Skip to main content

Advertisement

SpringerLink
Log in

A Recombinant Rabies Virus Expressing Fms-like Tyrosine Kinase 3 Ligand (Flt3L) Induces Enhanced Immunogenicity in Mice

  • Research Article
  • Published:
Virologica Sinica

Abstract

Rabies is a zoonotic disease that still causes 59,000 human deaths each year, and rabies vaccine is the most effective way to control the disease. Our previous studies suggested that the maturation of DC plays an important role in enhancing the immunogenicity of rabies vaccine. Flt3L has been reported to own the ability to accelerate the DC maturation, therefore, in this study, a recombinant rabies virus expressing mouse Flt3L, designated as LBNSE-Flt3L, was constructed, and its immunogenicity was characterized. It was found that LBNSE-Flt3L could enhance the maturation of DC both in vitro and in vivo, and significantly more TFH cells and Germinal Center B (GC B) cells were generated in mice immunized with LBNSE-Flt3L than those immunized with the parent virus LBNSE. Consequently, expressing of Flt3L could elevate the level of virus-neutralizing antibodies (VNA) in immunized mice which provides a better protection from a lethal rabies virus challenge. Taken together, our study extends the potential of Flt3L as a good adjuvant to develop novel rabies vaccine by enhancing the VNA production through activating the DC–TFH–GC B axis in immunized mice.

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
Fig. 7

Similar content being viewed by others

References

  • Abelaridder B (2015) Rabies: 100 per cent fatal, 100 per cent preventable. Vet Rec 177:148–149

    Article  CAS  Google Scholar 

  • Acharya AS, Kaur R, Lakra K (2012) Rabies epidemiology and control in India: a review. J Commun Dis 44:59–69

    PubMed  Google Scholar 

  • Adedeji AO, Okonko IO, Eyarefe OD, Adedeji OB, Babalola ET, Ojezele MO, Nwanze JC, Amusan TA (2010) An overview of rabies—history, epidemiology, control and possible elimination. Afr J Microbiol Res 4:2327–2338

    Google Scholar 

  • Adolfsson J, Borge JO, Bryder D, TheilgaardMönch K, ÅstrandGrundström I (2001) Upregulation of Flt3 expression within the bone marrow Lin − Sca1 + c-kit + stem cell compartment is accompanied by loss of self-renewal capacity. Immunity 15:659–669

    Article  CAS  PubMed  Google Scholar 

  • Alizadeh L, Dana MA, Dowom PB, Ghaemi A (2015) Immunology of rabies virus in the central nervous system. Osong Public Health Res Perspect 3:113–120

    Google Scholar 

  • Anandasabapathy N, Feder R, Mollah S, Tse SW, Longhi MP, Mehandru S, Matos I, Cheong C, Ruane D, Brane L (2014) Classical Flt3L-dependent dendritic cells control immunity to protein vaccine. J Exp Med 211:1875–1891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ayres JA, Barraviera B, Calvi SA, Carvalho NR, Peraçoli MTS (2006) Antibody and cytokine serum levels in patients subjected to anti-rabies prophylaxis with serum-vaccination. J Venom Anim Toxins Incl Trop Dis 12:435–455

    Article  CAS  Google Scholar 

  • Chen T, Zhang Y, Wang Z, Yang J, Li M, Wang K, Cui M, Fu ZF, Zhao L, Zhou M (2017) Recombinant rabies virus expressing IL-15 enhances immunogenicity through promoting the activation of dendritic cells in mice. Virol Sin 32:317–327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Conzelmann KK, Cox JH, Schneider LG, Thiel HJ (1990) Molecular cloning and complete nucleotide sequence of the attenuated rabies virus SAD B19. Virology 175:485–499

    Article  CAS  PubMed  Google Scholar 

  • Dodet B (2010) Report of the sixth AREB meeting, Manila, The Philippines, 10–12 November 2009. Vaccine 28:3265–3268

