LM MUELLER¹, FG GAUYE¹, PMH HAUSER¹, GG GREUB<sup>1

1</sup>Institute of Microbiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland

Lausannevirus belongs to the Marseilleviridae family, within the Nucleocytoplasmic large DNA viruses (NCLDVs). These giant viruses exhibit unique features, including a large genome, ranging from 100kb to 2.5 Mb and coding from 150 to more than 2500 genes, as well as the presence of genes coding for proteins involved in transcription and translation.
Lausannevirus replication and cell lysis have been reported only in the Acanthamoeba genus (A. castellanii and A. polyphaga). Although the pathogenicity of Lausannevirus towards humans has not been assessed yet, our previous seroepidemiological study showed that humans are exposed to this giant virus. A similar study conducted on blood samples of healthy blood donors also revealed human exposure to the “Giant Blood Marseille-like virus” (GBM). Furthermore, Senegalvirus (another member of the Marseilleviridae family) was isolated from human stools. Therefore, Marseilleviridae are part of the human virome and may affect human health.
Interestingly, comparative genomics analyses showed that a Dihydrofolate reductase (DHFR) encoding gene is present within the Lausannevirus genome. This enzyme catalyses the reduction of dihydrofolate in tetrahydrofolate, which is a precursor of different cofactors involved into the synthesis of several essential metabolites, it is for example a key factor in the purines de novo biosynthesis. DHFR is the main pharmacological target of antifolates such as trimethoprim, pyrimethamine and proguanil. Using a complementation system in the model organism Saccharomyces cerevisiae, the deleted S. cerevisiae DHFR was complemented with a plasmid expressing the heterologous DHFR of Lausannevirus, demonstrating the function of the latter. Using this heterologous expression system, we demonstrated the in vitro sensitivity of the Lausannevirus DHFR to proguanil and its resistance to pyrimethamine and trimethoprim. Proguanil may provide a unique and useful treatment if Lausannevirus and/or Marseillevirus prove to be a human pathogen.