Skip to main content

Advertisement

SpringerLink
Log in

The type I interferon response bridles rabies virus infection and reduces pathogenicity

  • Published:
Journal of NeuroVirology Aims and scope Submit manuscript

Abstract

Rabies virus (RABV) is a neurotropic virus transmitted by the bite of an infected animal that triggers a fatal encephalomyelitis. During its migration in the nervous system (NS), RABV triggers an innate immune response, including a type I IFN response well known to limit viral infections. We showed that although the neuroinvasive RABV strain CVS-NIV dampens type I IFN signaling by inhibiting IRF3 phosphorylation and STAT2 translocation, an early and transient type I IFN response is still triggered in the infected neuronal cells and NS. This urged us to investigate the role of type I IFN on RABV infection. We showed that primary mouse neurons (DRGs) of type I IFN(α/β) receptor deficient mice (IFNAR−/− mice) were more susceptible to RABV than DRGs of WT mice. In addition, exogenous type I IFN is partially efficient in preventing and slowing down infection in human neuroblastoma cells. Intra-muscular inoculation of type I IFNAR deficient mice [IFNAR−/− mice and NesCre (+/−) IFNAR (flox/flox) mice lacking IFNAR in neural cells of neuroectodermal origin only] with RABV reveals that the type I IFN response limits RABV dissemination in the inoculated muscle, slows down invasion of the spinal cord, and delays mortality. Thus, the type I IFN which is still produced in the NS during RABV infection is efficient enough to reduce neuroinvasiveness and pathogenicity and partially protect the host from fatal infection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

RABV:

Rabies virus

NC:

Nucleocapsid

References

  • Baloul L, Camelo S, Lafon M (2004) Up-regulation of Fas ligand (FasL) in the central nervous system: a mechanism of immune evasion by rabies virus. J Neurovirol 10:372–382

    Article  PubMed  CAS  Google Scholar 

  • Blondel D, Kheddache S, Lahaye X, Dianoux L, Chelbi-Alix MK (2010) Resistance to rabies virus infection conferred by the PMLIV isoform. J Virol 84:10719–10726

    Article  PubMed  CAS  Google Scholar 

  • Brzozka K, Finke S, Conzelmann KK (2005) Identification of the rabies virus alpha/beta interferon antagonist: phosphoprotein P interferes with phosphorylation of interferon regulatory factor 3. J Virol 79:7673–7681

    Article  PubMed  CAS  Google Scholar 

  • Brzozka K, Finke S, Conzelmann KK (2006) Inhibition of interferon signaling by rabies virus phosphoprotein P: activation-dependent binding of STAT1 and STAT2. J Virol 80:2675–2683

    Article  PubMed  CAS  Google Scholar 

  • Camelo S, Lafage M, Lafon M (2000) Absence of the p55 Kd TNF-alpha receptor promotes survival in rabies virus acute encephalitis. J Neurovirol 6:507–518

    Article  PubMed  CAS  Google Scholar 

  • Castellanos JE, Martinez-Gutierrez M, Hurtado H, Kassis R, Bourhy H, Acosta O, Lafon M (2005) Studying neurotrophin antiviral effect on rabies-infected dorsal root ganglia cultures. J Neurovirol 11:403–410

    Article  PubMed  CAS  Google Scholar 

  • Chelbi-Alix MK, Vidy A, El Bougrini J, Blondel D (2006) Rabies viral mechanisms to escape the IFN system: the viral protein P interferes with IRF-3, Stat1, and PML nuclear bodies. J Interferon Cytokine Res 26:271–280

    Article  PubMed  CAS  Google Scholar 

  • Chen S, Short JA, Young DF, Killip MJ, Schneider M, Goodbourn S, Randall RE (2010) Heterocellular induction of interferon by negative-sense RNA viruses. Virology 407:247–255

    Article  PubMed  CAS  Google Scholar 

  • Chopy D, Pothlichet J, Lafage M et al (2011) Ambivalent role of the innate immune response in rabies virus pathogenesis. J Virol 85:6657–6668

