An Early Microglial Response Is Needed To Efficiently Control Herpes Simplex Virus Encephalitis

Abstract

The role of a signaling pathway through macrophage colony-stimulating factor (MCSF) and its receptor, macrophage colony-stimulating factor 1 receptor (CSF1R), during experimental herpes simplex virus 1 (HSV-1) encephalitis (HSE) was studied by two different approaches. First, we evaluated the effect of stimulation of the MCSF/CSF1R axis before infection. Exogenous MCSF (40 μg/kg of body weight intraperitoneally [i.p.]) was administered once daily to BALB/c mice on days 4 and 2 before intranasal infection with 2,500 PFU of HSV-1. MCSF treatment significantly increased mouse survival compared to saline (50% versus 10%; P = 0.0169). On day 6 postinfection (p.i.), brain viral titers were significantly decreased, whereas beta interferon (IFN-β) was significantly increased in mice treated with MCSF compared to mice treated with saline. The number of CD68⁺ (a phagocytosis marker) microglial cells was significantly increased in MCSF-treated mice compared to the saline-treated group. Secondly, we conditionally depleted CSF1R on microglial cells of CSF1R-loxP-CX3CR1-cre/ERT2 mice (in a C57BL/6 background) through induction with tamoxifen. The mice were then infected intranasally with 600,000 PFU of HSV-1. The survival rate of mice depleted of CSF1R (knockout [KO] mice) was significantly lower than that of wild-type (WT) mice (0% versus 67%). Brain viral titers and cytokine/chemokine levels were significantly higher in KO than in WT animals on day 6 p.i. Furthermore, increased infiltration of monocytes into the brains of WT mice was seen on day 6 p.i., but not in KO mice. Our results suggest that microglial cells are essential to control HSE at early stages of the disease and that the MCSF/CSF1R axis could be a therapeutic target to regulate their response to infection.IMPORTANCE Microglia appear to be one of the principal regulators of neuroinflammation in the central nervous system (CNS). An increasing number of studies have demonstrated that the activation of microglia could result in either beneficial or detrimental effects in different CNS disorders. Hence, the role of microglia during herpes simplex virus encephalitis (HSE) has not been fully characterized. Using experimental mouse models, we showed that an early activation of the MCSF/CSF1R axis improved the outcome of the disease, possibly by inducing a proliferation of microglia. In contrast, depletion of microglia before HSV-1 infection worsened the prognosis of HSE. Thus, an early microglial response followed by sustained infiltration of monocytes and T cells into the brain seem to be key components for a better clinical outcome. These data suggest that microglia could be a potential target for immunomodulatory strategies combined with antiviral therapy to better control the outcome of this devastating disease.

Keywords: MCSF/CSF1R axis; central nervous system; herpes simplex virus; herpes simplex virus encephalitis; microglia; monocytes.