Noncytolytic Clearance of Sindbis Virus Infection from Neurons by Gamma Interferon Is Dependent on Jak/Stat Signaling

Abstract

The alphavirus Sindbis virus (SINV) causes encephalomyelitis in mice byAlphaviruses in the family Togaviridae are enveloped, plusstrand, mosquito-borne RNA viruses that can cause encephalomyelitis. Sindbis virus (SINV), the prototype alphavirus, causes arthritis and rash in humans (39, 48) and encephalomyelitis in mice, a small-animal model for study of the pathogenesis of acute encephalitis (32). Age is an important determinant of outcome, and neonatal mice die within the first few days after infection, while older mice clear SINV from the central nervous system (CNS) within 6 to 8 days without signs of paralysis or neurological damage (33,40). Maturity of the infected neuron determines the level of virus replication and the susceptibility to SINV-induced cell death independent of the immune response (28,43,46,56). Immature neurons replicate SINV to higher titers and are susceptible to virus-induced apoptosis, while mature neurons are intrinsically more resistant to SINV replication and survive virus infection (3, 4, 43). Recovery from infection requires immune-mediated clearance of virus from these surviving infected neurons.Because mature neurons are terminally differentiated cells with limited capacity for regeneration, recovery that does not result in neuronal damage requires noncytolytic, rather than the more traditional cytolytic, immune mechanisms for virus clearance. Antibody is produced, T cells begin to infiltrate the CNS 3 to 4 days after infection, and virus clearance begins shortly thereafter (19,50,52). Type I interferon (IFN) is essential for initial control of virus replication (5, 6, 17, 69), and both humoral (6, 43, 77) and cellular (3, 37) arms of the adaptive immune response play important roles in clearance. Mice deficient in all components of adaptive immunity (SCID or Rag Ϫ/Ϫ ) develop persistent nonfatal infection, and passive transfer of SINV antibody results in clearance of infectious virus from the CNS and decreased viral RNA without neurologic damage, indicating an important role for antibody in noncytolytic clearance (34). However, mice deficient in antibody (MT) are able to reduce levels of SINV in the cortex and hippocampus of the brain compared to SCID mice and to clear infectious virus from the brain stem and spinal cord through local production of IFN-␥, indicating a role for T cells in clearance from some, but not all, types of neurons (3). Studies with mice deficient in production of both IFN-␥ and antibody indicate a synergistic role for these mediators in clearing SINV from the CNS, but the mechanisms are not known (5).To identify mechanisms of immune-mediated clearance, various in vitro systems have been developed. CSM14.1 neuronal cells that have been differentiated in vitro become persistently infected with SINV, and treatment with IFN-␥ results in virus clearance and improved cell survival (4, 79). Characterization of the response of infected differentiated neurons to treatment with IFN-␥ has shown a transient increase in synthesis of viral RNA and protein 6 h after tre...

Differentiation of Neurons Restricts Arbovirus Replication and Increases Expression of the Alpha Isoform of IRF-7

“…6B). This confirmed results of previous studies showing a lack of STAT1 phosphorylation during SINV infection of AP-7 or CSM14.1 neurons (62).…”

“…The protective role of IFNs against encephalitic virus infections has been demonstrated in other in vitro systems and in vivo. Pretreatments of a variety of cultured cells, including neurons, with IFN-␣, -␤, or -␥ prevents more than 99% of infectious SINV production, significantly reduces synthesis of viral proteins, and preserves cellular viability and protein synthesis (20,62,70). The G3A mutation in VEEV TC-83 renders this strain responsive to IFN-␣/␤ priming and is correlated with decreased mortality in weanling mice (25,26,70).…”

Model-based rational design of an oncolytic virus with improved therapeutic potential

“…Production of IFN from IP cells allows these cells to transition into an 'activated population' (AP) where viral defenses slow virus release and further enhance IFN production. Over time, this population will gradually become a 'protected population' (PP) of cells that have cleared the infection and maintain active antiviral defense programmes [22][23][24] .…”

Arthrogenic Alphaviruses and Inflammatory Myopathies

“…Similar studies have been done using SINV infection in immunodeficient SCID or RAG-1 deficient mice. The studies found the clinical outcomes of SINV infection in immunodeficient neonatal mice to be comparable to that in immunocompetent neonatal mice (Burdeinick-Kerr et al, 2009;Levine & Griffin, 1993). Results of these studies suggest that the adaptive immune response does not play a role in the development of RRV-induced myositis and is not essential in the clinical outcome of alphaviral disease.…”