Can Trypanosome infection influence early tumour development?

About the Project

Title: Can Trypanosome infection influence early tumour development?

Synopsis: This project investigates how Trypanosoma infection influences early tumour development by modulating host immune responses. Using a zebrafish preneoplastic model, it aims to determine whether infection promotes or suppresses tumour growth through immune-mediated mechanisms.

Details: Chronic parasitic infections are increasingly recognised as potential cofactors in cancer development. Among these, Trypanosoma cruzi—the causative agent of Chagas disease—exerts complex effects on host immunity and tissue microenvironments that may influence tumour initiation and progression. Some studies report anti-tumour effects mediated by parasite molecules, while others indicate that persistent infection can drive chronic inflammation and immune dysregulation, promoting tumour growth. However, the role of Trypanosoma infection in early tumour development has not been examined in a controlled experimental setting. Understanding whether and how infection modulates host immune function during tumour initiation could reveal novel mechanisms linking infection and cancer.

This PhD project integrates expertise from two complementary research groups with support from a third computational biology supervisor. The Feng lab has developed an inducible zebrafish skin preneoplastic cell (PNC) model driven by oncogenic HRAS. In this model, using single cell RNAseq analysis, we found innate immune cells undergo a rapid phenotype transition and play a crucial role in early tumour development, with altered neutrophil activity leading to enhancement of tumourigenesis. The Forlenza group specialises in host–pathogen interactions and vaccine development, including Trypanosoma infection. Her team has established a zebrafish infection model using Trypanosoma carassii and shown two distinct innate immune responses: a controlled pro-inflammatory programme associated with survival, and an uncontrolled, pathology-driven state characterised by foamy macrophages and increased susceptibility. This provides a strong platform to test how infection-induced inflammation influences tumour initiation and progression.

Zebrafish offer key advantages for studying cancer–pathogen interactions, including optical transparency for in vivo imaging of tumours and immune dynamics, and genetic tractability for mechanistic dissection. Building on these strengths and this project will establish a model to determine how Trypanosoma infection modulates tumour initiation via immune rewiring, transcriptomic analysis will be used to define altered innate immune cellular state under various treatment conditions.

Aims:

1. Determine whether Trypanosoma infection promotes or suppresses PNC growth and progression.
2. Assess how Trypanosoma infection alters immune responses toward PNCs and modifies immune cell phenotypes.
3. Elucidate whether infection-mediated changes in PNC behaviour arise from modulation of host immune function.

Experimental Approach:

Aim 1: Infect zebrafish larvae from the HRAS-inducible PNC model using an established Trypanosoma protocol. Quantify PNC proliferation, apoptosis, and morphological alterations. Employ fluorescent in situ hybridisation to assess PNC gene expression and phenotype following infection.

Aim 2: Isolate fluorescently labelled immune cells from infected and uninfected PNC-bearing and control larvae for RNA sequencing. Perform live imaging using reporter lines marking neutrophils, macrophages, and signalling activity to visualise infection-induced immune dynamics.

Aim 3: Manipulate innate immune function pharmacologically or genetically to determine whether infection-driven changes in PNCs are immune-mediated.

This project will define how infection-induced immune states shape early tumour development. By integrating infection biology and tumour immunology in a tractable vertebrate model, this project will uncover fundamental mechanisms by which chronic parasitic infections influence cancer risk and progression, paving the way for improved strategies in cancer prevention and immunomodulatory therapy.

Potential impacts: Trypanosoma successfully establishes itself as a human pathogen by modulating immune system function. Understanding how Trypanosoma alters host immunity, and how this in turn influences tumorigenesis, will provide a solid foundation for developing cancer prevention strategies that target host factors in Trypanosoma-infected populations. Such approaches may also be applicable to tumourigenesis driven by other infectious agents.

Training environment: This cross-disciplinary project provides training in general immunology, tumour immunology, and host–pathogen interactions. The candidate will gain extensive wet-lab experience using zebrafish as model for cancer biology as well as infectious diseases, alongside developing computational skills for gene expression and disease association analyses.

The student will be mainly based at the Institute for Regeneration and Repair, which offers a wide range of professional and transferable skills training on the Little France Campus. Opportunities include regular postgraduate research-in-progress presentations, student flash talks, annual poster events, and science outreach activities. The student will also receive support to apply for internal early-career research (ECR) grants and to attend national or international conferences to present their work.

Recruitment: The project would be suited for students interested in cancer biology and tumour immunology and with a background in one of the following subjects: genetics, cell & molecular biology, developmental biology or immunology. Previous laboratory experiences would be preferred.

To apply: All applications must be submitted through the Future Medicine PhD fellowships website.

Funding Notes

Students will receive a stipend at UKRI levels, plus £30K in travel and research funds across all three years of the fellowship. All University fees will be covered.

The fellowships are open to students who are eligible for home fees at Edinburgh - i.e. you must be a UK national, or have settled status, and have been "ordinarily resident" in the UK for the three years immediately before the start of the fellowship. Other international applicants are not eligible for these fellowships.