Mouse hepatitis virus is cleared from the central nervous systems of mice lacking perforin-mediated cytolysis

Abstract

Perforin-deficient [perforin (؊/؊)] mice were infected with two strains of JHM virus (JHMV) to analyze the role of perforin-mediated cytotoxicity in acute lethal and subacute central nervous system (CNS) infections. During both acute and subacute infections, the overall mortality of the perforin (؊/؊) mice was not different from that of the controls. Perforin (؊/؊) mice survived longer than the controls, consistent with reduced morbidity. Both strains of virus were cleared from the perforin (؊/؊) mice as in the controls; however, the rate of clearance was delayed in the perforin (؊/؊) mice, indicating that perforin-mediated cytolysis is involved in viral clearance. The absence of perforin-mediated cytolysis did not prevent encephalomyelitis or extensive demyelination. Cells undergoing apoptosis were detected in the CNS of both the perforin (؊/؊) and control groups, indicating that perforin is not essential for programmed cell death. Neutralizing antibodies were not detected in either group of mice until day 9 postinfection, when the majority of the virus had been cleared. These data further confirm the importance of cell-mediated cytotoxicity and suggest that additional components of the immune response contribute to the clearance of JHMV from the CNS.

Reduced Macrophage Infiltration and Demyelination in Mice Lacking the Chemokine Receptor CCR5 Following Infection with a Neurotropic Coronavirus

“…IFN-␥ has been determined to exert a potent antiviral effect in MHV-infected mice, leaving these data to be somewhat surprising. However, it is possible that reduced levels of IFN-␥ protein are present in infected CCR5 Ϫ/Ϫ mice and/or that expression of other antiviral effector molecules such as perforin are reduced compared to CCR5 ϩ/ϩ mice (Lin et al, 1997). CCR5 Ϫ/Ϫ mice expressed increased levels of mRNA transcripts for CCL5 at day 12 when compared to CCR5 ϩ/ϩ mice.…”

Regulation of t cell responses during central nervous system viral infection

“…Whether this is the result of organ-specific differences in levels of MHC antigen expression is unclear, but viral clearance without the actual destruction of infected neurons, a nonrenewable cell population, would certainly be advantageous to the host. There now is convincing evidence in other systems that the antiviral actions of CD8 ÷ T cells within the CNS depend on their local production of soluble mediators such as interferon-y (IFN-y), and not on direct perforin-mediated cytolysis of target cells (Kfindig et al, 1993;Lin et al, 1997). In sum, while more than one mechanism may underlie their effects, it is clear that T cells can promote viral clearance from the CNS in many situations.…”

Epstein–Barr virus-induced gene 3 negatively regulates neuroinflammation and T cell activation following coronavirus-induced encephalomyelitis

“…JHMV infection results in an acute encephalomyelitis characterized by wide-spread replication primarily in astrocytes and oligodendrocytes with relatively few neurons being infected (Knobler et al, 1981;Buchmeier and Lane, 1999;Parra et al, 1999;Perlman et al, 1999;Bergmann et al, 2006). Control of viral replication during acute disease relies on virus-specific CD8 + T cells, which function by two different effector mechanisms within the CNS: IFN-γ secretion is responsible for controlling viral replication in oligodendrocytes whereas a perforindependent mechanism promotes viral clearance from astrocytes (Lin et al, 1997;Parra et al, 1999). Infiltrating CD4 + T cells provide a supporting role for the maintenance and expansion of CTLs within the CNS, as well as enhancing effector responses (Stohlman et al, 1998;Phares et al, 2012).…”