Growing up in the Caribbean, Maudry Laurent-Rolle, MD, PhD, assistant professor (infectious diseases), was no stranger to cases of dengue, and yellow fever across the Caribbean, South and Central America. This is where her interest in flaviviruses and arthropod-borne viruses first began. In graduate school, she further pursued this interest focusing her research on dengue, West Nile, and yellow fever. More specifically, exploring how these viruses circumvented the host immune response.
As a postdoctoral fellow under the mentorship of Peter Cresswell, PhD, FRS, Eugene Higgins Professor of Immunobiology and professor of cell biology, Yale School of Medicine (YSM), she developed an interest in how interferon stimulated genes prevented viral infections to identify novel host factors that could be targeted for therapeutic intervention.
“I initially focused on understanding the molecular mechanisms that viperin use to restrict viral replication. After work from the Almo group showed that the novel enzyme, cytidylate monophosphate kinase 2 (CMPK2) creates the substrate cytidine triphosphate (CTP) which viperin uses to generate an active intermediate, 3ʹ-deoxy-3′,4ʹ-didehydro-CTP, an antiviral molecule critical for viperin functions, I initiated similar studies on CMPK2 and Zika virus,” said Laurent-Rolle.
Laurent-Rolle calls CMPK2 “the coolest protein,” and her work on this protein has led to a new publication, CMPK2 restricts Zika virus replication by inhibiting viral translation, on which Laurent-Rolle is the senior author. Her mentor Cresswell serves with Laurent-Rolle as co-corresponding author.
The research team from YSM, University of Texas Medical Branch, Albert Einstein College of Medicine, and University of California, Riverside, looked into whether the CMPK2 protein could inhibit Zika virus replication, independent of viperin. They showed that the N-terminal domain of CMPK2 and not the known kinase domain, which produces CTP for viperin, is sufficient for its antiviral function by specifically inhibiting viral translation. They also showed that CMPK2 inhibits the replication of other medically relevant flaviruses, such as dengue virus, Kunjin virus, a subset of West Nile virus, and yellow fever.
“This is exciting. Independent of viperin, we have this new protein that seems to be targeting flaviviruses,” explained Laurent-Rolle.
Laurent-Rolle credits her post-doctoral associate and lead author on the paper, Joanna Pawlak, MSc, PhD, for her hardwork to push this project to publication, in addition to second author Jack Chun-Chieh Hsu, PhD. Chun-Chieh, assistant professor at Rutgers University, is a long-time collaborator with Laurent-Rolle who she credits as an expert in translation.
Laurent-Rolle admits that because she is also a clinician, she is always thinking about therapeutics. “How can you translate the antiviral activity of CMPK2 into a clinically useful compound? As a therapeutic? As prophylaxis? There will be more viral epidemics and pandemics and we should be working on all fronts to blunt the impact of arthropod-borne viruses on public health when new outbreaks occur.”
She is also looking at flaviruses from many other angles. In one project, she is part of a team working to prevent the mosquitoes themselves from transmitting diseases such as Zika, dengue, and yellow fever.
In addition to Laurent-Rolle, Cresswell, Pawlak and Chun-Chieh, other authors are Hongjie Xia, PhD; Patrick Han; Hee-Won Suh, PhD; Tyler L. Grove, PhD; Juliet Morrison, PhD; and Pei-Yong Shi, PhD.
Read more in “CMPK2 restricts Zika virus replication by inhibiting viral translation” in PLOS Pathogens.