Towards understanding the SURFIN protein family and var genes in Plasmodium falciparum

Plasmodium falciparum, the parasite responsible for severe malaria, has been shown to use different protein families for its survival and proliferation within the human host. Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), a protein responsible for the cytoadherence of parasitized red blood cells (pRBCs) has been implicated in severe disease. PfEMP1 is transported to the pRBCs surface together with a recently identified surface membrane protein, SURFIN4.2, a member of the SURFIN protein family. SURFINs are encoded by surf genes, which in the parasite clone 3D7, ten paralogs were identified two of which are most likely nonfunctional pseudogenes. However, little understanding about the function of SURFINs in the parasite is known.

This thesis aimed to further describe the SURFIN family and to study var gene expression in organs of fatal malaria patients:

- The gene expression and localization of another member of the family, the surf4.1 gene was analyzed. Previously annotated as a pseudogene, the analysis revealed the surf4.1 gene is a functionally complete gene transcribed from approximately 32hrs post invasion through to the infectious developmental stage, the merozoites.

- Experiments were conducted to identify a potential receptor for the SURFIN4.2, previously shown to be expressed on the surface of pRBC. The analysis involved a wild type CS2 parasite line (CS2WT) and a knockout line where surf4.2 gene was disrupted (CS2deltasurf4.2). Initial data suggests that the receptor, on the RBC surface, is resistant to chymotrypsin and is sensitive to heparin.

- Analysis of the SURFIN family using various bioinformatics tools identified two major groups of SURFINs, GroupA (3 members) and GroupB (4 members), and an intermediate group (2 members). An additional SURFIN did not fit in the above mentioned categories. With the exception of two pseudogenes, the SURFINs were observed to have conserved domains (SCDs) which were predicted to be duplicated and inserted in different locations within the sequence.

- The expression of var genes, that encode for PfEMP1 protein, was studied in various organs of fatal malaria patients. A clear dominance of certain var types in the brain was observed and the var types varied between organs.

List of scientific papers

I. Mphande FA, Ribacke U, Kaneko O, Kironde F, Winter G, Wahlgren M (2008). SURFIN4.1, a schizont-merozoite associated protein in the SURFIN family of Plasmodium falciparum. Malar J. 7: 116
https://pubmed.ncbi.nlm.nih.gov/18593471

II. Mphande FA, Persson K, Maier AG, Cowman AF, Wahlgren M (2009). Investigating a Receptor for Plasmodium falciparum SURFIN4.2 using CS2-wild type and CS2-surf4.2 knock out lines. [Manuscript]

III. Mphande FA, Brick K, Wahlgren M (2009). Dissecting the SURFIN family of Plasmodium falciparum. [Manuscript]

IV. Montgomery J, Mphande FA, Berriman M, Pain A, Rogerson SJ, Taylor TE, Molyneux ME, Craig A (2007). Differential var gene expression in the organs of patients dying of falciparum malaria. Mol Microbiol. 65(4): 959-67. Epub 2007 Jul 6
https://pubmed.ncbi.nlm.nih.gov/17617167