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Oral 4`fluorouridine rescues nonhuman primates from advanced Lassa fever

ABSTRACT: There are no approved treatments for Lassa fever, which is estimated to cause 100,000 to 300,000 infections and 5,000 deaths annually in West Africa. Recently, it was shown that 4'-fluorouridine (also known as EIDD-2749), an orally available ribonucleoside analogue, protected guinea pigs from lethal challenge with the lineage IV prototype Josiah strain of Lassa virus when treatment was delayed beyond the onset of clinical signs of disease. Here we assessed the therapeutic efficacy of 4'-fluorouridine in an African green monkey model of Lassa fever using the contemporary and apparently more pathogenic lineage VII Togo strain of Lassa virus. Daily treatment with 4'-fluorouridine beginning 6 days after Lassa virus infection, when the monkeys were viraemic and clinically ill, resulted in rapid and complete clearance of infectious virus in 4 out of 5 monkeys, and all treated monkeys survived to the pre-determined study end-point. Targeted transcriptomics showed that cellular responses and control of cytokinaemia contributed to the development of immunity. Our findings support the further development of 4'-fluorouridine both as a post-exposure prophylaxis to control outbreaks and as a therapeutic agent to treat symptomatic patients.

ORGANISM(S): Macaca fascicularis Chlorocebus sabaeus

PROVIDER: GSE294797 | GEO | 2025/10/08

REPOSITORIES: GEO

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Project description:Lassa fever virus (LASV) is a significant human pathogen that is endemic to several countries in West Africa. Infection with Lassa leads to the development of hemorrhagic fever in a significant number of public health cases and it is considered a potential bioweapon. Little is known about the complex immune mechanisms governing response to LASV infection, or the genetic determinants of susceptibility and resistance to infection. In the study presented here, we have used a whole-genome, microarray-based approach to determine the temporal host response to infection in the peripheral blood mononuclear cells of non-human primates (NHP) infected with LASV. Sequential sampling over the entire disease course showed that there are specific transcription signatures of the immune response to LASV infection, including the rapid up- regulation of interferon-responsive genes and toll-like receptor signaling pathways. However, this increase in early innate responses was coupled with a lack of pro- inflammatory cytokine response in LASV infected NHPs. There was a distinct lack of cytokines such as IL1b and IL23a, while immune suppressive cytokines such as IL27 and IL6 were upregulated. Comparison of cytokine gene expression with the amount of detectable protein in Lassa infected NHPs suggests that gene expression precedes the protein detection and thus is possibly a better tool for early diagnostics of the disease. Our results provide a comprehensive picture of the immune response to hemorrhagic LASV infection and provide a foundation for biomarker identification to allow clinical diagnosis of Lassa infection through analysis of the host response. RNA was isolated from a total of 46 PBMC samples from 15 cynomologus macaques infected with Lassa Virus. Samples were obtained at sequential timepoints post-infection, and included a pre-infection specimen from each animal. A subset of 30 samples (11 animals) were then processed and hybridized onto the Agilent 2-color arrays.

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Oral 4`fluorouridine rescues nonhuman primates from advanced Lassa fever

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