# Structure and Functionof a Parasitic TGF-beta Mimic, TGM

> **NIH NIH F30** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $51,036

## Abstract

Project Summary
Helminth parasites are a threat to global health, with nearly one-third of the world’s population currently
infected, constituting a high disease burden amongst both humans and animals alike. The high prevalence of
helminths can be attributed to their ability to manipulate and evade their host’s immune system using secreted
immunomodulatory molecules. Thus, understanding the mechanisms behind immune evasion is key to
therapeutic intervention. The mouse gastrointestinal parasite Heligmosomoides polygyrus is a model for
parasitic immunoregulation; infection results in the conversion of naïve CD4+ T-cells into Foxp3+ regulatory T-
cells (Tregs) and their expansion, which act to broadly suppress the host immune system. Only upon reduction
of this Treg population are mice able to expel the parasite, demonstrating that the parasite requires this
increased population of Foxp3+ Tregs for persistence in its host. Through an ongoing collaboration with the
Maizels lab, our labs have determined that the parasite is using a set of secreted complement control proteins
(CCP) to incite host immune hyporesponsiveness through mimicry of the transforming growth factor β isoforms
(TGF-). The TGF-β isoforms have essential roles in maintenance of the adaptive immune system, with TGF-β
known to be the major cytokine responsible for the conversion of naïve CD4+ T-cells into Tregs and expansion
of the Treg population. This immunosuppression is important in maintaining immune tolerance, but also
promotes soft tissue cancer progression by enabling oncogenic evasion of the immune system. Though lacking
sequence and structural similarity to TGF-β, the founding member of the parasitic protein family identified by
the Maizels group, TGM1, has been shown to directly bind to the mammalian TGF-β receptors, and along with
two close homologues, TGM2 and TGM4, upregulate the Treg population. Identifying the residues and protein
motifs responsible for binding the TGF- receptors can be used to engineer forms of TGM for: 1) anti-parasitics
that block the interaction between TGM family members and the TGF-β family receptors, and 2) TGF-
receptor kinase inhibitors for cancer immunotherapy. In this proposal, we will determine how two members of
the TGM family, TGM1 and TGM4, bind and assemble the TGF-β receptors to activate the TGF- pathway,
providing insight into parasitic molecular mimicry. The structure of TGM1 domains (Aim 1) and TGM4 (Aim 2)
domains alone and in complex with their cognate TGF-β family receptors will be determined through NMR, X-
ray crystallography, and ITC/SPR binding studies. Residues that contribute greatest to receptor binding will be
identified through residue-specific substitution and ITC/SPR binding studies (Aim 1, 2). In addition, we will
leverage this structural information to engineer an Fc-fusion construct of TGM with selective binding to the
TGF-β type I receptor, and test for inhibition of TGF-β Smad signaling and Foxp3+ Treg inductio...

## Key facts

- **NIH application ID:** 10315068
- **Project number:** 1F30AI157069-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Ananya Mukundan
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 1
- **Project period:** 2021-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10315068

## Citation

> US National Institutes of Health, RePORTER application 10315068, Structure and Functionof a Parasitic TGF-beta Mimic, TGM (1F30AI157069-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10315068. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*