Molecular mimicry and immune evasion in malaria parasites (TROJAN)

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. 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. Data suggests that the family at large may form an elaborate repertoire of immunomodulatory effectors. It is postulated that rifins are deployed to manipulate host immunity in order to facilitate parasite persistence in its host. It is further hypothesised that this immune regulation is underpinned by a complex specificity code and a distinct bet-hedging expression program. Firstly, 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. This tool will then be deployed to understand how expression of rifins is associated with malaria symptoms and persistence in long-term natural infections. Secondly, the project 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. Finally, it will help to understand how malaria-infected individuals respond to immunomodulation by interfering with rifin-receptor interactions. Altogether it will reveal how pathogen molecular mimicry and manipulation is central to their success. This study will transform the understanding of fundamental aspects of parasite biology as well as immune homeostasis and could provide new tools in the continuing fight against malaria.

Project details

Basic Science
Immunology

Nov 2024 — Oct 2029

$2.71M

France