Identification of Factors Contributing to Pathogenic Variability Among Lassa Virus Strains Using the Guinea Pig Model and Reverse Genetics

TL;DR

This study identifies the L protein as a key factor in the differing pathogenicity of two Lassa virus strains using guinea pigs and reverse genetics.

Contribution

The study identifies the L protein as a novel critical viral factor for Lassa virus pathogenicity.

Findings

The L protein is responsible for pathogenic differences between LASV strains LF2384 and LF2350.

Host immune gene expression kinetics differ between the two LASV strains in guinea pigs.

Reverse genetics and animal models reveal molecular mechanisms of LASV pathogenicity.

Abstract

Lassa virus (LASV) is the causative agent of Lassa fever (LF), a severe hemorrhagic disease with potential for lethal outcomes. Classified as a risk group 4 pathogen, it represents a significant public health threat in endemic regions. Our laboratory previously developed a novel lethal guinea pig model of Lassa fever using the clinical isolate LASV strain LF2384. However, the specific pathogenic factors underlying LF2384 infection in guinea pigs remained unclear. In this study, we aimed to investigate the immunological differences elicited by LF2384 and LF2350, another LASV strain isolated from a nonlethal case within the same outbreak. We compared the expression kinetics of key immune-related genes in guinea pigs infected with either LF2384 or LF2350. Using reverse genetics, we identified the L protein as a critical viral factor responsible for the observed pathogenic differences between the strains.

Using reverse genetics and animal models with 2 Lassa virus (LASV) strains exhibiting contrasting phenotypes, we identified host and viral factors that contribute to LASV pathogenicity. The findings in this study offer insight into the molecular mechanisms underlying LASV infection.

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