    Article  PubMed  CAS  Google Scholar 

  • Conrady CD, Drevets DA, Carr DJ (2010) Herpes simplex type I (HSV-1) infection of the nervous system: is an immune response a good thing? J Neuroimmunol 220:1–9

    Article  PubMed  CAS  Google Scholar 

  • D'Agostino PM, Amenta JJ, Reiss CS (2009) IFN-beta-induced alteration of VSV protein phosphorylation in neuronal cells. Viral Immunol 22:353–369

    Article  PubMed  Google Scholar 

  • Detje CN, Meyer T, Schmidt H, Kreuz D, Rose JK, Bechmann I, Prinz M, Kalinke U (2009) Local type I IFN receptor signaling protects against virus spread within the central nervous system. J Immunol 182:2297–2304

    Article  PubMed  CAS  Google Scholar 

  • Faul EJ, Wanjalla CN, McGettigan JP, Schnell MJ (2008) Interferon-beta expressed by a rabies virus-based HIV-1 vaccine vector serves as a molecular adjuvant and decreases pathogenicity. Virology 382:226–238

    Article  PubMed  CAS  Google Scholar 

  • Faul EJ, Wanjalla CN, Suthar MS et al (2010) Rabies virus infection induces type I interferon production in an IPS-1 dependent manner while dendritic cell activation relies on IFNAR signaling. PLoS Pathog 6:e1001016

    Article  PubMed  Google Scholar 

  • Floris S, Ruuls SR, Wierinckx A, van der Pol SM, Dopp E, van der Meide PH, Dijkstra CD, De Vries HE (2002) Interferon-beta directly influences monocyte infiltration into the central nervous system. J Neuroimmunol 127:69–79

    Article  PubMed  CAS  Google Scholar 

  • Fragkoudis R, Tamberg N, Siu R, Kiiver K, Kohl A, Merits A, Fazakerley JK (2009) Neurons and oligodendrocytes in the mouse brain differ in their ability to replicate Semliki Forest virus. J Neurovirol 15:57–70

    Article  PubMed  CAS  Google Scholar 

  • Fu ZF, Jackson AC (2005) Neuronal dysfunction and death in rabies virus infection. J Neurovirol 11:101–106

    Article  PubMed  CAS  Google Scholar 

  • Galelli A, Baloul L, Lafon M (2000) Abortive rabies virus central nervous infection is controlled by T lymphocyte local recruitment and induction of apoptosis. J Neurovirol 6:359–372

    Article  PubMed  CAS  Google Scholar 

  • Hornung V, Ellegast J, Kim S, Brzozka K, Jung A, Kato H, Poeck H, Akira S, Conzelmann KK, Schlee M, Endres S, Hartmann G (2006) 5′-Triphosphate RNA is the ligand for RIG-I. Science 314:994–997

    Article  PubMed  Google Scholar 

  • Ida-Hosonuma M, Iwasaki T, Yoshikawa T, Nagata N, Sato Y, Sata T, Yoneyama M, Fujita T, Taya C, Yonekawa H, Koike S (2005) The alpha/beta interferon response controls tissue tropism and pathogenicity of poliovirus. J Virol 79:4460–4469

    Article  PubMed  CAS  Google Scholar 

  • Ireland DD, Stohlman SA, Hinton DR, Atkinson R, Bergmann CC (2008) Type I interferons are essential in controlling neurotropic coronavirus infection irrespective of functional CD8 T cells. J Virol 82:300–310

    Article  PubMed  CAS  Google Scholar 

  • Ito N, Moseley GW, Blondel D, Shimizu K, Rowe CL, Ito Y, Masatani T, Nakagawa K, Jans DA, Sugiyama M (2010) Role of interferon antagonist activity of rabies virus phosphoprotein in viral pathogenicity. J Virol 84:6699–6710

