypanosoma cruzi, is a major public health issue, particularly in the Americas.
There are approximately 10 million infected people and more than ten thousand annual deaths from this
infection. The available therapeutic agents have limited efficacy beyond the acute phase of the T. cruzi
infection, as well as significant side effects, which limit their usefulness. A safe, effective and reliable vaccine
would clearly reduce the threat of T. cruzi infections and prevent Chagas disease (chronic infection). However,
no suitable vaccine is currently available for protecting against T. cruzi infection, in spite of considerable
research in this area. A major hurdle in T. cruzi vaccine development has been the lack of understanding of
the requirements for the induction of protective immunity. Recently, we established an effective inducible
system for T. cruzi employing the degradation domain based on the Escherichia coli dihydrofolate reductase
(ecDHFR). The DHFR degradation domain (DDD) can be stabilized by trimethoprim-lactate and can be used to
express detrimental or toxic proteins which can induce a self-destruction process in these parasites. T. cruzi
lines with Alpha-toxin, Cecropin A and GFP under the control of DDD with a hemagglutinin tag (HA) were
developed. T. cruzi bearing an inducible detrimental/toxin gene allow this parasite to undergo a self-
destructive process, resulting in the death of intracellular parasites and the elimination of tissue parasitism.
We found that our DDDHA strains were attenuated in mouse experiments producing no pathological changes.
Most importantly, inoculation with these DDDHA strains in mice provides significant protection against lethal
wild type infection with vaccinated mice producing a high serum level of IFN-γ during both immunization and
re-infection. CD4+, CD8+ T cells, monocytes and neutrophils undergo robust activation during challenge
infection of vaccinated hosts. These transgenic T. cruzi strains, therefore, provide an important new
opportunity to understand a protective immune response against T. cruzi infection. Using the GFP-DDDHA
strain, we will investigate which adaptive arm of immune system providing the protection. Genetic models (CD8,
CD4, B cell knockout mice) and antibody depletions as well as adoptive transfers will be used to investigate
which immune cells are important in providing protection in vaccinated mice during re-infection. We will
investigate how memory immune cells orchestrate extensive modifications of host innate immune responses in
vaccinated host upon re-infection with T. cruzi. Innate immune cells from spleens and livers will be investigated
for their activation kinetics by flow cytometry. Both blood phagocytes and NK cells recruitments to the infected
spleens will be analyzed by confocal microscopy. CD4+ and CD8+ T cells will be depleted by antibodies and
then innate immune cell activation in response to re-infection will be investigated. Global gen...

## Key facts

- **NIH application ID:** 9821195
- **Project number:** 5R21AI142110-03
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Huan Huang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $208,750
- **Award type:** 5
- **Project period:** 2018-11-09 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9821195

## Citation

> US National Institutes of Health, RePORTER application 9821195, Effective immunity against Trypanosoma cruzi infection induced by immunization (5R21AI142110-03). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9821195. Licensed CC0.

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