Immune-Mediated Control of Persistent Measles Virus Infection in the Central Nervous System
Katelynn A. Milora1, Katelyn D. Miller1,2, Christine M. Matullo1, Kevin J. O'Regan1, Riley M. Williams1, Glenn F. Rall1
1Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia PA
2Program in Cell and Molecular Biology, University of Pennsylvania, Philadelphia PA
The ability of large DNA viruses, such as herpesviruses, to infect the CNS and cause long-term infection with periodic reactivation has been well documented. Although not often associated with recurrent infections, genomic material from neurotropic RNA viruses has been shown to persist within the CNS long after resolution of acute disease. While these viral remnants are not commonly thought to reemerge into an active infection, it has been suggested that persistence of viral RNA and proteins contribute to fatal CNS diseases such as subacute sclerosing panencephalitis (SSPE), which can occur months to years following acute measles virus infection. Due to the inability of measles virus to infect murine neurons, our lab has created a transgenic mouse model in which the human measles virus receptor, CD46, is expressed under the transcriptional control of a neuron-specific promoter, neuron-specific enolase (NSE). Intracranial infection of these transgenic mice with the vaccine strain of measles virus, MV-Edmonston, results in no pathogenesis in immunocompetent mice, whereas mice deficient in RAG2 developed unrestricted neuronal infection leading to severe CNS disease and death. Surprisingly, RNA remnants were detected in immunocompetent NSE-CD46+ mice months after acute infection, despite no signs of illness. Upon lethal irradiation of NSE-CD46+ mice 90 days post infection, followed by bone marrow reconstitution from RAG KO mice, a significant portion of mice became moribund and experienced seizures and motor dysfunction that appeared distinct from symptoms preceding death during acute infections. Furthermore, this long-term tolerance was maintained through IFN production by CD103+ T-resident memory cells recruited to the parenchyma. Taken together, these studies help to elucidate mechanisms of immune-mediated control of long-term viral infections within the CNS.