Synergistic Roles of Antibody and Interferon in Noncytolytic Clearance of Sindbis Virus from Different Regions of the Central Nervous System

Abstract

Sindbis virus (SINV) is an alphavirus that causes infection of neurons and encephalomyelitis inSindbis virus (SINV) is an arthropod-borne alphavirus of the family Togaviridae, related to eastern equine encephalitis and western equine encephalitis viruses. In humans, SINV infection results in diseases ranging from a self-limiting flu-like illness to fever, polyarthritis, and rash. In mice, SINV infects neurons of the central nervous system (CNS) (26, 27), resulting in a well-characterized encephalomyelitis (19). The severity of disease in infected mice is dependent on the viral strain and the age and genetic background of the mouse (26,27,51,55,58). While neonatal mice die within the first few days of infection, adult immunocompetent mice clear infectious virus within 8 days after infection without neurological sequelae. Although infectious virus has not been detected after clearance, viral RNA is not completely eliminated, and the independent contributions of various components of the immune response to long-term control of virus replication are not known (28,32,34,56). As a result, SINV-induced encephalomyelitis is an excellent model for identification of innate and adaptive immune responses critical for control and clearance of virus from the CNS and for prevention of reactivation.Because neurons are terminally differentiated cells with very limited capacity for regeneration, recovery from encephalomyelitis requires noncytolytic mechanisms for clearance of intracellular virus. Antiviral antibody is one important mechanism. Passive transfer of antibodies to persistently infected severe combined immunodeficiency (SCID) mice clears infectious SINV from all regions of the CNS, but virus production resumes as antibody levels decline (34, 35). However, mice unable to make antibodies can clear infectious virus from the brain stem and spinal cord, but not the brain, at least in part through the action of gamma interferon (IFN-␥) produced by CD4 ϩ and CD8 ϩ T cells (6). Furthermore, CD8 ϩ T-cell-deficient mice clear SINV from the CNS through the production of antibody, but clearance of viral RNA is delayed, suggesting an independent contribution of cellular immunity to noncytolytic virus clearance (29). In vitro, IFN-␥ treatment of differentiated neurons infected with SINV restores cellular protein synthesis and downregulates viral RNA transcription and protein synthesis, facilitating activation of cellular mechanisms that lead to neuron survival and virus clearance (7). These studies suggested that T cells play a synergistic role with the humoral response in virus clearance from the CNS.However, even in mice with normal antibody and T-cell responses, the innate immune response is essential for initial control of SINV replication and prevention of death. Mice deficient in either the type I IFN-␣/␤ receptor or the IFNactivated transcription factor Stat-1 succumb to alphavirus infection and die before mounting a virus-specific immune response (8, 61). In vitro, treatment of infected cells with antibody to the SINV E2 gly...

Upon Intranasal Vesicular Stomatitis Virus Infection, Astrocytes in the Olfactory Bulb Are Important Interferon Beta Producers That Protect from Lethal Encephalitis

“…VSV infection induced similar IFN-␣ serum responses in WT and IFN-␤ Ϫ/Ϫ mice. This is in line with previous findings that upon infection with VSV, Sindbis virus, or Friend virus, IFN-␣ induction was independent of IFN-␤ (6,28,29).…”

In Semliki Forest virus encephalitis, antibody rapidly clears infectious virus and is required to eliminate viral material from the brain, but is not required to generate lesions of demyelination

“…Persistence of infectious virus for months in the brain is also observed in athymic nu/nu and SCID mice infected with SFV A7(74) and, as in the current study, levels of infectious virus show considerable variation between individual mice (Amor et al, 1996;Fazakerley et al, 1993). The TE strain of Sindbis virus has also been observed to persist for weeks in the brains of SCID and mMT mice (Burdeinick-Kerr et al, 2007;Levine et al, 1991). Clearly, at least for alphaviruses, antibody is required to clear infectious virus from the CNS.…”

Effector CD4+T-Cell Involvement in Clearance of Infectious Herpes Simplex Virus Type 1 from Sensory Ganglia and Spinal Cords

“…A role for CD4 ϩ T cells in supporting protective antibody within the CNS has been shown in studies of West Nile virus (55). In studies of infection with Sindbis virus and mouse hepatitis virus, antibody has been shown to be critical for the prevention of virus reactivation within the CNS (7,49). In our HSV model, we noted greatly diminished HSV-specific B-cell and CD8…”