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Principal Investigator: Junki Maruyama
Organization: UNIVERSITY OF TEXAS MED BR GALVESTON
Fiscal Year: 2023
Award: $249,000
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <Acute><Address><Africa><African><Amino Acids><Animal Model><Animal Models and Related Studies><Annual Reports><Arenaviridae><Arenaviridae Infections><Arenavirus><Arenavirus Infections><Arenavirus group><BSL-4 facility><BSL4 facility><Basic Research><Basic Science><Biologic Containment><Biological><Biological Containment><Bleeding><Blood><Blood Reticuloendothelial System><Case Fatality Rates><Cavia><Classification><Clinical><Clinical Chemistry><Clinical Data><Containment><Country><DNA Molecular Biology><Data><Development><Development and Research><Disease><Disease Outbreaks><Disorder><Dysfunction><EC 2.7.7.48><Family member><French Guinea><Functional disorder><Goals><Groups at risk><Guinea><Guinea Pigs><Guinea Pigs Mammals><Hematology><Hemorrhage><Histopathology><Host Factor><Host Factor Protein><Human><Immune response><Immunochemical Immunologic><Immunocompetent><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><In Vitro><Infection><Integration Host Factors><Laboratories><Lassa Fever><Lassa disease><Lassa fever virus><Lassa virus><Liberia><Methods><Modeling><Modern Man><Molecular><Molecular Biology><Nigeria><Outbreaks><Pathogenesis><Pathogenicity><Pathogenicity Factors><Pathologic><Patients><People at risk><Persons at risk><Phase><Phenotype><Physiopathology><Populations at Risk><Preventive><Proteins><Public Health><R & D><R&D><RNA Replicase><RNA-Dependent RNA Polymerase><RNA-Directed RNA Polymerase><Recombinants><Research><Risk><Rodent Model><Safety><Sensorineural Deafness><Sensorineural Hearing Loss><Sensory Hearing Loss><Sierra Leone><System><Systematics><Techniques><Therapeutic><Vaccines><Viral><Viral Diseases><Viral Gene Products><Viral Gene Proteins><Viral Genome><Viral Pathogenesis><Viral Proteins><Virulence><Virulence Factors><Virus><Virus Diseases><aminoacid><biologic><biosafety level 4 facility><blood loss><cost><developmental><experiment><experimental research><experimental study><experiments><guinea pig model><hospitalization rates><host response><immune competent><immune system response><immunoresponse><improved><in vivo><in vivo Model><in vivo evaluation><in vivo testing><insight><model of animal><non-human primate><nonhuman primate><novel><pathogen><pathogenic virus><pathophysiology><research and development><reverse genetics><sensorineural hearing impairment><tool><viral infection><viral pathogen><virus genome><virus infection><virus pathogen><virus pathogenesis><virus protein><virus-induced disease>