    Article  PubMed  CAS  Google Scholar 

  • Jackson AC, Randle E, Lawrance G, Rossiter JP (2008) Neuronal apoptosis does not play an important role in human rabies encephalitis. J Neurovirol 14:368–375

    Article  PubMed  CAS  Google Scholar 

  • Johnson N, McKimmie CS, Mansfield KL, Wakeley PR, Brookes SM, Fazakerley JK, Fooks AR (2006) Lyssavirus infection activates interferon gene expression in the brain. J Gen Virol 87:2663–2667

    Article  PubMed  CAS  Google Scholar 

  • Jolly C (2011) Cell-to-cell transmission of retroviruses: innate immunity and interferon-induced restriction factors. Virology 411:251–259

    Article  PubMed  CAS  Google Scholar 

  • Kuss SK, Etheredge CA, Pfeiffer JK (2008) Multiple host barriers restrict poliovirus trafficking in mice. PLoS Pathog 4:e1000082

    Article  PubMed  Google Scholar 

  • Lafon M (2008) Immune evasion, a critical strategy for rabies virus. Dev Biol (Basel) 131:413–419

    CAS  Google Scholar 

  • Lafon M, Wiktor TJ (1985) Antigenic sites on the ERA rabies virus nucleoprotein and non-structural protein. J Gen Virol 66(Pt 10):2125–2133

    Article  PubMed  CAS  Google Scholar 

  • Lafon M, Prehaud C, Megret F, Lafage M, Mouillot G, Roa M, Moreau P, Rouas-Freiss N, Carosella ED (2005) Modulation of HLA-G expression in human neural cells after neurotropic viral infections. J Virol 79:15226–15237

    Article  PubMed  CAS  Google Scholar 

  • Lafon M, Megret F, Meuth SG, Simon O, Velandia Romero ML, Lafage M, Chen L, Alexopoulou L, Flavell RA, Prehaud C, Wiendl H (2008) Detrimental contribution of the immuno-inhibitor b7-h1 to rabies virus encephalitis. J Immunol 180:7506–7515

    PubMed  CAS  Google Scholar 

  • Laothamatas J, Wacharapluesadee S, Lumlertdacha B, Ampawong S, Tepsumethanon V, Shuangshoti S, Phumesin P, Asavaphatiboon S, Worapruekjaru L, Avihingsanon Y, Israsena N, Lafon M, Wilde H, Hemachudha T (2008) Furious and paralytic rabies of canine origin: neuroimaging with virological and cytokine studies. J Neurovirol 14:119–129

    Article  PubMed  CAS  Google Scholar 

  • Lodmell DL, Wiedbrauk DL, Ewalt LC (1989) Interferon induced within the central nervous system during infection is inconsequential as a mechanism responsible for murine resistance to street rabies virus. J Gen Virol 70(Pt 2):473–478

    Article  PubMed  CAS  Google Scholar 

  • Marcovistz R, Germano PM, Riviere Y, Tsiang H, Hovanessian AG (1987) The effect of interferon treatment in rabies prophylaxis in immunocompetent, immunosuppressed, and immunodeficient mice. J Interferon Res 7:17–27

    Article  PubMed  CAS  Google Scholar 

  • Masatani T, Ito N, Shimizu K et al (2010a) Amino acids at positions 273 and 394 in rabies virus nucleoprotein are important for both evasion of host RIG-I-mediated antiviral response and pathogenicity. Virus Res 155:168–174

    Article  PubMed  Google Scholar 

  • Masatani T, Ito N, Shimizu K, Ito Y, Nakagawa K, Sawaki Y, Koyama H, Sugiyama M (2010b) Rabies virus nucleoprotein functions to evade activation of the RIG-I-mediated antiviral response. J Virol 84:4002–4012

    Article  PubMed  CAS  Google Scholar 

  • McFadden G, Mohamed MR, Rahman MM, Bartee E (2009) Cytokine determinants of viral tropism. Nat Rev Immunol 9:645–655

