Nutrient Uptake and Metabolism - Project A5

Role of host lipids in the establishment of the human malaria parasite in the mosquito

Host lab: ELENA LEVASHINA (MPIIB)

Partner lab: Alexander Maier (ANU)

Additional interaction partner: Martin Blume (RKI) 

Background: Establishment of Plasmodium falciparum in the mosquito is essential for malaria transmission. However, the host and mosquito factors that regulate the first steps of this critical process are not well understood. P. falciparum transmission stages represent an interesting evolutionary model of plasticity as they require a rapid parasite adaptation to fundamentally different environments (e.g. temperature, metabolites, immune system). The biological mechanisms that underlie parasite plasticity that deals with changing environment, however, remain unknown.

Scope: This project will explore the role of host lipids in maturation of transmissible parasite forms (gametocytes) and their development into ookinetes in the mosquito. By exposing the parasite to defined lipid environments, we will identify and characterize lipid species that are essential for gametocyte fertility and development.

Methods: This project combines P. falciparum culturing in vitro and mosquito infections in vivo. The parasites will be cultured in defined lipid environments and the crucial lipids will be identified by scoring the success of P. falciparum development in Anopheles gambiae. Labelled lipids will be used for characterizing lipid uptake and metabolism in P. falciparum mosquito stages. The crucial role of lipid uptake and metabolic pathways will be explored by genetic engineering using CRISPR/Cas9 technology.

3-year plan: Work on the mosquito stages will take place in Berlin, whereas the work on lipidomics, the development and activation of the gametocytes will predominately take place in Canberra.

Year 1. Establishment of screens for identification of lipids that shape gametocyte maturation in vitro and in vivo (Berlin).

Year 2. Lipid labelling and lipidomics analyses. Generation of lipid metabolism mutants in P. falciparum (Canberra).

Year 3. Functional characterization of mutant phenotypes during P. falciparum development in A. gambiae (Berlin).

Keywords: malaria, transmission, lipid metabolism, gametocytes, sexual differentiation, ookinete development

Keywords Methods: cell culture, infections in A. gambiae, metabolic labelling, reverse genetics, CRISPR/Cas9, cell biology, mass-spectrometry

References: 

1. Costa G, Gildenhard M, Eldering M, Lindquist RL, Hauser AE, Sauerwein R, Goosmann C, Brinkmann V, Carrillo-Bustamante P, Levashina EA. (2018) Non-competitive resource exploitation within mosquito shapes within-host malaria infectivity and virulence. Nat. Commun. 9: 3474.

2. Tran PN, Brown SH, Rug M, Ridgway MC, Mitchell TW, Maier AG. (2016) Changes in lipid composition during sexual development of the malaria parasite Plasmodium falciparum. Malar J. 15:73.