STING Expression in Peripheral Sensory Neurons Underlies Virus Recognition and Pain

Pain is an early and common symptom of viral infections, and yet we have a limited understanding about the mechanisms through which viruses induce pain. Peripheral sensory neurons are well-studied for their role in pain, and are emerging as new actors in pathogen recognition and defense. It has been reported that peripheral sensory neurons express several proteins associated with virus recognition, including the stimulator of interferon genes (STING). Although STING and interferon signaling has been recently proposed as a critical regulator of physiological pain and a promising new target for treating chronic pain, whether and how STING in peripheral sensory neurons participate in virus recognition, defense and pain is still completely unknown. Here, we report that intradermal delivery of viral oligonucleotides induced pain responses in mice via the expression of STING and the transient receptor potential vanilloid subtype 1 (TRPV1) in sensory neurons. In particular, we found that intradermal injections in mouse hindpaw of double-stranded DNA oligonucleotides derived from the herpes simplex virus (HSV-60) induced immediate spontaneous pain responses (hindpaw lifting, shacking and licking), as well as transitory mechanical pain hypersensitivities lasting up to 4 h. Remarkably, mice treated with the TRPV1 antagonist AMG9810 or resiniferatoxin, an ultrapotent TRPV1 agonist leading to the peripheral denervation, abrogated both HSV-60 induced pain responses. STING expression is enriched in TRPV1+ peripheral sensory neurons, and similar abrogation of HSV-60 induced pain responses was observed in conditional knockout mice lacking the expression of STING uniquely in peripheral sensory neurons. In support of these data, we also found that STING agonists directly can activate sensory neurons in vitro calcium imaging analysis and elicited pain responses in wild-type, but not TRPV1 knockout mice. Thus, our initial findings provide a previously undiscovered mechanism by which viruses are recognized by peripheral sensory neurons and induce pain. Grant support from NINDS R21 NS121946.