Ruprecht-Karls-Universität Heidelberg
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Lanzer0117 - Scientist (f/m) / PhD position
Project no:
Lanzer0117

Project leader:

Project supervisor:
Lanzer, Michael
Application deadline:
31. Aug 2017
Start of PhD project:
1. Oct 2017

Project description:

Title:
Effect of cytoskeletal remodelling on the mechanical and adhesive properties of malaria-infected erythrocytes
Summary:
Malaria is a severe and potentially deadly infectious disease caused by the protozoan parasite Plasmodium falciparum. However, not every infected person develops life-threatening symptoms. Some people are protected by naturally occurring genetic polymorphisms, such as those leading to sickle cell haemoglobin (HbS) or haemoglobin C (HbC). Recent data have shown that HbS and HbC confer protection by reducing the cytoadhesiveness of parasitised erythrocytes. For effective cytoadhesion, the major adhesin molecule PfEMP1 needs to be placed in parasite-induced knob-like protrusions on the erythrocyte plasma membrane. Infected HbS and HbC erythrocytes, however, possess fewer and abnormally enlarged knobs and the amount of PfEMP1 molecules presented is reduced and aberrantly displayed. We explain this phenotype by a changed interaction between the major knob determinant, the KAHRP protein, and components of the host cell’s cytoskeleton. The object of this project is to generate parasite lines with mutated protein interaction domains within KAHRP and to investigate how these mutations affect i) anchoring of the knobs to the membrane skeleton; ii) reorganization of the actin/spectrin network by the parasite; iii) presentation of PfEMP1; the capacity to cytoadhere under static and flow conditions; and biomechanical properties of the parasitized erythrocyte.
References:
1. Dasanna AK, Lansche C, Lanzer M, Schwarz US (2017) Rolling adhesion of schizont stage malaria-infected red blood cells in shear flow. Biophys J. 112:1908-1919.

2. Cyrklaff M, Srismith S, Nyboer B, Burda K, Hoffmann A, Lasitschka F, Adjalley S, Bisseye C, Simpore J, Mueller AK, Sanchez CP, Frischknecht F, Lanzer M (2016) Oxidative insult can induce malaria-protective trait of sickle and fetal erythrocytes. Nat Commun. 7:13401.

3. Helms G, Dasanna AK, Schwarz US, Lanzer M (2016) Modeling cytoadhesion of Plasmodium falciparum-infected erythrocytes and leukocytes-common principles and distinctive features. FEBS Lett. 590:1955-71.

4. Cyrklaff M, Sanchez CP, Kilian N, Bisseye C, Simpore J, Frischknecht F, Lanzer M (2011) Hemoglobins S and C interfere with actin remodeling in Plasmodium falciparum-infected erythrocytes. Science 334:1283-6.
Methods that will be used:
super resolution microscopy; molecular cloning; cell culture; transfection of P. falciparum; CRISPR/CAS9-based genome editing; confocal microscopy; flow chamber experiments; mechanical testing (e.g. with atomic force microscopy) and mathematical modelling in the framework of collaborations
Cooperation partners:
This is a joint project with Prof. Ulrich Schwarz from the Department of Theoretical Physics; Heidelberg University.
Personal qualifications:
Qualified candidate should have a degree from an internationally accredited institution of higher education. Technical skills in molecular cloning, cell culture, super resolution microscopy are desirable. Interest in interdisciplinary collaborations is highly desirable. Applications from all fields of natural sciences are welcome.
Keywords:
Plasmodium; malaria; high-resolution microscopy; cytoadhesion; cytoskeleton; spectrin; actin; biomechanics