Ruprecht-Karls-Universität Heidelberg
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Portugal0118 - Scientist (f/m) / PhD position
Project no:
Portugal0118

Project leader:

Project supervisor:
Portugal, Sílvia
Application deadline:
1. Jul 2018
Start of PhD project:
1. Aug 2018

Project description:

Title:
Plasmodium falciparum gene expression during dry season asymptomatic infections
Summary:
We have recently shown that dry season Plasmodium falciparum infections are maintained asymptomatically during the 6-month dry season in Mali, while P. falciparum-specific humoral responses decrease (Portugal, S. et al. 2017). During the latter part of the 48h erythrocytic cycle and in order to avoid clearance by the spleen, P. falciparum expresses one of its ~60 P. falciparum erythrocyte membrane protein 1 (PfEMP1), is encoded by var genes on the erythrocyte surface to promote cytoadherence to blood vessel endothelial cells (Storm, J. et al. 2014). Malaria immunity is partially mediated by acquiring IgG binding to, and inhibiting PfEMP1.
This leads to an evolutionary arms race between the parasite itself and the host immune system. As the host responds to a given parasite antigen with antibody production, the parasite changes its expressed protein to avoid host clearance. In the case of PfEMP1, with each subsequent blood stage parasite generation a small fraction of progeny switch to express a different var gene, allowing evasion of IgG responses during the infection. var genes encoding PfEMP1 are highly diversified in sequence but conserved in domain structure and composition, and specific variants confer immunogenic and cytoadhesive phenotypes that may determine the clinical outcomes of infection (Kaestli, M et al. 2006. Kirchgatter, K. et al. 2002). In comparison, PfEMP1 variants that interact with CD36 or yet undefined receptors appear not to contribute to the development of severe symptoms (Lavstsen, T et al. 2012, Jespersen, JS et al. 2008). To date, no study has addressed the expression profile of PfEMP1 encoding var genes during the chronic phase of blood stage infection in the dry season, a time during which new P. falciparum-specific antibodies seem not to be produced.
Thus, we now aim to understand how expression variant surface antigens such as PfEMP1 are modulated during the 6-month dry season. Specifically, we will determine which type of PfEMP1 genes are expressed by parasites during the dry season and how effectively they are detected by the immune system. We will sequence the transcribed PfEMP1 genes of individuals carrying chronic and asymptomatic P. falciparum parasites at different time-points during the six-month dry season to establish if specific variants are selected during this time, and at which rate new variants emerge. We will also determine the dynamics of humoral responses to different PfEMP1s during the dry season. These results will reveal if certain PfEMP1 types or traits are associated with asymptomatic infection in the dry season, and how pressure from the immune system contributes to PfEMP1 variant switching.
References:
S, Portugal, Tran TM, Ongoiba A, Bathily A, Li S, Doumbo S, Skinner J, Doumtabe D, Kone Y, Sangala J, Jain A, Davies DH, Hung C, Liang L, Ricklefs S, Homann MV, Felgner PL, Porcella PF, Färnert A, Doumbo OK, Kayentao K, Greenwood BM, Traore B, Crompton PD. Treatment of chronic asymptomatic Plasmodium falciparum infection does not increase the risk of clinical malaria upon reinfection. Clinical infectious Diseases 2017

Storm, J.; Craig, A. G., Pathogenesis of cerebral malaria--inflammation and cytoadherence. Front Cell Infect Microbiol 2014, 4, 100.

Kaestli, M.; Cockburn, I. A.; Cortes, A.; Baea, K.; Rowe, J. A.; Beck, H. P., Virulence of malaria is associated with differential expression of Plasmodium falciparum var gene subgroups in a case-control study. J Infect Dis 2006, 193 (11), 1567-74.

Kirchgatter, K.; Portillo Hdel, A., Association of severe noncerebral Plasmodium falciparum malaria in Brazil with expressed PfEMP1 DBL1 alpha sequences lacking cysteine residues. Mol Med 2002, 8 (1), 16-23.

Jespersen, J. S.; Wang, C. W.; Mkumbaye, S. I.; Minja, D. T.; Petersen, B.; Turner, L.; Petersen, J. E.; Lusingu, J. P.; Theander, T. G.; Lavstsen, T., Plasmodium falciparum var genes expressed in children with severe malaria encode CIDRalpha1 domains. EMBO Mol Med 2016, 8 (8), 839-50.

Lavstsen, T.; Turner, L.; Saguti, F.; Magistrado, P.; Rask, T. S.; Jespersen, J. S.; Wang, C. W.; Berger, S. S.; Baraka, V.; Marquard, A. M.; Seguin-Orlando, A.; Willerslev, E.; Gilbert, M. T.; Lusingu, J.; Theander, T. G., Plasmodium falciparum erythrocyte membrane protein 1 domain cassettes 8 and 13 are associated with severe malaria in children. Proc Natl Acad Sci U S A 2012, 109 (26), E1791-800.
Methods that will be used:
cell culture, molecular biology, qRT-PCR, DNA and RNAseq…
Cooperation partners:
Peter Crompton (NAID, NIH), Boubacar Traore (FMPOS, ICER
Mali), Thomas Lavstsen (Copenhagen University), Antoine Claessens (MRC The Gambia)
Personal qualifications:
- Graduate or Master’s Degree in Biology or related areas;
- Work practice in Plasmodium infection is desirable; as well as some
experience/knowledge of cell culture, q-RT PCR, bioinformatics and statistics
- Excellent knowledge of spoken and written English
- Excellent communication skills and team spirit; organizational skills and ability to
keep detailed records of experiments;
- Critical mind and enthusiasm;) and ability to work in multidisciplinary and
multicultural teams.
Keywords:
Plasmodium falciparum, malaria, dry season, var genes, PfEMP1