Abstract
Interferons (IFNs) and autophagy are critical neuronal defenses against viral infection. IFNs alter neuronal autophagy by promoting the accumulation of IFN-dependent LC3-decorated autophagic structures, termed LC3 clusters. Here, we analyzed LC3 clusters in sensory ganglia following herpes simplex virus 1 (HSV-1) infection. In the vicinity of acutely infected neurons, antigen-negative neurons contained structures resembling accumulated autophagosomes and autolysosomes that culminated in LC3 clusters. This accumulation reflects a delayed completion of autophagy. The endosomal sorting complexes required for transport (ESCRT) machinery participates in autophagosome closure and is also required for HSV-1 replication. In this study, our results showed that HSV-1 infection in vivo and in primary neurons caused a decrease in Vps4 (a key ESCRT pathway ATPase) RNA and protein with concomitant Stat1 activation and LC3 cluster induction. We also observed that IFNs were sufficient to decrease RNA and protein levels of Vps4 in primary neurons and in other cell types. The accumulation of ubiquitin was also observed at the LC3 cluster sites. Together, our results show that IFNs modulate the ESCRT machinery in neurons in response to HSV-1 infections.IMPORTANCE Neurons rely on IFNs and autophagy as major defenses against viral infections, and HSV must overcome such defenses in order to replicate. In addition to controlling host immunity, HSV must also control host membranes in order to complete its life cycle. HSV uses the host ESCRT membrane scission machinery for viral production and transport. Here we present evidence of a new IFN-dependent mechanism used by the host to prevent ESCRT subversion by HSV. This activity also impacts the dynamics of autophagy, possibly explaining the presence of recently described LC3 clusters in the HSV-infected nervous system. The induced accumulations of ubiquitin observed in these LC3 clusters resembled those observed in certain neurodegenerative diseases, suggesting possible mechanistic parallels between these conditions.
Highlights
Interferons (IFNs) and autophagy are critical neuronal defenses against viral infection
We observed that LC3 clusters in primary cultures were proximal to areas of high levels of ubiquitin. These results show that IFN-induced alterations of the endosomal sorting complexes required for transport (ESCRT) machinery in neurons likely act as a defense against herpes simplex virus 1 (HSV-1) infection
LC3GFPϩ/Ϫ mice were infected with HSV-1 and analyzed for LC3 clusters and HSV-1 antigen expression (Fig. 1A)
Summary
Interferons (IFNs) and autophagy are critical neuronal defenses against viral infection. In the vicinity of acutely infected neurons, antigen-negative neurons contained structures resembling accumulated autophagosomes and autolysosomes that culminated in LC3 clusters. This accumulation reflects a delayed completion of autophagy. Our results showed that HSV-1 infection in vivo and in primary neurons caused a decrease in Vps (a key ESCRT pathway ATPase) RNA and protein with concomitant Stat activation and LC3 cluster induction. This activity impacts the dynamics of autophagy, possibly explaining the presence of recently described LC3 clusters in the HSV-infected nervous system. IFN-␥ increases levels of autophagy during the antiviral response [17, 18], and autophagy is essential for antigen presentation and the development of the adaptive immune response [16]
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