Abstract
Viral infections of the central nervous system (CNS) lead to a broad range of pathologies. CNS infections with Orthopox viruses have been mainly documented as an adverse reaction to smallpox vaccination with vaccinia virus. To date, there is insufficient data regarding the mechanisms underlying pathological viral replication or viral clearance. Therefore, informed risk assessment of vaccine adverse reactions or outcome prediction is limited. This work applied a model of viral infection of the CNS, comparing neurovirulent with attenuated strains. We followed various parameters along the disease and correlated viral load, morbidity, and mortality with tissue integrity, innate and adaptive immune response and functionality of the blood–brain barrier. Combining these data with whole brain RNA-seq analysis performed at different time points indicated that neurovirulence is associated with host immune silencing followed by induction of tissue damage-specific pathways. In contrast, brain infection with attenuated strains resulted in rapid and robust induction of innate and adaptive protective immunity, followed by viral clearance and recovery. This study significantly improves our understanding of the mechanisms and processes determining the consequence of viral CNS infection and highlights potential biomarkers associated with such outcomes.
Highlights
Viral infection of the central nervous system (CNS) is associated with a broad spectrum of clinical manifestations ranging from asymptomatic to lethal disease
We show that at early post-infection (p.i.) stages, during the asymptomatic incubation period, Vaccinia Virus (VACV)-WR exerted robust immune silencing within the CNS that coincided with robust virus replication
No differences were observed between the virulence of VACV-Western Reserve (VACV-WR) and that of VACV-WRvFire at the indicated viral doses and route of infection, suggesting that the vFire cassette does not affect the virulence of the virus at the tested conditions
Summary
Viral infection of the central nervous system (CNS) is associated with a broad spectrum of clinical manifestations ranging from asymptomatic to lethal disease. Components of the immune system that have a role in controlling viral infections of the CNS include the innate and adaptive immune systems and local, brain-resident immune components. Viruses and bacteria have developed different strategies to evade these obstacles and penetrate the brain [1]. Poxviruses are not considered typical encephalitic or meningitic viruses, in certain circumstances, they can penetrate and infect the CNS. Historical anecdotal reports indicated that in addition to the known manifestations of smallpox, there are indications of severe encephalomyelitis following VARV infection of the CNS [2,3,4]. Previous reports indicate that in certain rare circumstances encephalitis developed following smallpox vaccination, considered as postvaccinal encephalitis [5,6,7,8]
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