Immune-Mediated Protection from Measles Virus-Induced Central Nervous System Disease Is Noncytolytic and Gamma Interferon Dependent

Abstract

Neurons of the mammalian central nervous system (CNS) are an essential and largely nonrenewable cell population. Thus, virus infections that result in neuronal depletion, either by virus-mediated cell death or by induction of the cytolytic immune response, could cause permanent neurological impairment of the host. In a transgenic mouse model of measles virus (MV) infection of neurons, we have previously shown that the host T-cell response was required for resolution of infection in susceptible adult mice. In this report, we show that this protective response did not result in neuronal death, even during the peak of T-cell infiltration into the brain parenchyma. When susceptible mice were intercrossed with specific immune knockout mice, a critical role for gamma interferon (IFN-␥) was identified in protection against MV infection and CNS disease. Moreover, the addition of previously activated splenocytes or recombinant murine IFN-␥ to MV-infected primary neurons resulted in the inhibition of viral replication in the absence of neuronal death. Together, these data support the hypothesis that the host immune response can promote viral clearance without concomitant neuronal loss, a process that appears to be mediated by cytokines.

CD8 T Cells Require Gamma Interferon To Clear Borna Disease Virus from the Brain and Prevent Immune System-Mediated Neuronal Damage

“…Antibodies seem to play a prominent role in the case of neuronal infection with Theiler's murine encephalitis virus (19), the neurotropic JHM variant of mouse hepatitis virus (17), Sindbis virus (8,37), and rabies virus (51). A contribution of IFN-␥ in viral clearance from neurons has previously been noted in a number of neurotropic virus infections, including vaccinia virus and vesicular stomatitis virus (35,36), measles virus (49,69), neurotropic mouse hepatitis virus (7,48,50), Sindbis virus (8), and lymphocytic choriomeningitis virus (65). However, the strict and exclusive dependence of BDV resistance on IFN-␥ during primary and secondary immune responses is unique.…”

“…The killing of infected cells is an inadequate mechanism in tissues where the regenerative capacity of essential cell populations is limited, such as the central nervous system (CNS). Interferon-␥ (IFN-␥) secreted by antigen-specific CD8 T cells was shown to mediate noncytolytic clearance from neurons of a number of viral pathogens, including measles virus (49), Sindbis virus (8), herpes simplex virus type 1 (40) and lymphocytic choriomeningitis virus (65). IFN-␥ is produced by CD4 Th1 cells, CD8 T cells, and NK cells.…”

Modulation of disease, T cell responses, and measles virus clearance in monkeys vaccinated with H-encoding alphavirus replicon particles

“…In contrast, monkeys depleted of B cells clear infectious virus normally (74), and children with hypogammaglobulinemia recover from infection (75). It is presumed that CD8 ϩ T cells clear virus by killing MV-infected cells, but it is possible that cytotoxic CD4 ϩ T cells or cytokines such as IFN-␥ secreted by CD4 and CD8 T cells inhibit intracellular virus replication and also contribute to clearance (76,77).…”

Immunological thresholds in neurological gene therapy: highly efficient elimination of transduced cells might be related to the specific formation of immunological synapses between T cells and virus-infected brain cells

“…In the CNS, antibodies and IFN-γ mediated mechanisms have been postulated to clear virus infection from neurons through non-cytolytic pathways (Patterson et al, 2002;Griffin, 2003). Non-cytolytic mechanisms might be more frequent in clearing virus from infected neurons, whereas cytotoxic mechanisms might be more common in clearing virus from infected astrocytes and oligodendrocytes (Griffin, 2003).…”