Viral factors responsible for Lassa virus pathogenicity

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Lassa virus (LASV) is endemic in West African countries and causes outbreaks of LF annually. Although LASV is one of the most alarming pathogens from a public health perspective, there are few effective vaccines or therapeutics against LF. LASV must be handled at biosafety level 4 (BSL-4), due to its high pathogenicity. This is one of the largest barriers to the development of preventive or therapeutic approaches against LF. Furthermore, animal models of LF are limited, which is essential for basic research and development of countermeasures. Recently, we developed a novel guinea pig model of LF and found that LASV strain LF2384 and LF2350 have completely different pathogenic phenotypes in guinea pigs. These two viruses have been isolated from human LF patients and pathogenicity of these viruses in guinea pigs is consistent with human cases. These unique combinations of immunocompetent rodent model and clinical isolated LASVs are strong tools, which allow us to reveal viral factors responsible for pathogenicity and molecular mechanisms underlying LASV pathogenicity. During K99 phase, we revealed that RNA-dependent RNA polymerase (L) is the determinant factor of pathogenic differences between LASV LF2384 and LF2350 by using the reverse genetic system and in vivo evaluation. While significant progress has been made in determining the pathogenic viral factor, much less is understood about the host response related to LASV pathogenesis. Therefore, in the proposed study, we will determine host factors responsible for LASV pathogenicity by using reverse genetics and in vivo experiments, and reveal novel molecular mechanisms of LASV L protein underlying LASV pathogenesis by using several in vitro molecular techniques. We will address this goal through three specific aims. In Specific Aim 1, we will reveal the pathophysiology of LASV infection in guinea pigs. In Specific Aim 2, we will determine the domain or amino acid residue(s) in L responsible for LASV pathogenicity by using reverse genetics and in vivo study. In Specific Aim 3, we will unveil molecular mechanisms underlying LASV pathogenicity. Taken together, we hope to address novel pathogenic mechanisms of LASV infection, leading to new insights to develop countermeasures against LF.