Interleukin-1β suppresses rabies virus infection by activating cGAS-STING pathway and compromising the blood-brain barrier integrity in mice

Abstract

Rabies, caused by rabies virus (RABV), is an ancient zoonotic disease that severely threatens the public health throughout the world. Previous study indicated that interleukin-1β (IL-1β) plays an important role in RABV infection. However, the mechanism how IL-1β affects RABV pathogenicity is still unknown yet. In this study, we confirmed that IL-1β was able to reduce viral titers of RABV in different cells, and the recombinant RABV expressing IL-1β, designated as rCVS-IL1β, could be suppressed in different cells due to the expression of IL-1β. Furthermore, the survival rates of mice infected with rCVS-IL1β by intramuscular route was significantly higher than those of mice infected with parent virus rCVS, which is associated with the less viral loads for entry into the central nervous system (CNS). We further characterized that the cGAS-STING pathway was activated in rCVS-IL1β infected bone marrow derived dendritic cells (BMDC), which could contribute to the decreased viral loads of RABV after intramuscular infection. Moreover, we also observed that the expression of IL-1β by rCVS-IL1β could compromise the blood-brain barrier (BBB) integrity by degrading the tight junction proteins, which allowing peripheral inflammatory cytokines, chemokines, and CD4⁺T cells to enter into the brain for the clearance of RABV in the CNS. Together, our study suggests that IL-1β could attenuate RABV pathogenicity through activating cGAS-STING pathway in to decrease the viral entry into the CNS and enhance the BBB permeability to promote RABV clearance in the CNS as well, which provides new insight into developing effective therapeutics for rabies.

Keywords: Blood-brain barrier; CGAS-STING pathway; Interleukin-1β; Rabies virus.