# Trypanosome cAMP signaling mediates parasite-vector interaction

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $255,521

## Abstract

PROJECT SUMMARY/ABSTRACT
African trypanosomes (Trypanosoma brucei) and related trypanosomatid parasites are responsible for vector-borne
diseases that cause great human suffering and economic burden in endemic countries. T. brucei is
transmitted between humans and other mammalian hosts by the tsetse fly, which is not merely a vessel for
moving parasites between hosts, but an integral part of the parasite's developmental life cycle necessary for
sustained transmission. In the absence of a vaccine to prevent infection in the mammalian host, targeting
parasite development within the insect vector is considered an option for reducing disease transmission,
though little is known of parasite interactions in the vector necessary for transmission. To survive, develop, and
be transmitted, T. brucei must sense and respond to changing environmental signals as it moves through
tissues within the insect vector. Little is known about parasite signaling pathways and vector-derived factors
that control parasite migration - this is a critical knowledge gap and potential target of new transmission-blocking
agents. Trypanosome cAMP signaling, originally shown to be critical for parasite chemotaxis in vitro,
has recently been connected to progression of parasites through the tsetse, in particular, migration from the
midgut (MG) to the proventriculus (PV). Initiation of cAMP signaling is controlled by an expanded protein family
of adenylate cyclases (ACs) that differ in their extracellular putative ligand-binding domains and exhibit tissue-specific
expression profiles during parasite migration through the tsetse. Trypanosome cAMP signaling is
therefore an attractive target for transmission-blocking agents, however, very little is known about regulation of
AC activity and downstream targets of cAMP signaling. This proposal brings together a multidisciplinary team
of investigators with collective expertise in trypanosome biology, cAMP signaling, transcriptomics, and genetic
manipulation of parasites, as well as tsetse biology, fly infections, and interactions between parasite, vector,
and microbiome. Our specific aims are to (1) identify endogenous, tsetse fly-derived modulators of T. brucei
chemotaxis; (2) define parasite cAMP effector genes responsible for parasite migration from the tsetse midgut
to proventriculus; and (3) define parasite receptors that perceive chemotactic signals in the fly. We will
leverage our established chemotaxis assay to test tsetse-derived factors for impacts on parasite chemotaxis
(Aim 1). To define genes required for MG ➔ PV migration in the tsetse, we will employ a MG ➔ PV defective
trypanosome mutant to identify MG-induced, cAMP-dependent transcriptome changes associated with
movement out of the MG (Aim 2). Finally, we will implement systems for genetic manipulation of fly-transmissible
T. brucei to allow functional assessment of trypanosome receptors and additional cAMP
signaling genes during tsetse infection (Aim 3). Completing these ...

## Key facts

- **NIH application ID:** 10989440
- **Project number:** 1R21AI180896-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** KENT L HILL
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $255,521
- **Award type:** 1
- **Project period:** 2024-05-21 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10989440

## Citation

> US National Institutes of Health, RePORTER application 10989440, Trypanosome cAMP signaling mediates parasite-vector interaction (1R21AI180896-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10989440. Licensed CC0.

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