A3 Characterizing the biological role of glycosylation in Plasmodium falciparum communication by extracellular vesicles (EVs) (Seeberger)
|Prof. Dr. Peter Seeberger (Vaccine Glycobiology),
Max Planck Institute of Colloids and Interfaces
|Max Planck Institute of Colloids and Interfaces,Am Mühlenberg 1, 14476 Potsdam
Freie Universität Berlin, Institute of Chemistry and Biochemistry, Arnimallee 22, 14167 Berlin
|Prof. Dr. Peter H. Seeberger, Oren Moscovitz
|Felix Goerdeler, Jost Lühle
State of the art:
Cell-cell communication by extracellular vesicles (EVs) secretion is a phenomenon which was
described in a wide range of organisms from humans to bacteria and also protozoan parasites. Biomolecules such as proteins, lipids, and nucleic acids, are being carried between
adjacent cells and participate in a diverse and wide range of biological pathways. Although
EVs biology is extensively studied for over a decade, the role of glycans in EVs function has
not been elucidated yet. This is mainly attributed to the structural complexity of native glycans,
and the lack of biological tools that can analyze or target specific glycan structures. As a
result, there are no published works that describe the role of glycans in EVs biology of
apicomplexan parasites. We shall use synthetic glycan structures distinct to Plasmodiun spp.,
and glycan binding antibodies alongside cutting edge glycomics. Our aim is to shed light on
the glycobiology aspects behind EVs communication and virulence levels in different strains
of Plasmodium parasites.
Previous own work:
The ongoing 1st PhD generation project developed antibodies that specifically target different
structures of P. falciparum Glycosylphosphatidylinositol (GPI) glycolipids. We initially used
these antibodies to inspect different GPI epitopes as suitable anti-malaria vaccine candidates.
Next, we could visualize and provide the first proof of highly abundant GPI expression on
the cellular membrane of mature P. falciparum parasites. This led to the idea of characterizing
the involvement of glycans and GPIs glycolipids in the biology of P. falciparum EVs as
membrane based particles that are secreted and uptaken by the parasites.
Hypotheses and work plan:
1) GPI glycolipids are also found on P. falciparum derived EVs.
2) EVs derived from P. falciparum contain additional distinct parasite glycan structures that
could be used as a target for further therapeutics or diagnostics tools.
3) Both cellular secretion and uptake of EVs are mediated by distinct glycan moieties.
4) Overall virulence of a given Plasmodium strain is at least partially dependent upon its EVs
glycan profile which dictates secretion/uptake of EVs.
5) Glycan trimming or anti-glycan tools will effect EVs communication and parasites
proliferation in vitro and in vivo.
6) EVs exchange between different virulent strains will alter their pathogenicity and change the
glycan profile on their EVs and cell surface.
We aim to: i) Compare glycan profiles from EVs secreted by infected red blood cells from
different stages of asexual parasite development. ii) Pinpoint unique P. falciparum glycans on
EVs membrane. iii) Test direct and indirect remodeling of P. falciparum EVs glycosylation and
the effect on their secretion and uptake. iv) Compare glycan profiles of EVs from different
parasite strains and correlate with virulence levels. v) Characterize an EVs mediated virulence
shift and the following change in glycan profiles, in a co-infection model using different
plasmodium strains. vi) Develop antibodies that target EVs specific glycan structures for
therapeutics and diagnostics purposes.