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

Autor:	Westover JB; Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, Utah, USA.; Institute for Antiviral Research, Utah State University, Logan, Utah, USA., Jung KH; Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, Utah, USA.; Institute for Antiviral Research, Utah State University, Logan, Utah, USA., Alkan C; Department of Pathology, The University of Texas Medical Branch, Galveston, Texas, USA., Boardman KM; Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, Utah, USA.; Institute for Antiviral Research, Utah State University, Logan, Utah, USA., Van Wettere AJ; Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, Utah, USA.; Utah Veterinary Diagnostic Laboratory, Logan, Utah, USA., Martens C; Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA., Rojas I; Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, Utah, USA.; Institute for Antiviral Research, Utah State University, Logan, Utah, USA., Hicks P; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Thomas AJ; Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, Utah, USA.; Center for Integrated BioSystems, Utah State University, Logan, Utah, USA., Saindane MT; Emory Institute for Drug Development, Emory University, Atlanta, Georgia, USA., Bluemling GR; Emory Institute for Drug Development, Emory University, Atlanta, Georgia, USA., Mao S; Emory Institute for Drug Development, Emory University, Atlanta, Georgia, USA., Kolykhalov AA; Emory Institute for Drug Development, Emory University, Atlanta, Georgia, USA.; Drug Innovation Ventures at Emory (DRIVE), Atlanta, Georgia, USA., Natchus MG; Emory Institute for Drug Development, Emory University, Atlanta, Georgia, USA., Bates P; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Painter GR; Emory Institute for Drug Development, Emory University, Atlanta, Georgia, USA.; Drug Innovation Ventures at Emory (DRIVE), Atlanta, Georgia, USA.; Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia, USA., Ikegami T; Department of Pathology, The University of Texas Medical Branch, Galveston, Texas, USA.; The Sealy Institute for Vaccine Sciences, The University of Texas Medical Branch, Galveston, Texas, USA.; The Center for Biodefense and Emerging Infectious Diseases, The University of Texas Medical Branch, Galveston, Texas, USA., Gowen BB; Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, Utah, USA.; Institute for Antiviral Research, Utah State University, Logan, Utah, USA.
Jazyk:	angličtina
Zdroj:	Journal of virology [J Virol] 2024 Apr 16; Vol. 98 (4), pp. e0013224. Date of Electronic Publication: 2024 Mar 21.
DOI:	10.1128/jvi.00132-24
Abstrakt:	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 preclinical development of a promising new antiviral drug candidate, EIDD-2749. Our findings shed light on how the virus causes disease and support the continued development of EIDD-2749 as a therapeutic for severe cases of HRTV infection. Competing Interests: G.R.B. and G.R.P. are coinventors on patent WO 2019/1736002 covering the composition of matter and use of EIDD-2749 and its analogs as an antiviral treatment. All other authors declare that they have no competing interests.
Databáze:	MEDLINE
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