Modeling Heartland virus disease in mice and therapeutic intervention with 4′-fluorouridine

作者：Jonna B. Westover, Kie Hoon Jung, Cigdem Alkan, Kirsten M. Boardman, Arnaud J. Van Wettere, Craig Martens, Inioska Rojas, Philip Hicks, Aaron J. Thomas, Manohar Saindane, Gregory R. Bluemling, Shuli Mao, Alexander A. Kolykhalov, Michael G. Natchus, Paul Bates, George R. Painter, Tetsuro Ikegami, Brian B. Gowen · 发表于：Journal of Virology · 年份：2024 · DOI：10.1128/jvi.00132-24 · 被引用次数：13 · 研究领域：Viral Infections and Vectors、Vector-Borne Animal Diseases、Vector-borne infectious diseases

Heartland virus (HRTV) is an emerging tick-borne bandavirus that causes a febrile illness of varying severity in humans, with cases reported in eastern and midwestern regions of the United States. No vaccines or approved therapies are available to prevent or treat HRTV disease. Here, we describe the genetic changes, natural history of disease, and pathogenesis of a mouse-adapted HRTV (MA-HRTV) that is uniformly lethal in 7- to 8-week-old AG129 mice at low challenge doses. We used this model to assess the efficacy of the ribonucleoside analog, 4'-fluorouridine (EIDD-2749), and showed that once-daily oral treatment with 3 mg/kg of drug, initiated after the onset of disease, protects mice against lethal MA-HRTV challenge and reduces viral loads in blood and tissues. Our findings provide insights into HRTV virulence and pathogenesis and support further development of EIDD-2749 as a therapeutic intervention for HRTV disease. IMPORTANCE: More than 60 cases of HRTV disease spanning 14 states have been reported to the United States Centers for Disease Control and Prevention. The expanding range of the Lone Star tick that transmits HRTV, the growing population of at-risk persons living in geographic areas where the tick is abundant, and the lack of antiviral treatments or vaccines raise significant public health concerns. Here, we report the development of a new small-animal model of lethal HRTV disease to gain insight into HRTV pathogenesis and the application of this model for the p...