Decoding the path to cellular variation within pathogen populations

Introduction

Heterogeneity amongst isogenic cells is pervasive throughout biology. Recently developed single-cell omics approaches are beginning to systematically reveal the repertoire of functionally distinct cell subpopulations within metazoan tissues.

Background

Pathogens frequently encounter changing and often hostile environments. To adapt to these challenges, unicellular pathogen populations also exhibit a large degree of cell-to-cell heterogeneity, which often affects the outcome of infections.

Research Gap

Yet, despite the importance of this cell-to-cell variation, very little is known about the mechanisms that control the level of heterogeneity in pathogen populations or why some isogenic populations are more heterogeneous than others.

Project Goal

The goal of switchDecoding is to unveil the path to cellular variation. To this end, I will go beyond identifying and describing new subpopulations of cells and elucidate the molecular pathways that establish them and modulate the level of cellular heterogeneity.

Model Organism

As a model, I will study the mechanism responsible for creating heterogeneity in surface antigen expression in the unicellular parasite Trypanosoma brucei. Antigenic variation is a widely employed strategy by evolutionarily divergent pathogens to evade the host immune response.

Methodology

Using a multidisciplinary approach, I will develop and combine:

1. Single-cell multi-omics
2. Lineage tracing
3. CRISPR-Cas-based genome manipulation strategies

These methods will be used to characterize the processes, pathways, and molecules regulating antigen switching in T. brucei.

Future Implications

A better understanding of the mechanisms affecting the level of heterogeneity within a pathogen population will enable us to better predict how pathogens adapt to environmental challenges, including those that lead to the emergence of drug resistance.

Conclusion

In the future, this knowledge will enable the development of novel intervention strategies: drugs that modulate cell-to-cell heterogeneity to facilitate the clearance of infections.