Summary auto-generated
This study investigated neurochemical changes in the brains of mice infected with Semliki Forest virus (SFV) that were protected from lethal encephalitis by co-administration of defective interfering (DI) viruses. While DI viruses completely prevented clinical disease and death, virus still replicated in the central nervous system and systemically. Despite appearing clinically normal, DI-treated mice exhibited significant alterations in brain neurotransmitter levels. On day 4 post-infection, homovanillic acid (a dopamine metabolite) was elevated in some protected mice. Most notably, by day 12 post-infection, glutamate decarboxylase (GAD), which synthesizes the neurotransmitter gamma-aminobutyric acid, was severely decreased in 58-64% of protected mice, with levels dropping to approximately 11-15% of normal values. These neurochemical abnormalities occurred in clinically normal mice with no detectable infectious virus and no visible brain pathology. The changes were transient, returning to normal by day 21. These findings represent a previously undocumented category of infection—subclinical with persistent neurochemical dysfunction—that may have implications for understanding viral contributions to human neurological and neuropsychiatric diseases.
Key findings
- Defective interfering viruses completely prevented lethal SFV encephalitis while allowing viral replication in the CNS and systemically
- Clinically normal, DI-protected mice exhibited severe and selective neurochemical abnormalities, including 250% decreases in GAD activity by day 12 post-infection
- These neurochemical disturbances persisted after infectious virus was cleared and occurred without visible pathological changes
- The neurochemical changes were specific to DI-modulated infection and differed from those seen in lethal infection or avirulent SFV infection
- This subclinical infection model with persistent biochemical dysfunction may provide insights into viral contributions to human neurological diseases
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Abstract
The lethal encephalitis caused in mice by Semliki Forest virus (SFV) is modulated to a subclinical infection by administration of defective interfering SFV, although virus still multiplies both in the central nervous system (CNS) and systemically. Here we report that such infections result in unique and selective changes in the normal levels of CNS neurotransmitters some of which persist after infectious virus can no longer be detected. This represents a previously undocumented category of infection which may have a bearing on the aetiology of those human neurological and neuropsychiatric diseases to which viruses are believed to contribute.