The NF-κB pathway negatively regulates the replication of rabies virus by triggering inflammatory responses

Abstract

Rabies, which is caused by the rabies virus (RABV), is a neurological disease of mammals, including humans. The disease is untreatable, as drugs and antibodies are prevented from entering brain tissue by the blood-brain barrier (BBB). However, it has been reported that BBB permeability can be enhanced in mice infected with a laboratory-attenuated strain of RABV, which is not the case in those infected with wild-type RABV. Moreover, it is not the RABV infection directly that enhances BBB, but rather the inflammatory molecules that are induced by the virus. Understanding the mechanism underlying the RABV-induced production of chemokines and cytokines is crucial for the prevention and management of rabies. In this study, we found that mice infected with the RABV challenge strain CVS11 showed significant inflammatory infiltration in the later stages of infection. At the cellular level, we confirmed that the NF-κB signaling pathway was activated following RABV infection, leading to significant upregulation of the expression of downstream chemokines and inflammatory factors (CCL2, CCL5, CXCL10, TNF-α, and IL-6). Surprisingly, the replication of RABV was upregulated when the NF-κB pathway was inhibited, and the levels of its downstream chemokines and inflammatory factors were reduced following treatment with the inhibitor JSH-23. This suggests that RABV infection activates the NF-κB pathway, which is then able to negatively regulate the replication of RABV. This pathway is therefore a potential target for drugs and other therapies in the treatment of rabies.