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Two modes of pseudorabies virus neuroinvasion and lethality in mice
Elizabeth E Brittle1, Ashley E Reynolds, L W Enquist
1Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Abstract:
We describe two distinct modes of neuroinvasion and lethality after murine flank inoculation with virulent and attenuated strains of pseudorabies virus (PRV). Mice infected with virulent (e.g., PRV-Becker, PRV-Kaplan, or PRV-NIA3) strains self-mutilate their flank skin in response to virally induced pruritus, die rapidly with no identifiable symptoms of central nervous system (CNS) infection such as behavioral abnormalities, and have little infectious virus or viral antigen in the brain. In distinct contrast, animals infected with an attenuated PRV vaccine strain (PRV-Bartha) survive approximately three times longer than wild-type PRV-infected animals, exhibit severe CNS abnormalities, and have an abundance of infectious virus in the brain at the time of death. Interestingly, these animals have no skin lesions and do not appear pruritic at any time during infection. The severe pruritus and relatively earlier time until death induced by wild-type PRV infection may reflect the peripheral nervous system (PNS) and immune responses to infection rather than a fatal, virally induced CNS pathology. Based on previously characterized afferent (sensory) and efferent (motor) neuronal pathways that innervate the skin, we deduced that wild-type virulent strains transit through the PNS via both afferent and efferent routes, whereas PRV-Bartha travels by only efferent routes in the PNS en route to the brain.
Insights
Virulent pseudorabies virus (PRV) strains cause pruritus and rapid death via peripheral nervous system (PNS) routes. In contrast, attenuated PRV vaccine strains cause central nervous system (CNS) disease and delayed mortality.
Area of Science:
- Virology
- Neuroscience
- Immunology
Background:
- Pseudorabies virus (PRV) is a significant pathogen with varying virulence.
- Understanding PRV neuroinvasion pathways is crucial for vaccine development and disease control.
- Distinct clinical presentations suggest different routes of viral entry and progression.
Purpose of the Study:
- To elucidate the differential neuroinvasion and lethality mechanisms of virulent and attenuated PRV strains in mice.
- To investigate the role of the peripheral nervous system (PNS) and central nervous system (CNS) in PRV pathogenesis.
- To compare the distinct clinical outcomes and viral distribution following infection with different PRV strains.
Main Methods:
- Murine flank inoculation with virulent (PRV-Becker, PRV-Kaplan, PRV-NIA3) and attenuated (PRV-Bartha) strains.
- Clinical observation for symptoms including pruritus, self-mutilation, and behavioral abnormalities.
- Assessment of viral load and antigen presence in the brain and skin.
- Analysis of viral transit routes through afferent and efferent neuronal pathways in the PNS.
Main Results:
- Virulent PRV strains induced pruritus, self-mutilation, rapid death, and minimal CNS viral presence.
- Attenuated PRV-Bartha strain resulted in delayed mortality, severe CNS abnormalities, and high viral loads in the brain.
- PRV-Bartha infected mice showed no skin lesions or pruritus.
- Virulent PRV strains utilized both afferent and efferent PNS routes, while PRV-Bartha primarily used efferent routes to reach the CNS.
Conclusions:
- The route of neuroinvasion dictates the clinical outcome and pathogenesis of PRV infection.
- Pruritus and rapid death in virulent PRV infections are linked to PNS involvement rather than direct CNS pathology.
- Attenuated PRV strains may preferentially target the CNS via efferent PNS pathways, leading to distinct neurological disease.
