Fas/FasL Contributes to HSV-1 Brain Infection and Neuroinflammation

Abstract

The Fas/FasL pathway plays a key role in immune homeostasis and immune surveillance. In the central nervous system (CNS) Fas/FasL is involved in axonal outgrowth and adult neurogenesis. However, little is known about the role of the Fas/FasL pathway in herpes encephalitis. In this study, we used a neuropathogenic clinical strain of herpes simplex virus type 1 (HSV-1) to explore infection-induced inflammation and immune responses in the mouse brain and the role of Fas/FasL in antiviral CNS immunity. HSV-1 CNS infection induced the infiltration of Fas- FasL-bearing monocytes and T cells in the brain and also to an up-regulation of Fas and FasL expression on resident astrocytes and microglia within infected sites. Upon infection, Fas- and FasL-deficient mice (lpr and gld) were partially protected from encephalitis with a decreased morbidity and mortality compared to WT mice. Fas/FasL deficiency promoted cell-mediated immunity within the CNS. Fas receptor stimulation abrogated HSV-1 induced activation and inflammatory reactions in microglia from WT mice, while lack of Fas or FasL led to a more pronounced activation of monocytes and microglia and also to an enhanced differentiation of these cells into a pro-inflammatory M1 phenotype. Furthermore, the specific immune system was more efficient in Fas- and FasL-deficient mice with significantly higher numbers of infiltrating HSV-1-specific cytotoxic T cells in the brain. Our data indicate that the Fas/FasL pathway leads to excessive neuroinflammation during HSV-1 infection, which is associated with a diminished anti-viral response and an excessive neuroinflammation.

Tripartite-Motif 21 (TRIM21) Deficiency Results in a Modest Loss of Herpes Simplex Virus (HSV)-1 Surveillance in the Trigeminal Ganglia Following Cornea Infection

“…Since the collection of tissue was a single time point, which coincided with when viral titers were assessed, it is possible earlier time points may have been more revealing. Alternatively, other anti-viral mechanisms, including apoptosis [ 69 , 70 ] or necroptosis [ 71 ], may contribute to host defense against HSV-1 infection in the TG, as TRIM21 is associated with the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced necrosome [ 72 ] and, thus, may prevent the use of elements within the cell that facilitate virus replication. At this point, we surmise that the microenvironment, which can include infiltrating myeloid-derived cells and NK cells, as well as the virus pathogen, greatly influences the positive or negative regulation of TRIM21 expression, which ultimately exerts influence on host resistance to virus infection, in this case, HSV-1.…”

Role of Microglia in Herpesvirus-Related Neuroinflammation and Neurodegeneration

“…The activation of microglia and the infiltration of immune cells from the peripheral circulation into the HSV-infected CNS is crucial for limiting viral infection and infection-related inflammation. However, if the virus is not controlled early after infection, an uncontrolled immune response can develop and lead to high mortality and morbidity [ 35 , 36 ].…”

“…Virus-activated microglia produce high amounts of CCL5, CXCL10, TNF, and IL-1β as well as lower amounts of IL-6, IL-8, CCL3, CCL4, and CCL2 in a TLR3-dependent manner [ 2 , 50 ]. Chemokines CCL5, CCL2, and CXCL10 further recruit peripheral immune cells to the infected brain [ 2 , 3 , 36 ], of which CXCL10 in particular has been shown to be important in mounting of HSV-1 specific T cell response [ 50 ]. IFN-β produced by microglia mediates the production of anti-inflammatory IL-10, which can suppress severe inflammation [ 35 ], while IL-6 is protecting from the loss of neurons [ 51 ].…”

“…Upon stimulation of HSV-1 infected microglia through Fas, they become resistant to Fas-mediated apoptosis and down-regulate inflammatory response—production of pro-inflammatory and anti-viral cytokines and chemokines such as CCL2, CXCL9, CXCL10, IFN-α, TNF-α and IL-6 [ 36 ]. HSV-1 infected in vitro cultures of microglia isolated from Fas- and FasL-deficient mice show strong inflammatory responses in comparison to microglia derived from wild type mice [ 36 ].…”

“…Upon stimulation of HSV-1 infected microglia through Fas, they become resistant to Fas-mediated apoptosis and down-regulate inflammatory response—production of pro-inflammatory and anti-viral cytokines and chemokines such as CCL2, CXCL9, CXCL10, IFN-α, TNF-α and IL-6 [ 36 ]. HSV-1 infected in vitro cultures of microglia isolated from Fas- and FasL-deficient mice show strong inflammatory responses in comparison to microglia derived from wild type mice [ 36 ]. Therefore, we propose that HSV-1 can interfere with Fas-mediated pro-inflammatory pathways within the CNS leading to disturbances in Fas-mediated apoptosis and pro-inflammatory response upon migration of FasL bearing lymphocytes into the infected neuronal site [ 36 ].…”