Background: Herpes simplex virus-1 (HSV-1) infections of the central nervous system (CNS) can result in HSV-1 encephalitis (HSE) which is characterized by severe brain damage and long-term disabilities. Different cell types including neurons and astrocytes become infected in the course of an HSE which leads to an activation of glial cells. Activated glial cells change their neurotrophic factor profile and modulate inflammation and repair. The superfamily of fibroblast growth factors (FGFs) is one of the largest family of neurotrophic factors comprising 22 ligands. FGFs induce pro-survival signaling in neurons and an anti-inflammatory answer in glial cells thereby providing a coordinated tissue response which favors repair over inflammation. Here, we hypothesize that FGF expression is altered in HSV-1-infected CNS cells.
Method: We employed primary murine cortical cultures comprising a mixed cell population of astrocytes, neurons, microglia, and oligodendrocytes. Astrocyte reactivity was morphometrically monitored by an automated image analysis algorithm as well as by analyses of A1/A2 marker expression. Altered FGF expression was detected by quantitative real-time PCR and its paracrine FGF activity. In addition, HSV-1 mutants were employed to characterize viral factors important for FGF responses of infected host cells.
Results: Astrocytes in HSV-1-infected cortical cultures were transiently activated and became hypertrophic and expressed both A1- and A2-markers. Consistently, a number of FGFs were transiently upregulated inducing paracrine neurotrophic signaling in neighboring cells. Most prominently, FGF-4, FGF-8, FGF-9, and FGF-15 became upregulated in a switch-on like mechanism. This effect was specific for CNS cells and for a fully functional HSV-1. Moreover, the viral protein ICP0 critically mediated the FGF switch-on mechanism.
Conclusions: HSV-1 uses the viral protein ICP0 for the induction of FGF-expression in CNS cells. Thus, we propose that HSV-1 triggers FGF activity in the CNS for a modulation of tissue response upon infection.
Keywords: Akt; Cortex; ERK; FGF; Fibroblast growth factors; HSV-1; ICP0; Neurotrophic factors; Signaling.
Conflict of interest statement
The authors declare that they have no competing interests.
A Role for DNA-dependent Activator of Interferon Regulatory Factor in the Recognition of Herpes Simplex Virus Type 1 by Glial CellsSR Furr et al. J Neuroinflammation 8, 99. PMID 21838860.The functional expression of DAI by microglia and astrocytes may represent an important innate immune mechanism underlying the rapid and potentially lethal inflammation a …
Characterization of a Nerve Growth Factor-Inducible Cellular Activity That Enhances Herpes Simplex Virus Type 1 Gene Expression and Replication of an ICP0 Null Mutant in Cells of Neural LineageR Jordan et al. J Virol 72 (7), 5373-82. PMID 9620991.Herpes simplex virus type 1 (HSV-1) ICP0 is required for efficient viral gene expression during lytic infection, especially at low multiplicities. A series of cellular ac …
The Glucocorticoid Receptor (GR) Stimulates Herpes Simplex Virus 1 Productive Infection, in Part Because the Infected Cell Protein 0 (ICP0) Promoter Is Cooperatively Transactivated by the GR and Krüppel-Like Transcription Factor 15JB Ostler et al. J Virol 93 (6). PMID 30602606.Following acute infection, herpes simplex virus 1 (HSV-1) establishes lifelong latency in neurons. Physical, emotional, and chemical stresses are linked to increasing the …
Deciphering Human Cell-Autonomous Anti-HSV-1 Immunity in the Central Nervous SystemFG Lafaille et al. Front Immunol 6, 208. PMID 26005444. - ReviewHerpes simplex virus 1 (HSV-1) is a common virus that can rarely invade the human central nervous system (CNS), causing devastating encephalitis. The permissiveness to HS …
Fibroblast Growth Factors in the Nervous SystemFP Eckenstein. J Neurobiol 25 (11), 1467-80. PMID 7852998. - ReviewFibroblast growth factors (FGFs) exhibit widespread mitogenic and neurotrophic activities. Nine members of the family are currently known, and FGF-1 and FGF-2 are present …