Deciphering environmental sensing in Malaria parasites – PlasmoSense

Plasmodium falciparum malaria parasites undergo continuous rounds of vegetative growth within human erythrocytes, which causes all malaria-associated symptoms and over 400,000 lethal cases annually. While the erythrocyte provides parasites with some essential nutrients and shields the intruder from host immune responses, the intra-erythrocytic localisation seemingly isolates P. falciparum from the outside world. Despite this spatial separation, recent findings demonstrated an intriguing ability of intra-erythrocytic parasites to sense environmental signals. For instance, parasites make use of metabolic cues to monitor levels of the host serum lipid lysophosphatidylcholine (lysoPC). Under lysoPC-limiting conditions, parasites induce specific adaptation responses including activation of compensatory metabolic pathways and increased production of transmission stages. LysoPC levels vary between different microenvironments in the host and drop dramatically in reaction to inflammation responses – rendering this lipid an ideal sensor for adaptive parasite processes.

Similarly, in the malaria mouse model P. berghei, parasites modulate intra-erythrocytic development in response to changing host nutrient levels and parasite kinase PbKIN is required for this process. Interestingly, glucose-derived signals can interfere with lysoPC sensing in P. falciparum, suggesting the activity of interlinked nutrient sensing pathways in intra-erythrocytic parasites. However, the molecular mechanisms underlying the perception and processing of nutritional cues by malaria parasites remain largely unknown. This knowledge gap is owed to the fact that malaria parasites lack key factors of nutrient-sensing pathways conserved among other eukaryotes, including those of the central TOR (target of rapamycin) nutrient sensing hubs.Preliminary data suggests that parasites “hijack” signalling factors of the host erythrocyte to monitor changes in their environment. In this project, we will unravel the mechanisms underlying environmental sensing of P. falciparum using a three-pronged research strategy.

First, we will combine chemical screening with phosphoproteomics approaches to identify erythrocyte-derived factors as well as parasite-encoded proteins involved in the perception and transduction of the lysoPC and glucose stimuli.

Second, we will validate the involvement of candidates in these pathways using CRISPR/Cas9-based reverse genetics in P. falciparum as well as CRISPR/Cas9-based gene editing in nucleated erythrocyte precursors, which will allow investigating the role of host cell-derived candidates. We will further complement these efforts by an innovative approach employing so-called humanised parasites, i.e. transgenic P. falciparum parasites expressing and exporting human proteins into the erythrocyte cytosol.

Third, a workable number of factors identified in the above aims will be subject to in-depth functional analyses.We expect this work to reveal unprecedented insights into environmental sensing of P. falciparum blood stage parasites.

We aim at characterising a functional crosstalk between human and parasite signalling components with an important role for parasite adaptation and survival during infection. The research plan proposed here not only constitutes an entirely new area of malaria research but also holds promise for disclosing a yet hidden potential for signalling-targeted therapeutic interventions.

Swiss National Science Foundation (SNSF) project detailsSwiss TPH project details

Enabling Technologies & Assays
Genetics and Genomics

Jun 2021 — May 2025

$876,000

Switzerland