Deciphering Human Cell-Autonomous Anti-HSV-1 Immunity in the Central Nervous System.

Fabien G Lafaille,Lorenz Studer,Shen-Ying Zhang,Luigi Notarangelo,Michael J Ciancanelli,Gregory Smith,Jean-Laurent Casanova

doi:10.3389/fimmu.2015.00208

Abstract

Herpes 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 HSV-1 of the various relevant cell types of the CNS, neurons, astrocytes, oligodendrocytes, and microglia cells, as well as their response to viral infection, has been extensively studied in humans and other animals. Nevertheless, human CNS cell-based models of anti-HSV-1 immunity are of particular importance, as responses to any given neurotropic virus may differ between humans and other animals. Human CNS neuron cell lines as well as primary human CNS neurons, astrocytes, and microglia cells cultured/isolated from embryos or cadavers, have enabled the study of cell-autonomous anti-HSV-1 immunity in vitro. However, the paucity of biological samples and their lack of purity have hindered progress in the field, which furthermore suffers from the absence of testable primary human oligodendrocytes. Recently, the authors have established a human induced pluripotent stem cells (hiPSCs)-based model of anti-HSV-1 immunity in neurons, oligodendrocyte precursor cells, astrocytes, and neural stem cells, which has widened the scope of possible in vitro studies while permitting in-depth explorations. This mini-review summarizes the available data on human primary and iPSC-derived CNS cells for anti-HSV-1 immunity. The hiPSC-mediated study of anti-viral immunity in both healthy individuals and patients with viral encephalitis will be a powerful tool in dissecting the disease pathogenesis of CNS infections with HSV-1 and other neurotropic viruses.

Highlights

Herpes simplex virus 1 (HSV-1) is a double-stranded DNA virus of the α-herpesvirinae subfamily [1]
No differences were observed between control and patients’ neural stem cells (NSCs) and astrocytes. These in vitro experiments demonstrated that central nervous system (CNS) neurons and oligodendrocyte progenitor cells (OPCs) control HSV-1 infection intrinsically in a TLR3-dependent manner, the in vivo protective role of astrocytes and NSCs cannot be excluded
Human neuronal cell lines as well as primary cells have allowed for the study of anti-HSV-1 immunity of the human CNS

Summary

Introduction

Herpes simplex virus 1 (HSV-1) is a double-stranded DNA virus of the α-herpesvirinae subfamily [1]. Pre-treatment with IFN-λ1 or -λ2 reduces HSV-1 replication in these cells and induces IRF7 expression, a key transcription factor creating a positive feedback loop for IFN production [29] These results indicated that the TLR3/IFN pathway is critical for control of HSV-1 virus infection in primary CNS neurons. These in vitro experiments demonstrated that CNS neurons and OPCs control HSV-1 infection intrinsically in a TLR3-dependent manner, the in vivo protective role of astrocytes and NSCs cannot be excluded Overall, these iPSC-based experiments are in agreement with studies based on cell lines and primary sources, suggesting that TLR3 and IFN responses play important roles in defense against HSV-1 infection in CNS cells (Table 1). HSE is, to our knowledge, the first example of hiPSC-mediated modeling of an inborn error of immunity, demonstrating a disease-relevant immunological cellular phenotype in disease-relevant CNS cell types

Conclusion

Findings

Author contributions