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Systemic viral dissemination and inflammation associate with fatal outcome in a new African green monkey mucosal exposure model of Lassa fever

ABSTRACT: Lassa virus (LASV) is the causative agent of Lassa fever (LF) and causes significant human morbidity and mortality in endemic areas of West Africa. LF is listed by the World Health Organization as one of the diseases posing the greatest threat to public health due to its pandemic potential and lack of medical countermeasures suitable for human use. Animal models are needed to test the efficacy of candidate vaccines and treatments and therapies to combat LF. Previous studies have shown that cynomolgus monkeys of Asian origin best reproduce clinical features of human LF. However, because of the worldwide shortage of macaques caused by the COVID-19 pandemic, research on high consequence pathogens including LASV has been severely hindered. To address this problem, we assessed the pathogenic potential of a contemporary LASV isolate in both Mauritius origin cynomolgus monkeys and African green monkeys (AGM) to find a more available alternative nonhuman primate species to model LF. Here, we show similarity in transcriptomic host responses related to interferon signaling, cytokinemia, and immune cell deregulation; however, AGMs more consistently reproduced hallmark features of lethal human LF better than Maurits origin cynomolgus macaques with AGMs developing more overt hemorrhagic manifestations closer to that seen in humans. We further show that the LD50 of LASV of AGMs exposed by a natural mucosal route is approximately 27 PFU. This low LD50 further highlights the concern about the public health threat posed by LASV. Our data support the further development and use of AGMs to test promising vaccines and treatments for LF.

ORGANISM(S): Macaca fascicularis Chlorocebus sabaeus

PROVIDER: GSE290786 | GEO | 2025/06/27

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)

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Systemic viral dissemination and inflammation associate with fatal outcome in a new African green monkey mucosal exposure model of Lassa fever

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