    Article  CAS  PubMed  Google Scholar 

  • Dupont CD, Pritchard GH, Hidano S, Christian DA, Wagage S, Muallem G, Wojno EDT, Hunter CA (2015) Flt3L is essential for survival and protective immune responses during toxoplasmosis. J Immunol 195:4369–4377

    Article  CAS  PubMed  Google Scholar 

  • Gao FS, Zhan YT, Wang XD, Zhang C (2018) Enhancement of anti-tumor effect of plasmid DNA-carrying MUC1 by the adjuvanticity of FLT3L in mouse model. Immunopharmacol Immunotoxicol 40:1–5

    Article  CAS  Google Scholar 

  • Garg R, Shrivastava P, Van Drunen Littel-van den Hurk S (2012) The role of dendritic cells in innate and adaptive immunity to respiratory syncytial virus, and implications for vaccine development. Expert Rev Vaccines 11:1441–1457

    Article  CAS  PubMed  Google Scholar 

  • Ge Y, Waldemer RJ, Nalluri R, Nuzzi PD, Chen J (2013) Flt3L is a novel regulator of skeletal myogenesis. J Cell Sci 126:3370–3379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gilboa E (2007) DC-based cancer vaccines. J Clin Investig 117:1195–1203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hooper DC, Morimoto K, Bette M, Weihe E, Koprowski H, Dietzschold B (1998) Collaboration of antibody and inflammation in clearance of rabies virus from the central nervous system. J Virol 72:3711–3719

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hu R, Tang Q, Tang J, Fooks AR (2009) Rabies in China: an update. Vector Borne Zoonotic Dis 9:1–12

    Article  PubMed  Google Scholar 

  • Kodama S, Hirano T, Noda K, Abe N, Suzuki M (2010) A single nasal dose of fms-like tyrosine kinase receptor-3 ligand, but not peritoneal application, enhances nontypeable Haemophilus influenzae-specific long-term mucosal immune responses in the nasopharynx. Vaccine 28:2510–2516

    Article  CAS  PubMed  Google Scholar 

  • Kreiter S, Diken M, Selmi A, Diekmann J, Attig S, Husemann Y, Koslowski M, Huber C, Tureci O, Sahin U (2011) FLT3 ligand enhances the cancer therapeutic potency of naked RNA vaccines. Cancer Res 71:6132–6142

    Article  CAS  PubMed  Google Scholar 

  • Kreiter S, Diken M, Selmi A, Petschenka J, Tureci O, Sahin U (2016) FLT3 ligand as a molecular adjuvant for naked RNA vaccines. Methods Mol Biol 1428:163–175

    Article  CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  • Lutz MB, Kukutsch N, Ogilvie AL, Rössner S, Koch F, Romani N, Schuler G (1999) An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods 223:77–92

    Article  CAS  PubMed  Google Scholar 

  • Mathers AR, Larregina AT (2006) Professional antigen-presenting cells of the skin. Immunol Res 36:127–136

    Article  CAS  PubMed  Google Scholar 

  • Miao X, Chen Y, Hao K, Zheng M, Chen B, Li K, Wang Y, Zhang W, Zhang Y, Mou X, Jiang S, Wang Z (2018) CD103(+) cell growth factor Flt3L enhances the efficacy of immune checkpoint blockades in murine glioblastoma model. Oncol Res 26:173–182

    Article  PubMed  PubMed Central  Google Scholar 

  • Morita R, Schmitt N, Bentebibel SE, Ranganathan R, Bourdery L, Zurawski G, Foucat E, Dullaers M, Oh S, Sabzghabaei N, Lavecchio EM, Punaro M, Pascual V, Banchereau J, Ueno H (2011) Human blood CXCR24(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity 34:108–121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murphy FA, Bauer SP (1974) Early street rabies virus infection in striated muscle and later progression to the central nervous system. Intervirology 3:256–268

