Microglia Reduce Herpes Simplex Virus 1 Lethality of Mice with Decreased T Cell and Interferon Responses in Brains

Abstract

Herpes simplex virus 1 (HSV-1) infects the majority of the human population and can induce encephalitis, which is the most common cause of sporadic, fatal encephalitis. An increase of microglia is detected in the brains of encephalitis patients. The issues regarding whether and how microglia protect the host and neurons from HSV-1 infection remain elusive. Using a murine infection model, we showed that HSV-1 infection on corneas increased the number of microglia to outnumber those of infiltrating leukocytes (macrophages, neutrophils, and T cells) and enhanced microglia activation in brains. HSV-1 antigens were detected in brain neurons, which were surrounded by microglia. Microglia depletion increased HSV-1 lethality of mice with elevated brain levels of viral loads, infected neurons, neuron loss, CD4 T cells, CD8 T cells, neutrophils, interferon (IFN)-β, and IFN-γ. In vitro studies demonstrated that microglia from infected mice reduced virus infectivity. Moreover, microglia induced IFN-β and the signaling pathway of signal transducer and activator of transcription (STAT) 1 to inhibit viral replication and damage of neurons. Our study reveals how microglia protect the host and neurons from HSV-1 infection.

Role of Microglia in Herpesvirus-Related Neuroinflammation and Neurodegeneration

“…The study by Uyar et al showed that transient and incomplete depletion (6 day post infection) of microglial response decreased infiltration of monocytes/macrophages, neutrophils and T cells into the brain [ 45 ]. Similar results were obtained by Tsai et al in a study where microglia were depleted by the use of PLX 5622, an inhibitor of colony-stimulating factor 1 receptor (CSF1R), necessary for microglia survival, growth, and proliferation [ 46 ].…”

“…Depletion of microglia before and during infection augments brain viral titers by about 10- and 100-fold on days 6–7 p.i. and increases mortality rates of infected mice by 60 and 85%, respectively [ 46 ]. Lack of microglia activation is accompanied by increased infiltration of CD4 T cells, CD8 T cells, neutrophils, and increased production of IFN-β, and IFN-γ [ 45 , 46 ].…”

“…and increases mortality rates of infected mice by 60 and 85%, respectively [ 46 ]. Lack of microglia activation is accompanied by increased infiltration of CD4 T cells, CD8 T cells, neutrophils, and increased production of IFN-β, and IFN-γ [ 45 , 46 ]. However, these compensatory mechanisms cannot reduce brain viral loads and mice lethality [ 45 , 46 ].…”

“…Lack of microglia activation is accompanied by increased infiltration of CD4 T cells, CD8 T cells, neutrophils, and increased production of IFN-β, and IFN-γ [ 45 , 46 ]. However, these compensatory mechanisms cannot reduce brain viral loads and mice lethality [ 45 , 46 ]. The study by Tsai et al showed in vitro that brain microglia induce the IFN-β-STAT1 signaling pathway, which suppresses viral replication and apoptosis of brain neurons [ 46 ].…”

“…However, these compensatory mechanisms cannot reduce brain viral loads and mice lethality [ 45 , 46 ]. The study by Tsai et al showed in vitro that brain microglia induce the IFN-β-STAT1 signaling pathway, which suppresses viral replication and apoptosis of brain neurons [ 46 ].…”