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David A Leib, Sarah Katzenell; Atypical autophagic responses in sensory neurons induced by HSV-1 infection and interferon signaling.. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2081.
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© ARVO (1962-2015); The Authors (2016-present)
Herpes simplex virus-1 (HSV-1) establishes lifelong latent infections in the sensory neurons of trigeminal ganglia (TG) wherein it retains the capacity to reactivate. Interferon β (IFNβ) drives antiviral responses, which are crucial to control of HSV-1 lytic replication and reactivation within the host neuron. Additionally, autophagy may play a role in these neuronal antiviral responses. We therefore sought to investigate the relationship between antiviral signaling and autophagy during HSV-1 infection of TG neurons in vitro and in vivo.
We cultured TG neurons from adult mice expressing GFP fused to the autophagy protein LC3. GFP-LC3 allows rapid and simple identification and quantification of fluorescent punctate autophagosomes. We used this system to measure neuronal autophagic responses to viral infection and IFNβ treatment. Additionally, we infected mice via the cornea and examined autophagic responses in TG during acute linfection.
In the absence of viral infection we observed a basal level of autophagy in the TG neurons that resulted in the formation of standard-sized autophagic puncta (0.5-1.5µm). Following infection, however we observed an accumulation of novel large puncta (≥4µm) which high resolution microscopy has shown to be an aggregation of autophagosomes. These structures co-localize with other autophagy markers (p62 and lysosomes), and were disrupted by bafilomycin, an inhibitor of autophagy maturation. Interestingly we showed that these large autophagsomes were also induced by IFNβ, and were dependent on STAT1 signaling. Moreover, these large puncta also appeared in TG following in vivo infection of mice via the cornea, and were preferentially present in neurons that were not expressing viral antigens, suggesting that neurons containing autophagosomes are resistant to productive viral gene expression.
Together these data suggest that these large autophagosomes may be a novel and critical component of the neuronal IFN-driven antiviral response that may regulate acute infection and the maintenance of latency. The antiviral modulation of autophagy may therefore be an attractive target for the control of acute and recurrent HSV infections.
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