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The pathogenicity of ribonucleotide reductase-null mutants of herpes simplex virus type 1 in mice
Y Yamada1, H Kimura, T Morishima
1Laboratory of Virology, Nagoya University School of Medicine, Japan.
Abstract:
The pathogenicity of ribonucleotide reductase (RR)-null mutants (hrR3 and ICP6 delta) of herpes simplex virus (HSV) type 1 was studied after intracerebral and corneal inoculation in newborn and adult ICR mice. ICP6 delta failed to replicate in brains of mice greater than or equal to 8 days old but exhibited significant virulence for newborn mice as a result of viral replication in the brains. The RR- and a thymidine kinase (TK)-deficient mutant of HSV-1 strain KOS could grow in eye tissues of adult ICR mice. Viral DNA of hrR3 was detected in brain tissues of intracerebrally infected mice or in the trigeminal ganglia of corneally infected mice greater than or equal to 50 days after infection, and infectious hrR3 could be recovered from these tissues by superinfection of the mice with wild-type HSV-2. These observations indicate that pathogenicity of RR- mutants in mice is highly dependent on the physiologic state of tissues infected and that RR- mutants have the ability to establish latency in nervous system tissues of mice by either the peripheral or intracerebral route. It was also demonstrated that the inability of the RR- mutants to invade the central nervous system was efficiently complemented by simultaneous infection with another defective virus, the TK- mutant of KOS.
Insights
Herpes simplex virus (HSV) ribonucleotide reductase (RR)-null mutants show varied pathogenicity in mice, with replication dependent on host age. These RR-deficient HSV mutants can establish latent infections in the nervous system.
Area of Science:
- Virology
- Molecular Biology
- Pathogenesis
Background:
- Herpes simplex virus (HSV) is a significant human pathogen.
- Ribonucleotide reductase (RR) is crucial for viral DNA synthesis.
- Understanding the role of RR in HSV pathogenesis is essential for developing antiviral strategies.
Purpose of the Study:
- To investigate the pathogenicity of HSV type 1 ribonucleotide reductase (RR)-null mutants.
- To determine the influence of host age and tissue type on viral replication and virulence.
- To assess the ability of RR-deficient mutants to establish latent infections.
Main Methods:
- Intracerebral and corneal inoculation of newborn and adult ICR mice with RR-null HSV mutants (hrR3 and ICP6 delta).
- Monitoring viral replication in various tissues, including brain, eyes, and trigeminal ganglia.
- Detection of viral DNA and recovery of infectious virus by superinfection.
Main Results:
- ICP6 delta showed age-dependent virulence, replicating in newborn mouse brains but not in older mice.
- RR-deficient and thymidine kinase (TK)-deficient mutants replicated in adult mouse eye tissues.
- Viral DNA and infectious virus were detected in nervous system tissues up to 50 days post-infection, indicating latency.
- Complementation of CNS invasion defect by co-infection with a TK-deficient mutant was observed.
Conclusions:
- Pathogenicity of RR-null HSV mutants is highly dependent on the physiological state of the host tissues.
- RR-deficient HSV mutants can establish latency in the mouse nervous system via peripheral or intracerebral routes.
- Simultaneous infection with a TK-deficient mutant can complement the inability of RR-mutants to invade the central nervous system.