Systemic viral spreading and defective host responses are associated with fatal Lassa fever in macaques

Nicolas Baillet,Stéphane Barron,Richard Allan,Frédéric Jacquot,Cathy Boehringer,Stéphanie Reynard,Grégory Jouvion,Aurélie Duthey,Hervé Raoul,Marie‐Agnès Dillies ,Caroline Picard,Émeline Perthame ,Alexandra Journeaux,Natalia Pietrosemoli,Audrey Vallvé ,Catherine Legras-Lachuer,Rachel Legendre,Mathieu Mateo,Laura Barrot,Caroline Carbonnelle,Xavier Carnec,Jimmy Hortion,Justine Schaeffer,Sylvain Baize

doi:10.1038/s42003-020-01543-7

Abstract

Lassa virus (LASV) is endemic in West Africa and induces a viral hemorrhagic fever (VHF) with up to 30% lethality among clinical cases. The mechanisms involved in control of Lassa fever or, in contrast, the ensuing catastrophic illness and death are poorly understood. We used the cynomolgus monkey model to reproduce the human disease with asymptomatic to mild or fatal disease. After initial replication at the inoculation site, LASV reached the secondary lymphoid organs. LASV did not spread further in nonfatal disease and was rapidly controlled by balanced innate and T-cell responses. Systemic viral dissemination occurred during severe disease. Massive replication, a cytokine/chemokine storm, defective T-cell responses, and multiorgan failure were observed. Clinical, biological, immunological, and transcriptomic parameters resembled those observed during septic-shock syndrome, suggesting that similar pathogenesis is induced during Lassa fever. The outcome appears to be determined early, as differentially expressed genes in PBMCs were associated with fatal and non-fatal Lassa fever outcome very early after infection. These results provide a full characterization and important insights into Lassa fever pathogenesis and could help to develop early diagnostic tools.

Highlights

Lassa virus (LASV) is endemic in West Africa and induces a viral hemorrhagic fever (VHF) with up to 30% lethality among clinical cases
The cascade of pathogenic mechanisms leading to systemic shock and death during Lassa fever, as well as the immune responses involved in the control of LASV infection, are poorly understood
We describe a model of fatal and nonfatal Lassa fever in the relevant non-human primates (NHPs) model based on infection by LASV strains isolated from fatal human cases belonging to clade 4 or 59

Summary

Introduction

Lassa virus (LASV) is endemic in West Africa and induces a viral hemorrhagic fever (VHF) with up to 30% lethality among clinical cases. Our current understanding of the pathogenesis and immune response comes from animal models but is still limited Animals, such as immunocompromised mice and strain 13 guinea pigs, are widely used to screen vaccines and therapeutics, but they fail to mirror human disease[12,13,14,15]. We further explored the pathogenesis of Lassa fever and the immune responses induced by LASV by infecting cynomolgus monkeys with two different LASV strains: Josiah and AV, using the same dose and route of inoculation. We performed a full characterization of Lassa fever pathophysiogenesis in an NHP model by analyzing clinical pathology, viral tropism and dynamics, histopathological changes, cytokine profile, immune responses, and transcriptomic signatures that are associated with fatal and nonfatal Lassa fever during the course of infection and disease

Methods

Results

Conclusion