    Article  PubMed  CAS  Google Scholar 

  • Menager P, Roux P, Megret F, Bourgeois JP, Le Sourd AM, Danckaert A, Lafage M, Prehaud C, Lafon M (2009) Toll-like receptor 3 (TLR3) plays a major role in the formation of rabies virus Negri Bodies. PLoS Pathog 5:e1000315

    Article  PubMed  Google Scholar 

  • Muller U, Steinhoff U, Reis LF, Hemmi S, Pavlovic J, Zinkernagel RM, Aguet M (1994) Functional role of type I and type II interferons in antiviral defense. Science 264:1918–1921

    Article  PubMed  CAS  Google Scholar 

  • Pfeiffer JK (2010) Innate host barriers to viral trafficking and population diversity: lessons learned from poliovirus. Adv Virus Res 77:85–118

    Article  PubMed  CAS  Google Scholar 

  • Prehaud C, Megret F, Lafage M, Lafon M (2005) Virus infection switches TLR-3-positive human neurons to become strong producers of beta interferon. J Virol 79:12893–12904

    Article  PubMed  CAS  Google Scholar 

  • Prehaud C, Wolff N, Terrien E, Lafage M, Megret F, Babault N, Cordier F, Tan GS, Maitrepierre E, Menager P, Chopy D, Hoos S, England P, Delepierre M, Schnell MJ, Buc H, Lafon M (2010) Attenuation of rabies virulence: takeover by the cytoplasmic domain of its envelope protein. Sci Signal 3:ra5

    Article  PubMed  Google Scholar 

  • Prinz M, Schmidt H, Mildner A, Knobeloch KP, Hanisch UK, Raasch J, Merkler D, Detje C, Gutcher I, Mages J, Lang R, Martin R, Gold R, Becher B, Bruck W, Kalinke U (2008) Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system. Immunity 28:675–686

    Article  PubMed  CAS  Google Scholar 

  • Raaben M, Groot Koerkamp MJ, Rottier PJ, de Haan CA (2009) Type I interferon receptor-independent and -dependent host transcriptional responses to mouse hepatitis coronavirus infection in vivo. BMC Genomics 10:350

    Article  PubMed  Google Scholar 

  • Rieder M, Conzelmann KK (2009) Rhabdovirus evasion of the interferon system. J Interferon Cytokine Res 29:499–509

    Article  PubMed  CAS  Google Scholar 

  • Rieder M, Brzozka K, Pfaller CK, Cox JH, Stitz L, Conzelmann KK (2011) Genetic dissection of interferon-antagonistic functions of rabies virus phosphoprotein: inhibition of interferon regulatory factor 3 activation is important for pathogenicity. J Virol 85:842–852

    Article  PubMed  CAS  Google Scholar 

  • Sadler AJ, Williams BR (2008) Interferon-inducible antiviral effectors. Nat Rev Immunol 8:559–568

    Article  PubMed  CAS  Google Scholar 

  • Scott CA, Rossiter JP, Andrew RD, Jackson AC (2008) Structural abnormalities in neurons are sufficient to explain the clinical disease and fatal outcome of experimental rabies in yellow fluorescent protein-expressing transgenic mice. J Virol 82:513–521

    Article  PubMed  CAS  Google Scholar 

  • Shimizu K, Ito N, Sugiyama M, Minamoto N (2006) Sensitivity of rabies virus to type I interferon is determined by the phosphoprotein gene. Microbiol Immunol 50:975–978

    PubMed  CAS  Google Scholar 

  • Steinhoff U, Muller U, Schertler A, Hengartner H, Aguet M, Zinkernagel RM (1995) Antiviral protection by vesicular stomatitis virus-specific antibodies in alpha/beta interferon receptor-deficient mice. J Virol 69:2153–2158

    PubMed  CAS  Google Scholar 

  • Thoulouze MI, Lafage M, Montano-Hirose JA, Lafon M (1997) Rabies virus infects mouse and human lymphocytes and induces apoptosis. J Virol 71:7372–7380

