Biology subjects

Koyanagi, N.

Publications and source records attributed to Koyanagi, N..

4 recordsLinked to original sources

bioRxiv2023

Regulatory Mimicry of Cyclin-Dependent Kinases by Conserved Herpesvirus Protein Kinases

Herpesviruses encode conserved protein kinases (CHPKs) that target cellular cyclin-dependent kinase (CDK) phosphorylation sites; thus, they are termed viral CDK-like kinases. Tyrosine 15 in the GxGxxG motifs of CDK1 and CDK2, whose phosphorylation down-regulates their catalytic activities, is conserved in the corresponding motifs of CHPKs. We found that herpes simplex virus 2 (HSV-2) CHPK UL13 mimicked the regulatory mechanism of CDKs. This regulatory mimicry was conserved in CHPKs encoded by herpesviruses subclassified into subfamilies other than HSV-2, suggesting CHPKs have regulatory and functional mimicry with CDKs. Phosphorylation of the corresponding Tyr in HSV-2 UL13 was required for the down-regulation of viral replication and pathogenicity, specifically in the central nervous system of mice, and for efficient viral recurrence in guinea pigs. These data highlight the dual impact of the regulatory mimicry of CDKs by CHPK on the fine-tuned regulation of lytic and latent HSV-2 infections in vivo.

microbiology↗

bioRxiv2023

Evasion of APOBEC1-mediated Intrinsic Immunity by a Herpesvirus Uracil DNA Glycosylase Is a Determinant of Viral Encephalitis

Herpes simplex virus 1 (HSV-1) is the most common cause of viral encephalitis, which can be lethal or result in severe neurological defects, even when treated with antiviral therapy. We demonstrated that activation of HSV-1 uracil-DNA glycosylase (vUNG) by phosphorylation, essential for its enzymatic activity, counteracted APOBEC1 to promote viral replication and encephalitis in the central nervous system (CNS) of mice. The activation of vUNG protected HSV-1 genomes from APOBEC1-mediated DNA editing, allowing efficient viral replication to occur. The presence of APOBEC1 markedly improved lethal encephalitis in mice infected with an HSV-1 mutant carrying a mutation in the phosphorylation site and an UNG inhibitor protected wild-type HSV-1-infected mice from lethal encephalitis. These findings re-define vUNG as an important factor that allows evasion from intrinsic anti-viral immunity mediated by APOBEC1 in the CNS, and suggest a new therapeutic approach for the treatment of fetal and critical HSV-1 encephalitis.

microbiology↗

bioRxiv2023

Direct Relationship between Protein Expression and Progeny Yield of Herpes Simplex Virus 1 Unveils a Rate-limiting Step for Virus Production

Although viral protein expression and progeny virus production were independently shown to be highly heterogenous in individual cells, their direct relationship, analyzed by considering their heterogeneities, has not been investigated to date. This study established a system to fractionate cells infected with a herpesvirus based on the levels of the global expression of viral late proteins, which are largely virion structural proteins, and to titrate virus yields in these fractions. This system demonstrated a direct relationship and indicated there was a threshold for the levels of viral late protein expression for progeny virus production and suggested that viral DNA cleavage/packaging was a rate-limiting step for progeny virus production. These findings, which were masked in previous studies performed at the entire population level, have uncovered a sophisticated viral strategy for efficient progeny virus production and shed new light on an effective target for the development of anti-viral drugs.

microbiology↗

bioRxiv2022

Dual Impacts of a Glycan Shield on the Envelope Glycoprotein B of HSV-1: Evasion from Human Antibodies In Vivo and Neurovirulence

Identification of the mechanisms of viral evasion from human antibodies is crucial both for understanding viral pathogenesis and for designing effective vaccines. However, the in vivo efficacy of the mechanisms of viral evasion from human antibodies has not been well documented. Here we show in cell cultures that an N-glycan shield on the HSV-1 envelope glycoprotein B (gB) mediated evasion from neutralization and antibody-dependent cellular cytotoxicity due to pooled {gamma}-globulins derived from human blood. We also demonstrated that the presence of human {gamma}-globulins in mice and HSV-1 immunity induced by viral infection in mice significantly reduced the replication of a mutant virus lacking the glycosylation site in a peripheral organ but had little effect on the replication of its repaired virus. These results suggest that the glycan shield on the HSV-1 envelope gB mediated evasion from human antibodies in vivo and from HSV-1 immunity induced by viral infection in vivo. Notably, we also found that the glycan shield on HSV-1 gB was significant for HSV-1 neurovirulence and replication in the central nervous system (CNS) of naive mice. Thus, we have identified a critical glycan shield on HSV-1 gB that has dual impacts, namely evasion from human antibodies in vivo and viral neurovirulence. IMPORTANCEHSV-1 establishes lifelong latent and recurrent infections in humans. To produce recurrent infections that contribute to transmission of the virus to new human host(s), the virus must be able to evade the antibodies persisting in latently infected individuals. Here we show that an N-glycan shield on the envelope glycoprotein B of HSV-1 mediates evasion from pooled {gamma}-globulins derived from human blood both in cell cultures and mice. Notably, the N-glycan shield was also significant for HSV-1 neurovirulence in naive mice. Considering the clinical features of HSV-1 infection, these results suggest that the glycan shield not only facilitates recurrent HSV-1 infections in latently infected humans by evading antibodies, but is also important for HSV-1 pathogenesis during the initial infection.

microbiology↗