A Neuron-Specific Role for Autophagy in Antiviral Defense against Herpes Simplex Virus

Brian Yordy et al. 2012. Cell Host Microbe. 12, 334-345.

Speaker: Li-Jie Kao (高力捷)                                                        Time: 15:00~16:00, Apr. 17, 2013

Commentator: Guey-Chuen Perng, Ph. D. (彭貴春老師)            Place: Room 601

Abstract

Type I interferons (IFNs) are the first line of host defense against viral infections. IFNs induce an antiviral state by activating IFN-stimulated genes. Several IFN-stimulated genes can induce cell death to control viral infections but may damage nonrenewable cell types, such as neurons. This suggests that neurons have another pathway to combat viruses. A previous study has shown that the autophagy protein, Beclin-1, has an antiviral activity to Sindbis virus and herpes simplex virus type 1 (HSV-1), which infect neurons¹. Thus, the authors used a mouse model of HSV-1 infection to demonstrate autophagy as a critical antiviral strategy in neurons. The authors infected neurons, keratinocytes, and mouse embryonic fibroblasts with various multiplicity of infections of HSV-1, and found significant induction of type I IFNs in keratinocytes and mouse embryonic fibroblasts, but not in neurons after infection. They also found neurons were less responsive to exogenous IFN-β than mitotic cells. These findings indicated that type I IFNs provide less protection against HSV-1 in neurons than mitotic cells. A previous study demonstrated that HSV-1 ICP34.5 contains a domain that binds to Beclin-1 and inhibits autophagy², so the authors used wild-type and keratinocyte-Atg5 knockout mice infected with wild-type HSV-1(bbdR) or mutant HSV-1 with ICP34.5-Beclin-1-binding domain deleted (bbd) to examine the antiviral role of autophagy. They found that autophagy was not required for reducing HSV-1 in epithelial cells. In contrast, autophagy was important for controlling HSV-1 in nonepithelial cell types in vivo. They also isolated dorsal root ganglionic neurons from neuron-Atg5 knockout mice and infected withbbdR or bbd to directly test the requirement of autophagy for anti-HSV activity. The authors further found that autophagy limiting HSV-1 replication was restricted to the peripheral nervous system because bbdR and bbd cannot significant replication in the brain stems or the spinal cords of infected mice. Therefore, the authors demonstrated that the immune system uses suitable strategies to combat viral infections depending on different cell types. These findings indicate that viral treatment should base on cell types to maximize the therapeutic efficiency and provide important implications to treat HSV or other neurotropic virus infections.

References

1.      Anthony Orvedahl and Beth Levine. Autophagy and viral neurovirulence. 2008. Cell Microbiol. 10, 1747–1756.

2.      Orvedahl et al. HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein. 2007. Cell Host Microbe. 1, 23-35.