Cell type-dependent requirement of autophagy in HSV-1 antiviral defense

Abstract

Type I interferons (IFNs) are induced during most viral infections and are considered to be the primary and universal means of innate viral control. However, several other innate mechanisms, including autophagy, have recently been shown to play an important role in antiviral defense. In our recent study, we utilized a herpes simplex virus 1 (HSV-1) infection model to investigate the relationship between cell type and innate antiviral immune mechanisms. Our study demonstrates that dorsal root ganglion (DRG) neurons undergo an innate antiviral response to HSV-1 that differs from the antiviral program induced in mitotic cells in three distinct ways. First, DRG neurons produce less type I IFN and undergo a less effective IFN antiviral program vs. mitotic cells in response to HSV-1 infection. Second, the type I IFN program initiated in DRG neurons induces less cell death than in mitotic cells. Third, in the absence of a robust type I IFN response, DRG neurons, but not mitotic cells, rely on autophagy in HSV-1 defense. Our findings reveal a cell type-specific requirement for autophagy in defense against HSV-1, and offer insight into the cell-appropriate antiviral defense mechanism employed by neurons.

Keywords: genital herpes; innate immunity; interferons; neurons; viral evasion.

Figure 1. Mitotic cells and DRG neurons rely on different innate strategies to control HSV-1 replication. In mitotic cells such as mouse embryonic fibroblasts and keratinocytes, HSV-1 infection induces a robust type I IFN response. Type I IFN induces vigorous upregulation of ISGs, which provide protection against HSV-1 infection in part by inducing death of infected cells. Autophagy is not required in this context. In neurons, HSV-1 infection results in limited type I IFN production. Moreover, exposure to exogenous type I IFN induces a limited upregulation of certain ISGs. This altered type I IFN response is not sufficient to induce either cell death or complete protection against HSV-1 infection. Within neurons, both type I IFN and autophagy contribute to innate control of HSV-1.