The malaria chemical atlas: Revealing the parasite-host functional interactome

Introduction

Malaria is the most life-threatening parasitic disease in humans. Invasion of the malaria parasite, Plasmodium falciparum (Pf), into the blood circulation rewires the harmonious networking between the resident cells.

Communication of Plasmodium falciparum

Until recently, Pf was not thought to be able to communicate when nested within infected human red blood cells (RBCs). However, we and others have laid the foundations of Pf communication via extracellular vesicles.

Hypothesis

We now hypothesize that in order to survive in the hostile host environment, Pf secretes chemical inducers (e.g., metabolites, peptides) to actively coordinate life decisions as a group and to control the surrounding host cells. Remarkably, we obtained proof-of-principle preliminary results in the form of an isolated, active chemical fraction that inhibits Pf population growth in a density-dependent manner.

Project Goals

Our overarching goal in MalChemAtlas is to expose this yet-to-be-revealed mode of communication in malaria: cell-to-cell chemical signaling. We will combine analytic chemical, biophysical, and omics technologies with machine-learning approaches to comprehensively reveal and characterize the functional chemicals that:

1. Facilitate parasite density, growth, and sexual development (parasite-parasite signaling).
2. Dictate parasite crosstalk with circulating host immune cells and naïve RBCs (parasite-host communication).
3. Affect downstream signaling cascades between the host’s innate and adaptive immunity (host-host communication).

Methodology

In this effort, we will leverage our extensive (HPLC-based) analytical fractionation pipeline, combined with NMR and metabolomics analyses, for identifying malaria-secreted autoinducers.

Implications of Findings

Our preliminary findings demonstrate the potential of our basic research to be applied to the translational level of intervention. Identifying “natural chemical killers” offers a previously unexplored direct strategy to fight malaria - the highest gain we can ask for when researching this deadly disease.