# Structure-function studies of the H. polygyrus TGF-beta, TGM

> **NIH NIH R03** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $72,349

## Abstract

Summary
Helminth parasites remain one of the world’s greatest challenges to human and animal health, with more than
two billion infected humans world-wide. Parasite control is restricted to short-term suppression with low cost
drugs due the unavailability of effective vaccines. Persistence of helminths in humans and animals is testament
to their highly evolved ability to evade the immune system, thus understanding the evasion mechanisms is key
to developing new interventions. In this proposal, the focus is on the mouse parasite Heligmosomoides
polygyrus, which infects animals as L3 larvae and colonizes and matures in the intestine. In mice infected with
H. polygyrus, there is a dramatic upregulation in the number of Foxp3+ regulatory T-cells (Tregs), which broadly
and potently mediate immune suppression. Interference of Treg function in infected mice results in expulsion of
H. polygyrus, demonstrating that the expanded pool of Foxp3+ Tregs is essential for persistence. In collaboration
with the Maizels group, we have shown that a secreted five-domain complement control protein (CCP) protein
that mimics mammalian TGF-b, a cytokine that potently suppresses the immune system by stimulating the
proliferation and differentiation of Tregs, is critical for immune hyporesponsiveness in H. polygyrus infected
animals. In spite of lacking any homology to mammalian TGF-β, this protein termed TGF-b mimic or TGM, binds
directly to the mammalian TGF-β receptors, TβRI and TβRII, to induce signaling and downstream effects on
Tregs. In this proposal, we will determine how TGM binds and assembles TβRI and TβRII into a signaling complex,
with the goal of using this information to better understand how TGM signals and identify homologous proteins
in other parasites that exploit the TGF-b pathway to evade host immune responses. In addition, this information
can be leveraged to engineer forms of TGM for: 1) treating autoimmune diseases, such as rheumatoid arthritis,
multiple sclerosis, or asthma, 2) suppressing the immune system in organ transplantation, and 3) developing
anti-parasitics that function by blocking the interaction between TGM and the TGF-β receptors. In support of the
proposed studies, we show using NMR and ITC/SPR binding studies that TGM domain 3 (TGM-D3) is the
primary domain responsible for binding TbRII, while TGM domain D2 (TGM-D2), together with a more minor
contribution from TGM domain 1 (TGM-D1), is responsible for binding TbRI. In order to accomplish the objectives
of the proposed research, we will determine the structures of TGM-D2 and TGM-D3 alone, and the TGM-D2:TbRI
and TGM-D3:TbRII complex structures, using NMR in Aim 1, and the structure of the TGM-D123:TbRII:TbRI
complex using X-ray crystallography in Aim 2. In order to identify the residues that contribute greatest to receptor
binding, site-directed mutagenesis and ITC- and SPR-based binding studies will be used, together with functional
studies in cultured TGF-b reporter cell lines and...

## Key facts

- **NIH application ID:** 10042831
- **Project number:** 1R03AI153915-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** ANDREW P HINCK
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $72,349
- **Award type:** 1
- **Project period:** 2020-06-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10042831

## Citation

> US National Institutes of Health, RePORTER application 10042831, Structure-function studies of the H. polygyrus TGF-beta, TGM (1R03AI153915-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10042831. Licensed CC0.

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