Fas/FasL-Mediated Apoptosis and Inflammation Contribute to Recovery from HSV-2-Mediated Spinal Cord Infection

Area of Science:

• Neuroimmunology
• Virology
• Cellular Immunology

Background:

• Herpes simplex virus type 2 (HSV-2) causes persistent infections, leading to genital herpes and, rarely, meningitis.
• The role of the Fas/FasL pathway in the central nervous system (CNS) during HSV-2 meningitis is not fully understood.

Purpose of the Study:

• To investigate the role of the Fas/FasL pathway in the murine model of HSV-2 meningitis.
• To determine the impact of Fas/FasL deficiency on disease severity, viral load, and immune responses within the CNS.

Main Methods:

• Utilized a murine model of HSV-2 meningitis.
• Analyzed Fas and FasL expression in CNS cells (microglia, astrocytes, infiltrating immune cells).
• Assessed disease progression, morbidity, mortality, CNS viral load, immune cell infiltration (CD4+ T-cells), cytokine/chemokine levels, and microglia polarization (M1/M2) in wild-type and Fas/FasL-deficient mice.
• Performed in vitro experiments to confirm the role of Fas/FasL in leukocyte apoptosis and glial cell cytokine production.

Main Results:

• Fas and FasL were induced in the CNS during HSV-2 infection.
• Mice lacking Fas or FasL exhibited increased disease severity, higher mortality, and elevated viral loads in the CNS.
• Fas/FasL-deficient mice showed impaired inflammatory responses, reduced CD4+ T-cell infiltration, lower Th1 cytokine levels, and altered microglia polarization.
• In vitro studies confirmed Fas/FasL's requirement for leukocyte apoptosis and adequate glial cell cytokine/chemokine production.

Conclusions:

• The Fas/FasL cell death receptor pathway is a critical defense mechanism in the spinal cord against HSV-2 meningitis.
• This pathway regulates HSV-2-induced inflammation by down-regulating excessive inflammation while promoting effective anti-viral immune responses.