AXONAL INTERFERON RESPONSES AND ALPHAHERPESVIRUS NEUROINVASION

Abstract

Infection by alphaherpesviruses, including herpes simplex virus (HSV) and pseudorabies virus (PRV), typically begins at a peripheral epithelial surface and continues into the peripheral nervous system (PNS) that innervates this tissue. Inflammatory responses are induced at the infected peripheral site prior to viral invasion of the PNS. PNS neurons are highly polarized cells with long axonal processes that connect to distant targets. When the peripheral tissue is first infected, only the innervating axons are exposed to this inflammatory milieu, which include type I interferon (e.g. IFNβ) and type II interferon (i.e. IFNγ). IFNβ can be produced by all types of cells, while IFNγ is secreted by some specific types of immune cells. And both types of IFN induce antiviral responses in surrounding cells that express the IFN receptors. The fundamental question is how do PNS neurons respond to the inflammatory milieu experienced only by their axons. Axons must act as potential front-line barriers to prevent PNS infection and damage. Using compartmented cultures that physically separate neuron axons from cell bodies, I found that pretreating isolated axons with IFNβ or IFNγ significantly diminished the number of HSV-1 and PRV particles moving from axons to the cell bodies in an IFN receptor-dependent manner. Furthermore, I found the responses in axons are activated differentially by the two types of IFNs. The response to IFNβ is a rapid, axon-only response, while the response to IFNγ involves long distance signaling to the PNS cell body. For example, exposing axons to IFNβ induced STAT1 phosphorylation (p-STAT1) only in axons, while exposure of axons to IFNγ induced p-STAT1 accumulation in distant cell body nuclei. Blocking transcription in cell bodies eliminated IFNγ-, but not IFNβ-mediated antiviral effects. Proteomic analysis of IFNβ- or IFNγ-treated axons identified several differentially regulated proteins. Therefore, unlike treatment with IFNγ, IFNβ induces a non-canonical, local antiviral response in axons. The activation of a local IFNβ response in axons represents a new paradigm for early cytokine control of neuroinvasion. And the two response modes induced by the two distinct types of IFN erect an efficient and appropriate barrier against PNS infection.