Red blood cell tension protects against severe malaria in the Dantu blood group
Silvia N. Kariuki,
Alejandro Marin-Menendez,
Viola Introini,
Benjamin J. Ravenhill,
Yen-Chun Lin,
Alex Macharia,
Johnstone Makale,
Metrine Tendwa,
Wilfred Nyamu, et al.
Malaria has had a major effect on the human genome, with many protective polymorphisms—such as the sickle-cell trait—having been selected to high frequencies in malaria-endemic regions. The blood group variant Dantu provides 74% protection against all forms of severe malaria in homozygous individuals, a similar degree of protection to that afforded by the sickle-cell trait and considerably greater than that offered by the best malaria vaccine. Until now, however, the protective mechanism has been unknown. Here we demonstrate the effect of Dantu on the ability of the merozoite form of the malaria parasite Plasmodium falciparum to invade red blood cells (RBCs). We find that Dantu is associated with extensive changes to the repertoire of proteins found on the RBC surface, but, unexpectedly, inhibition of invasion does not correlate with specific RBC–parasite receptor–ligand interactions. By following invasion using video microscopy, we find a strong link between RBC tension and merozoite invasion, and identify a tension threshold above which invasion rarely occurs, even in non-Dantu RBCs. Dantu RBCs have higher average tension than non-Dantu RBCs, meaning that a greater proportion resist invasion. These findings provide both an explanation for the protective effect of Dantu, and fresh insight into why the efficiency of P. falciparum invasion might vary across the heterogenous populations of RBCs found both within and between individuals.
An exported kinase family mediates species-specific erythrocyte remodelling and virulence in human malaria
Heledd Davies,
Hugo Belda,
Malgorzata Broncel,
Xingda Ye,
Claudine Bisson,
Viola Introini,
Dominique Dorin-Semblat,
Jean-Philippe Semblat,
Marta Tibúrcio, et al.
The most severe form of human malaria is caused by Plasmodium falciparum. Its virulence is closely linked to the increase in rigidity of infected erythrocytes and their adhesion to endothelial receptors, obstructing blood flow to vital organs. Unlike other human-infecting Plasmodium species, P. falciparum exports a family of 18 FIKK serine/threonine kinases into the host cell, suggesting that phosphorylation may modulate erythrocyte modifications. We reveal substantial species-specific phosphorylation of erythrocyte proteins by P. falciparum but not by Plasmodium knowlesi, which does not export FIKK kinases. By conditionally deleting all FIKK kinases combined with large-scale quantitative phosphoproteomics we identified unique phosphorylation fingerprints for each kinase, including phosphosites on parasite virulence factors and host erythrocyte proteins. Despite their non-overlapping target sites, a network analysis revealed that some FIKKs may act in the same pathways. Only the deletion of the non-exported kinase FIKK8 resulted in reduced parasite growth, suggesting the exported FIKKs may instead support functions important for survival in the host. We show that one kinase, FIKK4.1, mediates both rigidification of the erythrocyte cytoskeleton and trafficking of the adhesin and key virulence factor PfEMP1 to the host cell surface. This establishes the FIKK family as important drivers of parasite evolution and malaria pathology.
Spontaneous parametric down conversion in a doubly resonant one-dimensional photonic crystal
Viola Introini,
M. J. Steel,
J. E. Sipe,
L. G. Helt,
Marco Liscidini
We study spontaneous parametric down conversion (SPDC) in a one-dimensional photonic crystal designed to operate in a doubly resonant configuration, where the frequencies of the pump and the generated photons are both tuned to band-edge resonances. We investigate the spectral correlations of the generated photons as a function of the spectral width of the pump, and demonstrate that the SPDC generation rate can scale with the fifth power of the structure length in the limit of a quasi-continuous-wave pump. We show that such an unusual scaling can be simply connected with the scaling of second-harmonic generation in the same structure, illustrating the general link between spontaneous and stimulated parametric nonlinear processes.
Contact
Research GroupViola Introini
Max-Planck-Zentrum für Physik und Medizin Kussmaulallee 2 Room 01.220 91054 Erlangen, Germany