    PubMed  CAS  Google Scholar 

  • Torres-Anjel MJ, Volz D, Torres MJ, Turk M, Tshikuka JG (1988) Failure to thrive, wasting syndrome, and immunodeficiency in rabies: a hypophyseal/hypothalamic/thymic axis effect of rabies virus. Rev Infect Dis 10(Suppl 4):S710–S725

    Article  PubMed  Google Scholar 

  • Trinchieri G (2010) Type I interferon: friend or foe? J Exp Med 207:2053–2063

    Article  PubMed  CAS  Google Scholar 

  • Trottier MD Jr, Palian BM, Reiss CS (2005) VSV replication in neurons is inhibited by type I IFN at multiple stages of infection. Virology 333:215–225

    Article  PubMed  CAS  Google Scholar 

  • Veldhuis WB, Floris S, van der Meide PH, Vos IM, de Vries HE, Dijkstra CD, Bar PR, Nicolay K (2003) Interferon-beta prevents cytokine-induced neutrophil infiltration and attenuates blood–brain barrier disruption. J Cereb Blood Flow Metab 23:1060–1069

    Article  PubMed  CAS  Google Scholar 

  • Vercammen E, Staal J, Beyaert R (2008) Sensing of viral infection and activation of innate immunity by toll-like receptor 3. Clin Microbiol Rev 21:13–25

    Article  PubMed  CAS  Google Scholar 

  • Vidy A, Chelbi-Alix M, Blondel D (2005) Rabies virus P protein interacts with STAT1 and inhibits interferon signal transduction pathways. J Virol 79:14411–14420

    Article  PubMed  CAS  Google Scholar 

  • Vidy A, El Bougrini J, Chelbi-Alix MK, Blondel D (2007) The nucleocytoplasmic rabies virus P protein counteracts interferon signaling by inhibiting both nuclear accumulation and DNA binding of STAT1. J Virol 81:4255–4263

    Article  PubMed  CAS  Google Scholar 

  • Wang ZW, Sarmento L, Wang Y, Li XQ, Dhingra V, Tseggai T, Jiang B, Fu ZF (2005) Attenuated rabies virus activates, while pathogenic rabies virus evades, the host innate immune responses in the central nervous system. J Virol 79:12554–12565

    Article  PubMed  CAS  Google Scholar 

  • Zhao L, Toriumi H, Kuang Y, Chen H, Fu ZF (2009) The roles of chemokines in rabies virus infection: overexpression may not always be beneficial. J Virol 83:11808–11818

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are grateful to Christophe Préhaud for helpful advice and to the animal keepers from the Institut Pasteur animal facility for breeding the IFNAR−/− mice.

This work was supported by internal grants of Institut Pasteur. Damien Chopy is the recipient of a fellowship from the French Ministère de l’Enseignement Supérieur et de la Recherche.

Author information

Authors and Affiliations

  1. Département de Virologie Institut Pasteur, Unité de Neuroimmunologie Virale, 75015, Paris, France

    Damien Chopy, Mireille Lafage & Monique Lafon

  2. CNRS, URA 3015, F -75015, Paris, France

    Damien Chopy, Mireille Lafage & Monique Lafon

  3. Institut Pasteur, F-75015, Paris, France

    Damien Chopy, Mireille Lafage & Monique Lafon

  4. Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Medical School Hannover, Hannover, Germany

    Claudia N. Detje & Ulrich Kalinke

Authors
  1. Damien Chopy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Claudia N. Detje
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mireille Lafage
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ulrich Kalinke
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Monique Lafon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Monique Lafon.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary data 1–2

(PDF 585 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chopy, D., Detje, C.N., Lafage, M. et al. The type I interferon response bridles rabies virus infection and reduces pathogenicity. J. Neurovirol. 17, 353–367 (2011). https://doi.org/10.1007/s13365-011-0041-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13365-011-0041-6

Keywords

Search

Navigation