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Microglial cells initiate vigorous yet non-protective immune responses during HSV-1 brain infection
Cristina P Marques1, Shuxian Hu, Wen Sheng
1Center for Infectious Diseases and Microbiology Translational Research, University of Minnesota Medical School, Minneapolis, USA.
Abstract:
Central nervous system (CNS) infection with herpes simplex virus (HSV)-1 triggers neuroinflammatory responses leading to peripheral immune cell infiltration into the brain. Previous in vitro studies from our laboratory, using primary human brain cells, implicated microglia as the cellular source of infection-induced chemokines, such as CXC ligand 10 (CXCL10) and CC ligand 2 (CCL2). Here, we evaluated the role of microglial cells in HSV-induced neuroimmune responses using an in vivo murine model of herpes encephalitis. Data obtained during this study demonstrated robust levels of CXCL10, CCL2 and CXCL9 detectable in the brains of infected BALB/c mice between 5 and 8 days post-infection (p.i.). Microglial cells were identified as a source of this HSV-induced chemokine production. Additional experiments established that induction of these immune mediators preceded the presence of CD3, CD4, CD8, and CD45 mRNA in the brain, and immunohistochemical analysis confirmed the presence of infiltrating CD3(+) cells. Further analysis suggested that microglia-derived chemokines drive peripheral immune cell chemotaxis, as antibodies to CXCL10 and CCL2 blocked the migration of murine splenocytes toward HSV-infected microglia by approximately 59.3+/-4.1% and 17.5+/-1.4%, respectively. Taken together, these results demonstrate that a vigorous microglia-driven cascade of pro-inflammatory immune responses is not sufficient to protect susceptible mice from HSV-1 brain infection.
Insights
Microglia drive neuroinflammation in herpes simplex virus (HSV)-1 brain infections by producing chemokines. However, this response is insufficient to protect susceptible mice from herpes encephalitis.
Area of Science:
- Neuroimmunology
- Virology
- Cellular Biology
Background:
- Herpes simplex virus (HSV)-1 infection of the central nervous system (CNS) causes neuroinflammation.
- Microglia are implicated as key cells in producing chemokines during HSV-1 infection.
- Peripheral immune cell infiltration into the brain is a hallmark of CNS viral infections.
Purpose of the Study:
- To investigate the role of microglial cells in HSV-induced neuroimmune responses in vivo.
- To determine if microglia are the primary source of chemokines during herpes encephalitis.
- To assess the impact of microglia-derived chemokines on peripheral immune cell migration.
Main Methods:
- Utilized a murine model of herpes encephalitis (HSV-1 infection).
- Quantified chemokine levels (CXCL10, CCL2, CXCL9) in infected mouse brains.
- Identified chemokine-producing cells using immunohistochemistry.
- Assessed immune cell infiltration (CD3, CD4, CD8, CD45 mRNA).
- Blocked chemokine function using specific antibodies to evaluate immune cell migration.
Main Results:
- Elevated levels of CXCL10, CCL2, and CXCL9 were detected in infected mouse brains.
- Microglial cells were confirmed as the source of these HSV-induced chemokines.
- Chemokine induction preceded significant immune cell infiltration into the brain.
- Antibodies against CXCL10 and CCL2 partially inhibited murine splenocyte migration towards HSV-infected microglia.
Conclusions:
- Microglia initiate a pro-inflammatory chemokine cascade in response to HSV-1 brain infection.
- Microglia-derived chemokines play a role in attracting peripheral immune cells to the infected brain.
- Despite the microglia-driven response, susceptible mice are not protected from herpes encephalitis.
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