Interferon in rabies virus infection.

Rabies is among the longest known and most dangerous and feared infectious diseases for humans and animals and still is responsible for tenth of thousands of human deaths per year. The rabies virus (RABV) is a rather atypical member of the Rhabdoviridae family as it has completely adapted during evolution to warm-blooded hosts and is directly transmitted between them, whereas most other rhabdoviruses are transmitted by insect vectors. The virus is also unique with respect to its extremely broad host species range and a very narrow host organ range, namely its strict neurotropism. It is becoming increasingly clear that the host innate immune system, particularly the type I interferon system, and the viral counteractions profoundly shape this virus-host relationship. In the past few years, exciting new insight was obtained on how viruses are sensed by innate immune receptors, how the downstream signaling networks for activation of interferon are working, and how viruses can interfere with the system. While RABV 5'-triphosphate RNAs were identified as the major pathogen-associated molecular pattern sensed by cytoplasmic RIG-I-like receptors (RLR), the RABV phosphoprotein (P) has emerged as a potent multifunctional antagonist able to counteract the signaling cascades leading to transcriptional activation of interferon genes as well as interferon signaling pathways, thereby limiting expression of antiviral and immune-stimulatory genes.

Genetic dissection of interferon-antagonistic functions of rabies virus phosphoprotein: inhibition of interferon regulatory factor 3 activation is important for pathogenicity.

The rabies virus (RV) phosphoprotein (P) is a type I interferon (IFN) antagonist preventing both transcriptional induction of IFN and IFN-mediated JAK/STAT signaling. In addition, P is an essential cofactor of the viral polymerase and is required for encapsidation of viral RNA into nucleoprotein during replication. By site-directed mutagenesis, we have identified a domain of P required for efficient inhibition of IFN induction. Phosphoproteins lacking amino acids (aa) 176 to 181, 182 to 186, or 176 to 186 were severely compromised in counteracting phosphorylation of IRF3 and IRF7 by TBK1 or IKKi while retaining the full capacity of preventing nuclear import of activated STATs and of supporting virus transcription and replication. Recombinant RV carrying the mutated phosphoproteins (the SAD ΔInd1, SAD ΔInd2, and SAD ΔInd1/2 viruses) activated IRF3 and beta IFN (IFN-ß) transcription in infected cells but still blocked STAT-mediated expression of IFN-stimulated genes. Due to a somewhat higher transcription rate, the SAD ΔInd1 virus activated IRF3 more efficiently than the SAD ΔInd2 virus. After intracerebral injection into mouse brains at high doses, the SAD ΔInd1 virus was completely apathogenic for wild-type (wt) mice, while the SAD ΔInd2 virus was partially attenuated and caused a slower progression of lethal rabies than wt RV. Neurovirulence of IFN-resistant RV thus correlates with the capacity of the virus to prevent activation of IRF3 and IRF7.