    Article  CAS  PubMed  Google Scholar 

  • Mwangi DM, Honda Y, Graham SP, Pelle R, Taracha EL, Gachanja J, Nyanjui JK, Bray J, Palmer GH, Brown WC, Mwangi W (2011) Treatment of cattle with DNA-encoded Flt3L and GM–CSF prior to immunization with Theileria parva candidate vaccine antigens induces CD4 and CD8 T cell IFN-gamma responses but not CTL responses. Vet Immunol Immunopathol 140:244–251

    Article  CAS  PubMed  Google Scholar 

  • Nurieva RI, Chung Y, Hwang D, Yang XO, Kang HS, Ma L, Wang YH, Watowich SS, Jetten AM, Tian Q, Dong C (2008) Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29:138–149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Okonko IO, Adedeji OB, Babalola ET, Fajobi EA, Fowotade A, Adewale OG (2010) Why is there still rabies in the world?—An emerging microbial and global health threat. Glob Vet 4:34–50

    Google Scholar 

  • Pabst R, Luhrmann A, Steinmetz I, Tschernig T (2003) A single intratracheal dose of the growth factor Fms-like tyrosine kinase receptor-3 ligand induces a rapid differential increase of dendritic cells and lymphocyte subsets in lung tissue and bronchoalveolar lavage, resulting in an increased local antibody production. J Immunol 171:325–330

    Article  CAS  PubMed  Google Scholar 

  • Rasalingam P, Rossiter JP, Mebatsion T, Jackson AC (2005) Comparative pathogenesis of the SAD-L16 strain of rabies virus and a mutant modifying the dynein light chain binding site of the rabies virus phosphoprotein in young mice. Virus Res 111:55–60

    Article  CAS  PubMed  Google Scholar 

  • Schnell MJ, Mebatsion T, Conzelmann KK (1994) Infectious rabies viruses from cloned cDNA. EMBO J 13:4195–4203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scotch M, Odofin L, Rabinowitz P (2009) Linkages between animal and human health sentinel data. BMC Vet Res 5:15–24

    Article  PubMed  PubMed Central  Google Scholar 

  • Song M, Tang Q, Rayner S, Tao XY, Li H, Guo ZY, Shen XX, Jiao WT, Fang W, Wang J, Liang GD (2014) Human rabies surveillance and control in China, 2005–2012. BMC Infect Dis 14:212–221

    Article  PubMed  PubMed Central  Google Scholar 

  • Sudarshan MK, Madhusudana SN, Mahendra BJ, Rao NS, Ashwath Narayana DH, Abdul Rahman S, Meslin F, Lobo D, Ravikumar K, Gangaboraiah (2007) Assessing the burden of human rabies in India: results of a national multi-center epidemiological survey. Int J Infect Dis 11:29–35

    Article  CAS  PubMed  Google Scholar 

  • Svensson MN, Andersson SE, Erlandsson MC, Jonsson IM, Ekwall AK, Andersson KM, Nilsson A, Bian L, Brisslert M, Bokarewa MI (2013) Fms-like tyrosine kinase 3 ligand controls formation of regulatory T cells in autoimmune arthritis. PLoS ONE 8:e54884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tian D, Luo Z, Zhou M, Li M, Yu L, Wang C, Yuan J, Li F, Tian B, Sui B (2015) Critical role of K1685 and K1829 in the large protein of rabies virus in viral pathogenicity and immune evasion. J Virol 90:232–244

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Waskow C, Liu K, Darrassejèze G, Guermonprez P, Ginhoux F, Merad M, Shengelia T, Yao K, Nussenzweig M (2008) The receptor tyrosine kinase Flt3 is required for dendritic cell development in peripheral lymphoid tissues. Nat Immunol 9:676–683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wen Y, Wang H, Wu H, Yang F, Tripp RA, Hogan RJ, Fu ZF (2011) Rabies virus expressing dendritic cell-activating molecules enhances the innate and adaptive immune response to vaccination. J Virol 85:1634–1644

    Article  CAS  PubMed  Google Scholar 

  • WHO (2013) WHO expert consultation on rabies. Second report. World Health Organ Tech Rep Ser 982:1

