Glu in Rabies Virus Glycoprotein is Involved in Virus Attenuation Through Astrocyte Infection and Interferon Responses

Overview

Journal iScience

Publisher Cell Press

Date 2022 Apr 11

PMID 35402872

Authors

Yukari Itakura

Koshiro Tabata

Kohei Morimoto

Naoto Ito

Herman M Chambaro

Ryota Eguchi

Ken-Ichi Otsuguro

William W Hall

Yasuko Orba

Hirofumi Sawa

Michihito Sasaki

Affiliations

Soon will be listed here.

Abstract

The amino acid residue at position 333 of the rabies virus (RABV) glycoprotein (G333) is a major determinant of RABV pathogenicity. Virulent RABV strains possess Arg, whereas the attenuated strain HEP-Flury (HEP) possesses Glu. To investigate the potential attenuation mechanism dependent on a single amino acid at G333, comparative analysis was performed between HEP and HEPR mutant with Arg. We examined their respective tropism for astrocytes and the subsequent immune responses in astrocytes. Virus replication and subsequent interferon (IFN) responses in astrocytes infected with HEP were increased compared with HEPR both and . Furthermore, involvement of IFN in the avirulency of HEP was demonstrated in IFN-receptor knockout mice. These results indicate that Glu contributes to RABV attenuation by determining the ability of the virus to infect astrocytes and stimulate subsequent IFN responses.

Citing Articles

Deep mutational scanning of rabies glycoprotein defines mutational constraint and antibody-escape mutations.

Aditham A, Radford C, Carr C, Jasti N, King N, Bloom J bioRxiv. 2025; .

PMID: 39763725 PMC: 11702696. DOI: 10.1101/2024.12.17.628970.

Reverse genetic approaches allowing the characterization of the rabies virus street strain belonging to the SEA4 subclade.

Kawaguchi N, Itakura Y, Intaruck K, Ariizumi T, Harada M, Inoue S Sci Rep. 2024; 14(1):18509.

PMID: 39122768 PMC: 11316049. DOI: 10.1038/s41598-024-69613-y.

Construction of Vero cell-adapted rabies vaccine strain by five amino acid substitutions in HEP-Flury strain.

Harada M, Matsuu A, Park E, Inoue Y, Uda A, Kaku Y Sci Rep. 2024; 14(1):12559.

PMID: 38822013 PMC: 11143356. DOI: 10.1038/s41598-024-63337-9.

Single Amino Acid Substitution in the Matrix Protein of Rabies Virus Is Associated with Neurovirulence in Mice.

Harada M, Matsuu A, Kaku Y, Okutani A, Inoue Y, Posadas-Herrera G Viruses. 2024; 16(5).

PMID: 38793581 PMC: 11125599. DOI: 10.3390/v16050699.

Morphogenesis of Bullet-Shaped Rabies Virus Particles Regulated by TSG101.

Itakura Y, Tabata K, Saito T, Intaruck K, Kawaguchi N, Kishimoto M J Virol. 2023; 97(5):e0043823.

PMID: 37042780 PMC: 10231130. DOI: 10.1128/jvi.00438-23.

References

Shuai L, Feng N, Wang X, Ge J, Wen Z, Chen W . Genetically modified rabies virus ERA strain is safe and induces long-lasting protective immune response in dogs after oral vaccination. Antiviral Res. 2015; 121:9-15. DOI: 10.1016/j.antiviral.2015.06.011. View

Davis B, Fensterl V, Lawrence T, Hudacek A, Sen G, Schnell M . Ifit2 Is a Restriction Factor in Rabies Virus Pathogenicity. J Virol. 2017; 91(17). PMC: 5553164. DOI: 10.1128/JVI.00889-17. View

Zhang Z, Ma Z, Zou W, Guo H, Liu M, Ma Y . The Appropriate Marker for Astrocytes: Comparing the Distribution and Expression of Three Astrocytic Markers in Different Mouse Cerebral Regions. Biomed Res Int. 2019; 2019:9605265. PMC: 6613026. DOI: 10.1155/2019/9605265. View

Ito N, Takayama M, Yamada K, Sugiyama M, Minamoto N . Rescue of rabies virus from cloned cDNA and identification of the pathogenicity-related gene: glycoprotein gene is associated with virulence for adult mice. J Virol. 2001; 75(19):9121-8. PMC: 114481. DOI: 10.1128/JVI.75.19.9121-9128.2001. View

Sarmento L, Li X, Howerth E, Jackson A, Fu Z . Glycoprotein-mediated induction of apoptosis limits the spread of attenuated rabies viruses in the central nervous system of mice. J Neurovirol. 2005; 11(6):571-81. DOI: 10.1080/13550280500385310. View

