Malaria, a vector-borne disease, causes great morbidity and mortality in tropical and subtropical regions of the world. Crucial to the continuing burden of disease is the parasite’s ability to evade clearance in the host; both the ability to evade the host immune system by changing surface proteins inserted into the host red blood cell, a process termed antigenic variation, and the ability to develop drug resistance. Important to both of these parasite adaptations is the capacity of this eukaryotic pathogen, with a haploid genome for most of its lifecycle, to generate and incorporate DNA mutations. We aim to study malaria DNA recombination and repair in the context of disease pathogenesis, focusing on antigenic variation and the development of drug resistance.
To better understand the generation of genetic diversity within the multi-copy gene family, we are manipulating the parasite genome to determine how the parasite repairs damaged DNA. Similarly, we are studying the mechanisms by which a parasite becomes resistant to antimalarials by focusing on the ways in which the parasites acquire mutations in DNA. Using genetically modified parasites we are studying the ability of the parasite to generate point mutations and gene duplications that have been previously associated with drug resistance in the field. We are able to manipulate both copy number and specific sequences in order to further study the interplay of different pathways implicated in parasite drug resistance.
Heinberg A, Kirkman L. The molecular basis of antifolate resistance in Plasmodium falciparum: looking beyond point mutations. Ann N Y Acad Sci. 2015 Apr;1342(1):10-8.
Kirkman LA, Deitsch KW. Recombination and Diversification of the Variant Antigen Encoding Genes in the Malaria Parasite Plasmodium falciparum. Microbiol Spectr. 2014 Dec;2(6).
Kirkman LA, Lawrence EA, Deitsch KW. Malaria parasites utilize both homologous recombination and alternative end joining pathways to maintain genome integrity. Nucleic Acids Res. 2014 Jan;42(1):370-9.
Kümpornsin K, Modchang C, Heinberg A, Ekland EH, Jirawatcharadech P, Chobson P, Suwanakitti N, Chaotheing S, Wilairat P, Deitsch KW, Kamchonwongpaisan S, Fidock DA, Kirkman LA, Yuthavong Y, Chookajorn T. Origin of robustness in generating drug-resistant malaria parasites. Mol Biol Evol. 2014 Jul;31(7):1649-60.
Calhoun SF, Reed J, Alexander N, Mason CE, Deitsch KW, Kirkman LA. Chromosome End Repair and Genome Stability in Plasmodium falciparum. mBio. 2017 Aug 8;8(4):e00547-17.
Zhang X, Alexander N, Leonardi I, Mason C, Kirkman LA, Deitsch KW. Rapid antigen diversification through mitotic recombination in the human malaria parasite Plasmodium falciparum. PLoS Biol. 2019 May 13;17(5):e3000271.
Siao MC, Borner J, Perkins SL, Deitsch KW, Kirkman LA. Evolution of Host Specificity by Malaria Parasites through Altered Mechanisms Controlling Genome Maintenance. mBio. 2020 Mar 17;11(2):e03272-19.