Gamma Interferon Is Critical for Neuronal Viral Clearance and Protection in a Susceptible Mouse Strain following Early Intracranial Theiler's Murine Encephalomyelitis Virus Infection

Abstract

A major area of investigation in neurovirology is directed toward understanding the factors that participate in neuronal viral clearance versus viral persistence. Clearance of virus from the infected central nervous system (CNS) is unique because of the intact blood-brain barrier, the relative absence of major histocompatibility complex (MHC) molecules on neuronal cells, and the lack of well-established lymphatic drainage. Nevertheless, once viruses replicate in the CNS, there is a vigorous immune response directed toward the clearance of virus antigen from infected cells. Antibody plays a critical role in neutralizing extracellular viral particles and also has been proposed to participate in the clearance of intracellular virus (4, 21). However, the manner in which antibody enters cells or interacts with surface cellular receptors to prevent viral persistence in neurons is not well understood.The classical way in which intracellular virus is eliminated is by cytotoxic T cells that are restricted by class I MHC. The control of MHC expression on neurons is dependent upon electrical activity (36). Neurons with normal electrical activity suppress MHC expression, whereas silent or injured neurons up-regulate class I MHC expression, an activity that makes them susceptible to class I MHC-mediated injury. Disruption of electrical activity induces class II MHC expression on microglia and astrocytes (36). Following virus infection in the CNS, class I MHC is rapidly up-regulated (1, 26) in neuronal cells. In particular, soluble factors such as alpha/beta interferon (IFN-␣/␤) (39) are required for the up-regulation of MHC in most CNS cells, including neurons. Cytotoxic T-cell responses in brain infiltrating mononuclear inflammatory cells have been demonstrated (23,24,25,28) and have been shown to participate in viral clearance. However, the consequences to the CNS are a "double-edged sword." Virus is cleared at the expense of the destruction of neurons that are not renewable and whose death results in permanent functional deficits. For example, cytotoxic T cells have been shown to transect neurites expressing class I MHC (31). Therefore, this vigorous cytotoxic response may participate directly in immune-mediated pathology.However, there are examples where viruses are cleared from the CNS without significant destruction of brain parenchyma (2). In these situations, the hypothesis proposed is that factors secreted by cytotoxic lymphocytes participate in viral clearance without cytotoxicity. Of the factors that are secreted by immune cells and that are thought to play a critical role in viral clearance, IFN-␥ has received the most attention (33). IFN-␥ is a 50-kDa N-glycosylated noncovalent homodimer composed of two identical 17-kDa polypeptides. It is produced by activated NK cells and T cells. IFN-␥ induces many immunomodulatory effects on CNS cells, including activation of macrophages, promotion of leukocyte adhesion to allow trafficking of cells to the * Corresponding author. Mailing address:

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“…Instead, the factors secreted by cells in the inflammatory infiltrate may control virus infection in neurons and other CNS cells. Gamma interferon (IFN-␥) has been shown in several model systems to be essential for virus control in the CNS (27,46,48). Other cytokines such as interleukin-6 (IL-6) may also help protect neurons from virus injury (35).…”

“…We used the VP2 fragment of TMEV, a viral capsid region of DA virus, for reverse transcription-PCR (RT-PCR) (48). The primer pair sequences for VP2 of DA virus were as follows: 5Ј-TGGTCGACTCTGTGGTTACG-3Ј (forward) and 5Ј-GCCGGTCTTGCAA AGATAGT-3Ј (reverse).…”

“…We removed the brain and spinal cords from animals infected with TMEV. Total RNA was extracted from brain and spinal cord (48). Briefly, the tissues were frozen and stored in liquid nitrogen.…”