  • Wu X, Smith TG, Franka R, Wang M, Carson WC, Rupprecht CE (2014) The feasibility of rabies virus-vectored immunocontraception in a mouse model. Trials Vaccinol 3:11–18

    Article  Google Scholar 

  • Wunner WH, Briggs DJ (2010) Rabies in the 21 century. PLoS Negl Trop Dis 4:e591

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Xu Q, Zhu YF, Wang HC, Gong ZW, Yu YZ (2016) Enhanced efficacy of DNA vaccination against botulinum neurotoxin serotype A by co-administration of plasmids encoding DC-stimulating Flt3L and MIP-3alpha cytokines. Biologicals 44:441–447

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou Q, Wang F, Yang F, Wang Y, Zhang X, Sun S (2010) Augmented humoral and cellular immune response of hepatitis B virus DNA vaccine by micro-needle vaccination using Flt3L as an adjuvant. Vaccine 28:1357–1362

    Article  CAS  PubMed  Google Scholar 

  • Zhou M, Zhang G, Ren G, Gnanadurai CW, Li Z, Chai Q, Yang Y, Leyson CM, Wu W, Cui M, Fu ZF (2013) Recombinant rabies viruses expressing GM–CSF or flagellin are effective vaccines for both intramuscular and oral immunizations. PLoS ONE 8:e63384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou M, Wang L, Zhou S, Wang Z, Ruan J, Tang L, Jia Z, Cui M, Zhao L, Fu ZF (2015) Recombinant rabies virus expressing dog GM–CSF is an efficacious oral rabies vaccine for dogs. Oncotarget 6:38504–38516

    PubMed  PubMed Central  Google Scholar 

  • Zurkova K, Hainz P, Krystofova J, Kutinova L, Sanda M, Nemeckova S (2010) Attenuation of vaccinia virus by the expression of human Flt3 ligand. Virol J 7:109–124

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

This study was partially supported by the National Program on Key Research Project of China (2016YFD0500400 and 2017YFD0501701), the National Natural Science Foundation of China (31872494, 31402176, 31372419, and 31522057), the Fundamental Research Funds for the Central Universities (No. 2662016QD036 to MZ), the Ministry of Science and Technology of China (863 program, No. 2011AA10A212), and the Ministry of Agriculture of China (Special Fund for Agro-scientific Research in the Public Interest, No. 201303042 to ZFF).

Author information

Author notes

  1. Yachun Zhang and Jie Yang have contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China

    Yachun Zhang, Jie Yang, Mingming Li, Min Cui, Zhen F. Fu, Ling Zhao & Ming Zhou

  2. Key Laboratory of Preventive Veterinary Medicine of Hubei Province, Huazhong Agricultural University, Wuhan, 430070, China

    Yachun Zhang, Jie Yang, Mingming Li, Min Cui, Zhen F. Fu, Ling Zhao & Ming Zhou

  3. Department of Pathology, University of Georgia, Athens, GA, 30602, USA

    Zhen F. Fu

Authors
  1. Yachun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jie Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mingming Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Min Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhen F. Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ling Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ming Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Experimental design was conducted by MZ and LZ. Experiments were finished by YZ, JY, and ML. Data analysis was conducted by MZ, LZ, ZFF, and MC. The manuscript was written by YZ, and revised by MZ and LZ.

Corresponding authors

Correspondence to Ling Zhao or Ming Zhou.

Ethics declarations

Animal and Human Rights Statement

The animal experiments were carried out in strict accordance with the protocols approved by The Scientific Ethics Committee of Huazhong Agricultural University (permit number: HZAUMO-2015-029). All institutional and national guidelines for the care and use of laboratory animals were followed.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Y., Yang, J., Li, M. et al. A Recombinant Rabies Virus Expressing Fms-like Tyrosine Kinase 3 Ligand (Flt3L) Induces Enhanced Immunogenicity in Mice. Virol. Sin. 34, 662–672 (2019). https://doi.org/10.1007/s12250-019-00144-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12250-019-00144-x

Keywords

Search

Navigation