Sato M, Hata N, Asagiri M, Nakaya T, Taniguchi T, Tanaka N . Positive feedback regulation of type I IFN genes by the IFN-inducible transcription factor IRF-7. FEBS Lett. 1999; 441(1):106-10. DOI: 10.1016/s0014-5793(98)01514-2. View

Honda Y, Kawai A, Matsumoto S . Comparative studies of rabies and Sindbis virus replication in human neuroblastoma (SYM-I) cells that can produce interferon. J Gen Virol. 1984; 65 ( Pt 10):1645-53. DOI: 10.1099/0022-1317-65-10-1645. View

Tan G, Ng J, Trasti S, Schul W, Yip G, Alonso S . A non mouse-adapted dengue virus strain as a new model of severe dengue infection in AG129 mice. PLoS Negl Trop Dis. 2010; 4(4):e672. PMC: 2860513. DOI: 10.1371/journal.pntd.0000672. View

Lentz T, Burrage T, Smith A, Crick J, Tignor G . Is the acetylcholine receptor a rabies virus receptor?. Science. 1982; 215(4529):182-4. DOI: 10.1126/science.7053569. View

10.

Morimoto K, Foley H, McGettigan J, Schnell M, Dietzschold B . Reinvestigation of the role of the rabies virus glycoprotein in viral pathogenesis using a reverse genetics approach. J Neurovirol. 2000; 6(5):373-81. DOI: 10.3109/13550280009018301. View

11.

Wang J, Wang Z, Liu R, Shuai L, Wang X, Luo J . Metabotropic glutamate receptor subtype 2 is a cellular receptor for rabies virus. PLoS Pathog. 2018; 14(7):e1007189. PMC: 6070288. DOI: 10.1371/journal.ppat.1007189. View

12.

Faber M, Pulmanausahakul R, Hodawadekar S, Spitsin S, McGettigan J, Schnell M . Overexpression of the rabies virus glycoprotein results in enhancement of apoptosis and antiviral immune response. J Virol. 2002; 76(7):3374-81. PMC: 136034. DOI: 10.1128/jvi.76.7.3374-3381.2002. View

13.

Kallfass C, Ackerman A, Lienenklaus S, Weiss S, Heimrich B, Staeheli P . Visualizing production of beta interferon by astrocytes and microglia in brain of La Crosse virus-infected mice. J Virol. 2012; 86(20):11223-30. PMC: 3457137. DOI: 10.1128/JVI.01093-12. View

14.

Coulon P, Ternaux J, Flamand A, Tuffereau C . An avirulent mutant of rabies virus is unable to infect motoneurons in vivo and in vitro. J Virol. 1998; 72(1):273-8. PMC: 109373. DOI: 10.1128/JVI.72.1.273-278.1998. View

15.

Yan X, MohanKumar P, Dietzschold B, Schnell M, Fu Z . The rabies virus glycoprotein determines the distribution of different rabies virus strains in the brain. J Neurovirol. 2002; 8(4):345-52. DOI: 10.1080/13550280290100707. View

16.

Klein A, Eggerbauer E, Potratz M, Zaeck L, Calvelage S, Finke S . Comparative pathogenesis of different phylogroup I bat lyssaviruses in a standardized mouse model. PLoS Negl Trop Dis. 2022; 16(1):e0009845. PMC: 8797209. DOI: 10.1371/journal.pntd.0009845. View

17.

Gaudin Y, Tuffereau C, Segretain D, Knossow M, Flamand A . Reversible conformational changes and fusion activity of rabies virus glycoprotein. J Virol. 1991; 65(9):4853-9. PMC: 248944. DOI: 10.1128/JVI.65.9.4853-4859.1991. View

18.

Ito N, Okamoto T, Sasaki M, Miyamoto S, Takahashi T, Izumi F . Safety enhancement of a genetically modified live rabies vaccine strain by introducing an attenuating Leu residue at position 333 in the glycoprotein. Vaccine. 2021; 39(28):3777-3784. DOI: 10.1016/j.vaccine.2021.05.002. View

19.

Carrano A, Das P . Altered Innate Immune and Glial Cell Responses to Inflammatory Stimuli in Amyloid Precursor Protein Knockout Mice. PLoS One. 2015; 10(10):e0140210. PMC: 4598170. DOI: 10.1371/journal.pone.0140210. View

20.

POSTIC B, FENJE P . Effect of administered interferon on rabies in rabbits. Appl Microbiol. 1971; 22(3):428-31. PMC: 376326. DOI: 10.1128/am.22.3.428-431.1971. View