Molecular mimicry and immune evasion in malaria parasites

Introduction

Parasites have evolved elaborate strategies that maximise their fitness. Central to these strategies is their interaction with the host immune system, for instance with immune receptors which mediate pathogen recognition or immune tolerance.

Background

Human malaria parasites encode a family of ~200 rifins, some of which are molecular mimics of human self-identifying proteins and that bind tolerance-inducing receptors. However, very few host targets of rifin proteins are known. Our data suggests that the family at large may form an elaborate repertoire of immunomodulatory effectors.

Hypotheses

We postulate that rifins are deployed to manipulate host immunity in order to facilitate parasite persistence in its host. We further hypothesise that this immune regulation is underpinned by a complex specificity code and a distinct bet-hedging expression program.

Project Objectives

In the Trojan project, we will investigate and contextualise immunomodulation by malaria parasites in the arms race between the parasite and its host. The project will focus on the following objectives:

1. Gene Expression Measurement: Given the sequence diversity of rifins, we will optimise a method to measure gene expression without the need for a reference genome on a single cell level. We will then deploy this tool to understand how expression of rifins is associated with malaria symptoms and persistence in long-term natural infections.

2. Deciphering Immune Targets: We will decipher the range of immune targets of rifins as well as the rifin-specificity code and use lineage tracing to understand how diverse immunomodulatory expression patterns arise.

3. Understanding Host Response: Finally, we will seek to understand how malaria-infected individuals respond to immunomodulation by interfering with rifin-receptor interactions.

Conclusion

Altogether we will reveal how pathogen molecular mimicry and manipulation is central to their success. This study will transform our understanding of fundamental aspects of parasite biology as well as immune homeostasis and could provide new tools in the continuing fight against malaria.