Unraveling factors responsible for pathogenic differences in Lassa virus strains

Lassa virus (LASV) is the etiological agent of Lassa fever (LF), a severe hemorrhagic disease with potential for lethal outcomes. Apart from acute symptoms, LF survivors often endure long-term complications, notably hearing loss, which significantly impacts their quality of life and socioeconomic status in endemic regions of West Africa. Classified as a Risk Group 4 agent, LASV poses a substantial public health threat in affected areas. Our laboratory previously developed a novel lethal guinea pig model of LF utilizing the clinical isolate LASV strain LF2384. However, the specific pathogenic factors underlying LF2384 infection in guinea pigs remained elusive. In this study, we aimed to elucidate the differences in the immunological response induced by LF2384 and LF2350, another LASV isolate from a non-lethal LF case within the same outbreak. Through comprehensive immunological gene profiling, we compared the expression kinetics of key genes in guinea pigs infected with LASV LF2384 and LF2350. Our analysis revealed differential expression patterns for several immunological genes, including CD94, CD19-2, CD23, IL-7, and CIITA, during LF2384 and LF2350 infection. Moreover, through the generation of recombinant LASVs, we sought to identify the specific viral genes responsible for the observed pathogenic differences between LF2384 and LF2350. Our investigations pinpointed the L protein as a crucial determinant of pathogenicity in guinea pigs infected with LASV LF2384. Author summaryLassa virus (LASV) is known to cause lethal hemorrhagic fever, Lassa fever, and is classified as a Risk Group-4 agent, which need to be handled in the highest biocontainment laboratories, biosafety level-4 (BSL-4), due to its high pathogenicity and the lack of preventive or treatment methods. LASV infection has a huge impact on public health and socioeconomics in endemic areas, however, its pathogenic mechanism is still largely unknown. In order to unveil the mechanisms of LASV pathogenesis, we compared the pathogenicity of two LASV isolates, which have opposite phenotypes in guinea pigs. Additionally, we determined the viral factor responsible for pathogenic differences between LASV isolates using reverse genetics. In summary, our study provides valuable insights into the immunological and virological factors underlying the pathogenic differences between LASV strains associated with lethal and non-lethal LF cases. Understanding these distinctions is essential for informing strategies for the diagnosis, treatment, and prevention of LF.