Maruyama Lab Research Project

Viral factors responsible for Lassa virus pathogenicity

Lassa virus (LASV) is a member of family Arenaviridae and causes an acute hemorrhagic disease, Lassa fever (LF), in humans. LASV is endemic in West African countries such as Nigeria, Guinea, Liberia, and Sierra Leone, and outbreaks occur annually. Although an estimated 37.7 million people are at risk for LF, countermeasures against the virus are extremely limited. Due to its high pathogenicity as well as a lack of vaccines and therapeutics, LASV is classified as a Risk Group 4 agent, and must be handled in the highest biological containment facility, biosafety level-4 (BSL-4). This is one of the largest barriers against the development of preventive or therapeutic approaches for LF. In order to develop effective countermeasures against LASV, such as vaccines and therapeutics, understanding the viral factors responsible for its pathogenicity is essential.

Animal models of LF are limited, especially models utilizing clinical isolates representing the various different lineages of LASV. The nonhuman primate (NHP) model, which is the gold standard for LF studies, correlates well with lethal human LF. However, there is a concern about the high cost and numerous safety issues when handling them in high-containment laboratories. Recently, our laboratory developed a novel guinea pig model of LF (Maruyama et al, mSphere, 2019). In this model, outbred Hartley guinea pigs present with a uniformly lethal infection when infected with a clinical isolate of LASV from a lethal LF case, strain LF2384, without any host-virus adaptation. We also found that the LASV isolated form a non-lethal LF case from the same region, strain LF2350, does not induce a lethal infection in guinea pigs. These results indicate that this novel guinea pig LF model could be used to study differences in virulence of various LASVs and that it recapitulates human clinical data. This powerful tool will allow us to study the pathogenic factors of LASV using a combination of molecular biology and in vivo studies.

The long-term goal of our research is to identify the viral factors responsible for LASV pathogenicity and to understand the molecular mechanisms underlying LASV infection. We utilize reverse genetic systems and animal model to reveal pathogenic mechanisms of LASV. These results will provide further biological insights to LASV, a comprehensive understanding of host immune responses, viral factors, and molecular biology in LASV infection, as well as allowing for improved development of preventive and therapeutic methods against LF.

This project was funded by NIH Pathway to Independence Award (Parent K99/R00 Independent Clinical Trial Not Allowed) from NIH.

Development of antivirals against hemorrhagic fever viruses

Many viruses causing hemorrhagic fevers need to be handled in the BSL-4 facility due to their high pathogenicity and lack of preventive or therapeutic methods. To seek the antivirals against hemorrhagic fever viruses, in vitro and in vivo efficacy of antivirals will be evaluated in the BSL-4 laboratory. Our target viruses are filoviruses (Ebola and Marburg viruses), arenaviruses (Lassa, Junin, Machupo, Guanarito, Sabia, and Chapare viruses), henipaviruses (Nipah and Hendra viruses), and Crimean-Congo hemorrhagic fever virus. This is a collaborative project with Hokkaido University (Japan), Bonn University (Germany), and pharmaceutical companies.

This project was funded by U.S.-Japan Cooperative Medical Science Program Collaborative Awards 2021 from CRDF Global and Pilot Grant program from IHII.

Mechanisms of olfactory dysfunction induced by SARS-CoV-2 infection

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is causing the ongoing global pandemic of coronavirus disease 2019 (COVID-19). In addition to life-threatening pneumonia, SARS-CoV-2 infection also causes olfactory dysfunction, which is a unique feature of COVID-19. It has been reported that this olfactory dysfunction occurs in 33.9–85.6% of all COVID-19 cases.

We have previously reported that SARS-CoV-2-infected hamsters exhibit severe damage to the olfactory epithelium of the nasal turbinates as early as 3 days post-infection, and the olfactory behavioral test confirmed olfactory dysfunction induced by SARS-CoV-2 infection (Urata et al, ACS Chem Neurosci, 2021; Reyna et al, Sci Reports, 2022). Our developed animal model of olfactory dysfunction is a powerful tool for analyzing the viral factors and host response associated with the olfactory dysfunction in COVID-19 patients.

To reveal the detailed mechanisms of olfactory dysfunction induced by SARS-CoV-2 infection, the objectives of this project are 1) to analyze the host response leading to olfactory dysfunction in the hamster model of COVID-19, 2) to determine viral factors associated with the olfactory dysfunction induced by SARS-CoV-2 infection, and 3) to develop a treatment method against olfactory dysfunction caused by SARS-CoV-2 infection.