title: Lausannevirus Encodes a Functional Dihydrofolate Reductase Susceptible to Proguanil.
abstract: Lausannevirus belongs to the familyMarseilleviridaewithin the group of nucleocytoplasmic large DNA viruses (NCLDVs). These giant viruses exhibit unique features, including a large genome, ranging from 100 kb to 2.5 Mb and including from 150 to more than 2,500 genes, as well as the presence of genes coding for proteins involved in transcription and translation. The large majority of Lausannevirus open reading frames have unknown functions. Interestingly, a bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS) is encoded in the Lausannevirus genome. The enzyme plays central roles in DNA precursor biosynthesis. DHFR is the pharmacological target of antifolates, such as trimethoprim, pyrimethamine, and proguanil. First, the functionality of Lausannevirus DHFR-TS was demonstrated by the successful complementation of a DHFR-deficientSaccharomyces cerevisiaestrain with a plasmid expressing the heterologous gene. Additionally, using this heterologous expression system, we demonstrated thein vitrosusceptibility of Lausannevirus DHFR-TS to proguanil and its resistance to pyrimethamine and trimethoprim. Proguanil may provide a unique and useful treatment if Lausannevirus proves to be a human pathogen. To our knowledge, this is the first time that a DHFR-TS has been described and characterized in an NCLDV.
authors.affiliation: Institute of Microbiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Mueller
authors.affiliation: Institute of Microbiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: P M
authors.initials: PM
authors.lastname: Hauser
authors.affiliation: Institute of Microbiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Gauye
authors.affiliation: Institute of Microbiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland gilbert.greub@chuv.ch.
authors.forename: G
authors.initials: G
authors.lastname: Greub
mesh_terms: D004267:DNA Viruses / Q000201:enzymology* / Q000235:genetics*; D004789:Enzyme Activation / Q000187:drug effects; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D002727:Proguanil / Q000494:pharmacology*; D011739:Pyrimethamine / Q000494:pharmacology; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D013940:Thymidylate Synthase / Q000378:metabolism*; D014295:Trimethoprim / Q000494:pharmacology
chemical_list: D005493:Folic Acid Antagonists; D014295:Trimethoprim; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase; D002727:Proguanil; D011739:Pyrimethamine
keywords: DHFR-TS; Lausannevirus; antifolate drugs; folate metabolism; proguanil