Biology subjects

Asai, Y.

Publications and source records attributed to Asai, Y..

4 recordsLinked to original sources

bioRxiv2025

Evaluating the impact of NPC1 SNPs on entry efficiency of Filovirus in vitro: agent-based model approach

The interaction between the Niemann-Pick C1 (NPC1) protein and the glycoprotein (GP) of filoviruses is essential for viral entry into host cells. Single nucleotide polymorphisms (SNPs) in NPC1, which lead to amino acid substitutions, can significantly alter viral entry efficiency. However, the quantitative impact of these SNPs remains unclear. To address this, we investigate in vitro cell-to-cell infection using a plaque assay with vesicular stomatitis virus (VSV) expressing Ebola and Marburg GP. We employe an agent-based model (ABM) to estimate entry efficiency by simulating plaque growth, enabling a comparative analysis of SNP-specific effects on viral entry. Our quantitative analysis reveals that D508N, P424A, and S425L substitutions in NPC1 reduce entry efficiency in both viruses. These findings provide insights into host-pathogen interactions and demonstrate the value of ABM in virology research, potentially guiding therapeutic strategies targeting viral entry mechanisms. Author summaryEbola and Marburg viruses are highly pathogenic filoviruses that cause severe hemorrhagic fever in humans, with case fatality rates reaching around 50%. These viruses pose significant public health challenges due to their potential for large-scale outbreaks. A key step in their infection process is the interaction between the Niemann-Pick C1 (NPC1) protein on host cells and the viral glycoprotein, which facilitates viral entry. Genetic variations in NPC1 caused by single nucleotide polymorphisms (SNPs) can lead to amino acid substitutions, potentially altering the efficiency of viral entry. To better understand this process, we developed an agent-based model, a computational approach that simulates individual cell interactions and provides spatial resolution not achievable with traditional modeling techniques, to simulate viral plaque growth in vitro. By applying this model, we quantified how specific NPC1 substitutions, such as D508N, P424A, and S425L, affect the entry efficiency of Ebola and Marburg viruses. Our findings highlight the potential of computational modeling to uncover the impact of genetic variations on viral infections and provide insights that may inform therapeutic strategies against these deadly viruses.

systems biology↗

bioRxiv2020

Light-dependent induction of Edn2 expression and attenuation of retinal pathology by endothelin receptor antagonists in Prominin-1- deficient mice

Retinitis pigmentosa (RP) and macular dystrophy (MD) are prevalent retinal degenerative diseases associated with gradual photoreceptor death. These diseases are often caused by genetic mutations that result in degeneration of the retina postnatally after it has fully developed. The Prominin-1 gene (Prom1) is a causative gene for RP and MD, and Prom1- knockout (KO) mice recapitulate key features of these diseases including light-dependent retinal degeneration and stenosis of retinal blood vessels. The mechanisms underlying progression of such degeneration have remained unknown, however. We here analysed early events associated with retinal degeneration in Prom1-KO mice. We found that photoreceptor cell death and glial cell activation occur between 2 and 3 weeks after birth. High-throughput analysis revealed that expression of the endothelin-2 gene (Edn2) was markedly up-regulated in the Prom1-deficient retina during this period. Expression of Edn2 was also induced by light stimulation in Prom1-KO mice that had been reared in the dark. Finally, treatment with endothelin receptor antagonists attenuated photoreceptor cell death, gliosis, and retinal vessel stenosis in Prom1-KO mice. Our findings suggest that inhibitors of endothelin signalling may delay the progression of RP and MD and therefore warrant further study as potential therapeutic agents for these diseases.

neuroscience↗

bioRxiv2019

Modeling the efficiency of filovirus entry into cells in vitro: Effects of SNP mutations in the receptor molecule

Interaction between filovirus glycoprotein (GP) and the Niemann-Pick C1 (NPC1) protein is essential for membrane fusion during virus entry. Some single-nucleotide polymorphism (SNPs) in two surface-exposed loops of NPC1 are known to reduce viral infectivity. However, the dependence of differences in entry efficiency on SNPs remains unclear. Using vesicular stomatitis virus pseudotyped with Ebola and Marburg virus GPs, we investigated the cell-to-cell spread of viruses in cultured cells expressing NPC1 or SNP derivatives. Eclipse and virus-producing phases were assessed by in vitro infection experiments, and we developed a mathematical model describing spatial-temporal virus spread. This mathematical model fit the plaque radius data well from day 2 to day 6. Based on the estimated parameters, we found that SNPs causing the P424A and D508N substitutions in NPC1 most effectively reduced the entry efficiency of Ebola and Marburg viruses, respectively. Our novel approach could be broadly applied to other virus plaque assays. Author SummaryEbola virus belongs to the family Filoviridae, together with Marburg virus and Cueva virus. In 2015, the World Health Organization included Ebola and Marburg viruses among the infectious diseases that should be globally prioritized because these filoviruses can cause severe hemorrhagic fever in humans and nonhuman primates, and antiviral agents to these viruses are very limited. Filovirus particles bear the envelope glycoprotein (GP), which is the only viral surface protein and thus responsible for receptor binding and membrane fusion. Interaction between filovirus GP and the Niemann-Pick C1 (NPC1) protein is essential for membrane fusion during virus entry. Some single-nucleotide polymorphism (SNPs) in two surface-exposed loops of NPC1 are known to reduce viral infectivity. However, the dependence of differences in entry efficiency on SNPs remains unclear. In this study, combining in vitro experiments and mathematical models, we evaluated on the interaction between GP and wildtype and mutant NPC1, enabling us to estimate the cellular entry efficiency during plaque formation.

microbiology↗

bioRxiv2019

Two strategies underlying the trade-off of hepatitis C virus proliferation: stay-at-home or leaving-home?

Viruses proliferate through both genome replication inside infected cells and transmission to new target cells or to new hosts. Each viral genome molecule in infected cells is used either for amplifying the intracellular genome as a template (\"stay-at-home strategy\") or for packaging into progeny virions to be released extracellularly (\"leaving-home strategy\"). The balance between these strategies is important for both initial growth and transmission of viruses. In this study, we used hepatitis C virus (HCV) as a model system to study the functions of viral genomic RNA in both RNA replication in cells and in progeny virus assembly and release. Using viral infection assays combined with mathematical modelling, we characterized the dynamics of two different HCV strains (JFH-1, a clinical isolate, and Jc1-n, a laboratory strain), which have different viral assembly and release characteristics. We found that 1.27% and 3.28% of JFH-1 and Jc1-n intracellular viral RNAs, respectively, are used for producing and releasing progeny virions. Analysis of the Malthusian parameter of the HCV genome (i.e., initial growth rate) and the number of de novo infections (i.e., initial transmissibility) suggests that the leaving-home strategy provides a higher level of initial transmission for Jc1-n, while, in contrast, the stay-at-home strategy provides a higher initial growth rate for JFH-1. Thus, theoretical-experimental analysis of viral dynamics enables us to better understand the proliferation strategies of viruses. Ours is the first study to analyze stay-leave trade-offs during the viral life cycle and their significance for viral proliferation.

evolutionary biology↗