Direct evidence for the adaptive role of copy number variation on antifolate susceptibility in Plasmodium falciparum. Issue 4 (24th April 2013)

• Record Type: Journal Article
• Authors: Heinberg, Adina; Siu, Edwin; Stern, Chaya; Lawrence, Elizabeth A.; Ferdig, Michael T.; Deitsch, Kirk W.; Kirkman, Laura A.
• Is Part Of: Molecular microbiology. Volume 88:Issue 4(2013)
• Page Start: 702
• Page End: 712
• Publication Date: 2013-04-24
• Subjects: Molecular microbiology -- Periodicals; 572.829
• DOI: 10.1111/mmi.12162
• Languages: English
• ISSNs: 0950-382X

Abstract

<abstract abstract-type="main"> <title>Summary</title> <p>Resistance to antimalarials targeting the folate pathway is widespread. GTP‐cyclohydrolase (<italic>gch1</italic>), the first enzyme in this pathway, exhibits extensive copy number variation (CN) in parasite isolates from areas with a history of longstanding antifolate use. Increased CN of <italic>gch1</italic> is associated with a greater number of point mutations in enzymes targeted by the antifolates, pyrimethamine and sulphadoxine. While these observations suggest that increases in <italic>gch1</italic> CN are an adaptation to drug pressure, changes in CN have not been experimentally demonstrated to directly alter drug susceptibility. To determine if changes in <italic>gch1</italic> expression alone modify pyrimethamine sensitivity, we manipulated <italic>gch1</italic> CN in several parasite lines to test the effect on drug sensitivity. We report that increases in <italic>gch1</italic> CN alter pyrimethamine resistance in most parasites lines. However we find evidence of a detrimental effect of very high levels of <italic>gch1</italic> overexpression in parasite lines with high endogenous levels of <italic>gch1</italic> expression, revealing the importance of maintaining balance in the folate pathway and implicating changes in <italic>gch1</italic> expression in preserving proper metabolic flux. This work expands our understanding of parasite adaptation to drug pressure and provides a possible mechanism for how specific mutations become fixed within parasite populations.</p> </abstract>