Rabies virus nucleoprotein functions to evade activation of the RIG-I-mediated antiviral response.
The rabies virus Ni-CE strain causes nonlethal infection in adult mice after intracerebral inoculation, whereas the parental Nishigahara (Ni) strain kills mice. We previously reported that the chimeric CE(NiN) strain with the N gene from the Ni strain in the genetic background of the Ni-CE strain kills adult mice, indicating that the N gene is related to the different pathogenicities of Ni and Ni-CE strains. In the present study, to obtain an insight into the mechanism by which the N gene determines viral pathogenicity, we compared the effects of Ni, Ni-CE, and CE(NiN) infections on host gene expressions using a human neuroblastoma cell line. Microarray analysis of these infected cells revealed that the expression levels of particular genes in Ni- and CE(NiN)-infected cells, including beta interferon (IFN-beta) and chemokine genes (i.e., CXCL10 and CCL5) were lower than those in Ni-CE-infected cells. We also demonstrated that Ni-CE infection activated the interferon regulatory factor 3 (IRF-3)-dependent IFN-beta promoter and induced IRF-3 nuclear translocation more efficiently than did Ni or CE(NiN) infection. Furthermore, we showed that Ni-CE infection, but not Ni or CE(NiN) infection, strongly activates the IRF-3 pathway through activation of RIG-I, which is known as a cellular sensor of virus infection. These findings indicate that the N protein of rabies virus (Ni strain) has a function to evade the activation of RIG-I. To our knowledge, this is the first report that the Mononegavirales N protein functions to evade induction of host IFN and chemokines.
Laboratory of Zoonotic Diseases, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
Tatsunori
T
Masatani
Naoto
N
Ito
Kenta
K
Shimizu
Yuki
Y
Ito
Keisuke
K
Nakagawa
Yoshiharu
Y
Sawaki
Hiroyuki
H
Koyama
Makoto
M
Sugiyama
D021581:Active Transport, Cell Nucleus; D002460:Cell Line; D018946:Chemokine CCL5 / Q000096:biosynthesis; D054357:Chemokine CXCL10 / Q000096:biosynthesis; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors*; D020869:Gene Expression Profiling; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016899:Interferon-beta / Q000096:biosynthesis; D009474:Neurons / Q000821:virology; D009698:Nucleoproteins / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D011820:Rabies virus / Q000472:pathogenicity*; D011971:Receptors, Immunologic; D014764:Viral Proteins / Q000502:physiology*; D037521:Virulence Factors / Q000502:physiology*
C483024:CCL5 protein, human; C114753:CXCL10 protein, human; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D009698:Nucleoproteins; D011971:Receptors, Immunologic; D014764:Viral Proteins; D037521:Virulence Factors; D016899:Interferon-beta; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases