Graduate Student Researcher University of California, Irvine Newport Beach, California, United States
Introduction/Rationale: Before invading the peripheral nervous system (PNS) and establishing a lifelong infection, alpha herpesviruses (aHV) initiate a productive infection at mucosal epithelial cells. In response, these cells release antiviral cytokines alarming their neighbors, such as the axons of innervating peripheral neurons (PNs) before spreading newly made viral progeny. Two key antiviral cytokines secreted by infected mucosal epithelia include type I (e.g. IFN-) and type III interferons (IFN-). Type I IFN’s antiviral capacity has been well characterized, but the effect of IFN-λ on the PNS is not well understood. Our lab previously showed that IFN- treatment of PNs induces a STAT1 specific antiviral response. In this study, we aim to uncover the local (axonal) neuronal responses to IFN since nerve endings are the first to be exposed to mucosal cytokines.
Methods: We culture primary rat superior cervical ganglionic (SCG) neurons in a compartmentalized tri-chamber system to recapitulate their in-situ morphology. This allows for precise local IFN- treatment and retrograde infection of isolated axons with aHV.
Results: Our data shows that axonal IFN- treatment induces the activation of STAT1 locally within axons without nuclear translocation. This local effect decreased the particle motility and retrograde infection efficiency of pseudorabies virus (PRV). We further showed that this protection is reduced by fludarabine, a STAT1 activation inhibitor. Thus, our findings exhibit that IFN-’s local antiviral effect against aHV is p-STAT1 dependent in axons.
Conclusion: Overall, our data suggests that PNs can uniquely respond to cytokines through a noncanonical axonal mechanism that interferes with aHV neuroinvasion. These findings offer new insights into spatially and temporally regulated neuronal responses and how these can be translated into novel antiviral therapies.
