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Oral 4`fluorouridine rescues nonhuman primates from advanced Lassa fever

ABSTRACT: There are no approved treatments for Lassa fever (LF) 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 (4`-FlU; EIDD-2749), an orally available ribonucleoside analog, protected guinea pigs from lethal challenge with the lineage IV prototype Josiah strain of Lassa virus (LASV) when treatment was delayed beyond the onset of clinical signs of disease. Here, we assessed the therapeutic efficacy of 4`-FlU in a novel African green monkey model of LF using the more contemporary and seemingly more pathogenic lineage VII Togo strain of LASV. Daily treatment of 4`-FlU beginning 6 days after LASV infection, when animals were viremic and clinically ill, resulted in 100% protection. Our findings support the further development of 4`-FlU as both a postexposure prophylaxis to control outbreaks and a therapeutic to treat symptomatic patients.

ORGANISM(S): Chlorocebus sabaeus Macaca fascicularis

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.

Project description:Lassa fever (LF) is a rodent-borne viral disease that can be fatal for human beings. In this study, an attenuated Lassa vaccine candidate, ML29, was tested in SIV-infected rhesus macaques for its ability to elicit immune responses without instigating signs of virulent disease. ML29 is a reassortant between Lassa and Mopeia viruses that causes a transient infection in non-human primates and confers sterilizing protection from lethal Lassa viral challenge. However, since the LF endemic area of West Africa also has high HIV seroprevalence, it is important to determine whether vaccination could be safe in the context of AIDS. SIV-infected and uninfected rhesus macaques were vaccinated with the ML29 virus and monitored for classical and non-classical signs of arenavirus disease. Classical disease signs included viremia, rash, weight loss, high liver enzyme levels, and virus invasion of the central nervous system. Non-classical signs derived from profiling the blood transcriptome of virulent and non-virulent arenavirus infections included increased expression of interferon response genes and decreased expression of COX2, IL-1?, coagulation intermediates and nuclear receptors needed for stress signaling. Here it is demonstrated that SIV-infected and uninfected rhesus macaques responded similarly to ML29 vaccination, and that none developed signs of arenavirus disease or persistence. Furthermore, 5 of 5 animals given a heterologous challenge with a lethal dose of LCMV-WE survived without developing disease signs. 30 RNA samples from Monkey PBMC: 4 uninf. Monkey PBMC, 8 SIV-infected Monkey PBMC(From 8 Monkeys), 5 SIV+ML29-sc infected week1(Monkey PBMC), 5 SIV+ML29-sc infected week2(Monkey PBMC), 1 SIV+ML29-ig infected week1(Monkey PBMC), 1 SIV+ML29-ig infected week2(Monkey PBMC), 2 SIV+Arm-sc infected week1(Monkey PBMC), 2 SIV+Arm-sc infected week2(Monkey PBMC), 1 only ML29-iv infected week1(Monkey PBMC), 1 only ML29-iv infected week2(Monkey PBMC)

Project description:Rhesus macaques (Macaca mulatta) infected with a lethal dose of lymphocytic choriomeningitis virus-strain WE (LCMV-WE) provide a model for Lassa fever virus infection of man. Like Lassa fever in human beings, disease begins with flu-like symptoms but can progress to morbidity fairly rapidly. Previously, we profiled the blood transcriptome of LCMV-infected monkeys (M. Djavani et al. J. Virol. 2007: PMID 17522210) showing distinct pre-viremic and viremic stages that discriminated between virulent and benign infections. In the present study, changes in liver gene expression from macaques infected with virulent LCMV-WE were compared to gene expression in uninfected monkeys as well as to monkeys that were infected but not diseased. We observed gene expression changes that occurred before the viremic stage of the disease, and could potentially serve as biomarkers that discriminate between exposure to a hemorrhagic fever virus and exposure to a benign virus. Based on a functional pathway analysis of differentially expressed genes, virulent LCMV-WE had a much broader effect on liver cell function than non-virulent virus. During the first few days of infection, virulent virus impacted gene expression associated with the generation of energy, such as fatty acid metabolism and glucose metabolism, with the complement and coagulation cascades, and with steroid metabolism, MAPK signaling and cell adhesion. For example, the energy profile resembled that of an organism entering starvation: acetyl-CoA carboxylase, a key enzyme of fatty acid synthesis, was shut down and gene products involved in gluconeogenesis were up-regulated. In conclusion, this study identifies several potential gene markers of LCMV-WE-associated liver disease and contributes to the database of gene expression changes correlated with LCMV pathogenesis in primates. 6 groups: uninfected controls, LCMV-WE infected (pre-viremic; day 1 to day 3), LCMV-WE infected (viremic; day 4 to day 7), LCMV-WE infected (post-viremic; day 8 to day 12), LCMV-Armstrong (LCMV-ARM; non-virulent strain) infected, and LCMV-ARM/LCMV-WE infected but not diseased. Each sample is from the liver of a different rhesus macaque.

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Oral 4`fluorouridine rescues nonhuman primates from advanced Lassa fever

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