Interferon-λ Attenuates Rabies Virus Infection by Inducing Interferon-Stimulated Genes and Alleviating Neurological Inflammation

Abstract

Rabies, caused by rabies virus (RABV), is a fatal neurological disease that still causes more than 59,000 human deaths each year. Type III interferon IFN-λs are cytokines with type I IFN-like antiviral activities. Although IFN-λ can restrict the infection for some viruses, especially intestinal viruses, the inhibitory effect against RABV infection remains undefined. In this study, the function of type III IFN against RABV infection was investigated. Initially, we found that IFN-λ2 and IFN-λ3 could inhibit RABV replication in cells. To characterize the role of IFN-λ in RABV infection in a mouse model, recombinant RABVs expressing murine IFN-λ2 or IFN-λ3, termed as rB2c-IFNλ2 or rB2c-IFNλ3, respectively, were constructed and rescued. It was found that expression of IFN-λ could reduce the pathogenicity of RABV and limit viral spread in the brains by different infection routes. Furthermore, expression of IFN-λ could induce the activation of the JAK-STAT pathway, resulting in the production of interferon-stimulated genes (ISGs). It was also found that rRABVs expressing IFN-λ could reduce the production of inflammatory cytokines in primary astrocytes and microgila cells, restrict the opening of the blood-brain barrier (BBB), and prevent excessive infiltration of inflammatory cells into the brain, which could be responsible for the neuronal damage caused by RABV. Consistently, IFN-λ was found to maintain the integrity of tight junction (TJ) protein ZO-1 of BBB to alleviate neuroinflammation in a transwell model. Our study underscores the role of IFN-λ in inhibiting RABV infection, which potentiates IFN-λ as a possible therapeutic agent for the treatment of RABV infection.

Human plasmacytoid dendritic cells at the crossroad of type I interferon-regulated B cell differentiation and antiviral response to tick-borne encephalitis virus

“…In addition, we found that TBEV induces also IFNL1 in human PBMC mirroring which was observed in human medulloblastoma-derived neuronal cell line (DAOY) [ 9 ]. However, we do not know whether in our experimental model IFNL1 synergizes with type I IFN in controlling virus replication or if it acts to dampen the pro-inflammatory response [ 63 ].…”

Human norovirus exhibits strain-specific sensitivity to host interferon pathways in human intestinal enteroids

“…Our findings suggest strain-specific sensitivities to IFN as a factor for global dominance of pandemic strains, provide a new arsenal of stable HIE knockout lines for several IFN pathways, and highlight strain differences as a consideration for development of effective therapies. interferons (IFNs) and their downstream effectors, IFNstimulated genes (ISGs), form a first line of defense against many viral infections (22)(23)(24)(25). Studies of other human enteric viruses, including human rotavirus as well as murine norovirus, provide strong support for the role of IFN responses in controlling viral replication in mice and cultured cells; in many cases, there are strain-specific mechanisms by which these viruses antagonize host innate immune responses (26)(27)(28)(29).…”

Targeting interferon-λ signaling promotes recovery from central nervous system autoimmunity

“…Examination of IFNL within the CNS has primarily been in the context of neuroinvasive viral illnesses. During West Nile virus (WNV) encephalitis, IFNL substantially limits neuroinvasion by stabilizing the blood brain barrier (18,56). In our present work, lack of IFNL signaling reduces numbers of infiltrating T cells within the CNS and ameliorates EAE.…”