Targeting nucleoprotein via CD40L preferentially modulates immune response and enhances protection against influenza virus infection
Anwar
M.
Hashem1, 2, 3,
Caroline
Gravel2,
Monika
Tocchi2,
Bozena
Jaentschke2,
Xingliang
Fan4,
Changgui
Li4,
Michael
Rosu-Myles2,
Alexander
Pereboev5,
Runtao
He6,
Wang
Junzhi4* and
Xuguang
Li2, 3, 7*
-
1
King Abdulaziz University, Department of Medical Microbiology and Parasitology, Faculty of Medicine, Saudi Arabia
-
2
Health Canada, Centre for Vaccine Evaluation, Biologics and Genetic Therapies Directorate, HPFB, Canada
-
3
University of Ottawa, Department of Biochemistry, Microbiology and Immunology, Canada
-
4
National Institutes for the Control of Food and Drug, China
-
5
University of Alabama at Birmingham, Division of Human Gene Therapy, Department of Medicine, Department of Obstetrics and Gynecology, Department of Pathology and Surgery, and Gene Therapy Center, United States
-
6
Public Health Agency of Canada, National Microbiology Laboratory, Canada
-
7
University of Ottawa, Emerging Pathogens Research Centre, Canada
CD40 ligand (CD40L) is one of the key regulators of the immune system (1,2). Here, we determined the potential of CD40L as both a targeting ligand and a molecular adjuvant in host defense against influenza (3,4). Specifically, recombinant adenovirus (rAd) carrying a fused gene encoding for influenza viral nucleoprotein (NP) and CD40L was generated (rAd-SNP40L) and studied in a mouse model (5,6). A single dose of rAd-SNP40L secreting the fusion protein NP-CD40L provided substantially enhanced protection against lethal virus challenge in normal mice. Mechanistically, rAd-SNP40L preferentially induced early and persistent B-cell germinal center formation, accelerated immunoglobulin isotype-switching and TH1-skewed NP-specific immune response. Moreover, it significantly enhanced primary and secondary NP-specific cytotoxic T-lymphocyte (CTL) activity and multiple cytokine producing-CD8+ T cells. Transfer of sera or CD8+ T cells from rAd-SNP40L-immunized mice rendered the recipient naïve mice resistant to viral challenge, suggesting a role for both NP-specific antibodies and CTLs in protection. Moreover, rAd-SNP40L afforded equally effective protection in CD40L-/- and CD4-/- mice, confirming that the rAd-SNP40L-mediated protection against influenza is CD40L-mediated and CD4+ T cell-independent. Importantly, mice immunized with a single dose of rAd-SNP40L retained complete protection against lethal challenge four months post-immunization, indicating a robust and long-lasting memory immune response induction against influenza.
Acknowledgements
We thank Louise Larocque, Marsha Russell, Emily Chomyshyn and Michelle Lemieux for technical assistance. We are so grateful to Dr. Martha Navarro and all technicians in the animal facility for their help. A.M.H. is supported by a scholarship from King Abdulaziz University, through the Saudi Arabian Cultural Bureau in Canada. This work was supported by the Canadian Regulatory Strategy for Biotechnology.
References
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2. Quezada SA, Jarvinen LZ, Lind EF, Noelle RJ. CD40/CD154 interactions at the interface of tolerance and immunity. Annu Rev Immunol (2004) 22: 307–328.
3. Pereboev AV, Nagle JM, Shakhmatov MA, Triozzi PL, Matthews QL, Kawakami Y, Curiel DT, Blackwell JL. Enhanced gene transfer to mouse dendritic cells using adenoviral vectors coated with a novel adapter molecule. Mol Ther (2004) 9: 712–720.
4. Huang D, Pereboev AV, Korokhov N, He R, Larocque L, Gravel C, Jaentschke B, Tocchi M, Casley WL, Lemieux M, Curiel DT, Chen W, Li X. Significant alterations of biodistribution and immune responses in Balb/c mice administered with adenovirus targeted to CD40(+) cells. Gene Ther (2008) 15: 298–308.
5. Epstein SL, Kong W-P, Misplon JA, Lo C-Y, Tumpey TM, Xu L, Nabel GJ. Protection against multiple influenza A subtypes by vaccination with highly conserved nucleoprotein. Vaccine (2005) 23: 5404–5410.
6. Hashem AM, Jaentschke B, Gravel C, Tocchi M, Doyle T, Rosu-Myles M, He R, Li X. Subcutaneous immunization with recombinant adenovirus expressing influenza A nucleoprotein protects mice against lethal viral challenge. Hum Vaccin Immunother (2012) 8: 425–430.
Keywords:
CD40L,
Influenza Virus,
nucleoprotein,
Recombinant Adenvirus,
Polyfunctional CD8+ T cells
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Translational immunology and immune intervention
Citation:
Hashem
AM,
Gravel
C,
Tocchi
M,
Jaentschke
B,
Fan
X,
Li
C,
Rosu-Myles
M,
Pereboev
A,
He
R,
Junzhi
W and
Li
X
(2013). Targeting nucleoprotein via CD40L preferentially modulates immune response and enhances protection against influenza virus infection.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.01133
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Received:
23 Jul 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Dr. Wang Junzhi, National Institutes for the Control of Food and Drug, Beijing, China, wangjz@nifdc.org.cn
Dr. Xuguang Li, Health Canada, Centre for Vaccine Evaluation, Biologics and Genetic Therapies Directorate, HPFB, Ottawa, ON, Canada, sean.li@hc-sc.gc.ca