# Control of VSG pre-mRNA processing in infectious Trypanosoma brucei

> **NIH NIH R01** · YALE UNIVERSITY · 2023 · $418,750

## Abstract

Project Summary
 This application focuses on the protozoan parasite Trypanosoma brucei, which is transmitted among
mammalian hosts by tsetse-flies and, due to effective immune evasion, causes chronic and lethal infections,
specifically African sleeping-sickness in humans and nagana in cattle. Whereas human African trypanosomiasis
has been declining recently, livestock infections remain prevalent and have a profound effect on economic
development in sub-Saharan Africa. There are no vaccines and therapeutic drugs have serious side effects and
decreasing efficacy. Thus, there is a pressing need for research to better understand the biology of these
pathogens and the mechanisms they use to survive within their hosts. T. brucei undergoes a complex life cycle
between the mammalian host and the blood-feeding tsetse fly vector. To cope with the changing environment,
the parasite transitions through distinct life cycle forms that have evolved to assure survival and successful
transmission to the next host. For instance, when residing in the mammalian host, T. brucei expresses a
variant surface glycoprotein (VSG) coat, which is the paradigm for antigenic variation. Although there are
hundreds of VSG genes in the genome, bloodstream-form VSG expression is restricted to 1 of about 15
specialized telomeric bloodstream expression sites (BES). In the salivary glands of the insect vector metacyclic
trypanosomes are covered by a specific and small subset of VSGs, the metacyclic VSGs (mVSGs), which
enable transmission to a vertebrate host. mVSG expression is triggered by an unknown mechanism and in
vitro can be achieved in the absence of tsetse tissues by induced expression of the RNA-binding protein 6
(RBP6). One major goal of this application will be to examine how trypanosomes receive instructions to begin
synthesizing the mVSG coat, and when each cell begins expressing a single mVSG. We will use single-cell
RNA-Seq and long-term live-cell imaging to answer mechanistic questions. In addition, our novel finding that
mVSG genes encode an exonic splicing enhancer exposed a completely new aspect of VSG regulation and
may explain the tightly-controlled extremely high output of mature mRNAs.

## Key facts

- **NIH application ID:** 10685494
- **Project number:** 5R01AI165480-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** CHRISTIAN TSCHUDI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $418,750
- **Award type:** 5
- **Project period:** 2021-09-23 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10685494

## Citation

> US National Institutes of Health, RePORTER application 10685494, Control of VSG pre-mRNA processing in infectious Trypanosoma brucei (5R01AI165480-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10685494. Licensed CC0.

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