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N-terminal fusion of a toll-like receptor 2-ligand to a Neospora caninum chimeric antigen efficiently modifies the properties of the specific immune response

Published online by Cambridge University Press:  02 March 2016

ADRIANA AGUADO-MARTÍNEZ ,
AFONSO P. BASTO ,
JOACHIM MÜLLER ,
VRENI BALMER ,
VERA MANSER ,
ALEXANDRE LEITÃO  and
ANDREW HEMPHILL
ADRIANA AGUADO-MARTÍNEZ*
Affiliation:
Institute for Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, CH-3012 Bern, Switzerland
AFONSO P. BASTO
Affiliation:
CIISA, Faculdade de Medicina Veterinária, ULisboa, Avenida da Universidade Técnica, 1300–477 Lisboa, Portugal
JOACHIM MÜLLER
Affiliation:
Institute for Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, CH-3012 Bern, Switzerland
VRENI BALMER
Affiliation:
Institute for Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, CH-3012 Bern, Switzerland
VERA MANSER
Affiliation:
Institute for Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, CH-3012 Bern, Switzerland
ALEXANDRE LEITÃO
Affiliation:
CIISA, Faculdade de Medicina Veterinária, ULisboa, Avenida da Universidade Técnica, 1300–477 Lisboa, Portugal
ANDREW HEMPHILL
Affiliation:
Institute for Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, CH-3012 Bern, Switzerland
*
*Corresponding author: Institute of Parasitology, University of Bern, Länggas-Strasse 122, 3012 Bern, Switzerland. Tel: +41 31 631 2593. Fax: +41 31 631 2477. E-mail: [email protected]
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Summary

Immunoprophylactic products against neosporosis during pregnancy should induce an appropriately balanced immune response. In this respect, OprI, a bacterial lipoprotein targeting toll like receptor (TLR)2, provides promising adjuvant properties. We report on the manipulation of the innate and the T-cell immune response through the fusion of OprI with the Neospora caninum chimeric protein Mic3-1-R. In contrast to Mic3-1-R, OprI-MIC3-1-R significantly activated bone-marrow dendritic cells from naïve mice. Mice immunized with OprI-Mic3-1-R induced an immune response with mixed T helper (Th)1 and Th2 properties (high levels of both immunoglobulin (Ig)G1 and IgG2a and of interleukin (IL)-10, IL-12(p70) and interferon-γ responses) whereas Mic3-1-R+saponin induced a clear Th2-biased response (low IgG2a and high IL-4 and IL-10). After mating and challenge with N. caninum, increased expression of interferon-γ was only found in placentas from OprI-Mic3-1-R immunized dams. However, no protection against vertical transmission and neonatal mortality was observed in either of the two groups. These results indicated that more exhaustive studies must be done to elucidate the immune mechanisms associated with transplacental transmission. Antigen linkage to TLR2-ligands, such as OprI, is a useful tool to investigate this enigma by reorienting the innate and adaptive immune responses against other candidate antigens in future studies.

Keywords

Neosporosisinnate and adaptive immune responseouter membrane lipoprotein Itoll-like receptor 2chimeric antigen
Type
Research Article
Information
Parasitology , Volume 143 , Issue 5 , April 2016 , pp. 606 - 616
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Copyright
Copyright © Cambridge University Press 2016 

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References

REFERENCES

Akira, S. (2009). Pathogen recognition by innate immunity and its signaling. Proceedings of the Japan Academy Series B Physical and Biological Sciences 85, 143–156.CrossRefGoogle ScholarPubMed
Arranz-Solís, D., Aguado-Martínez, A., Müller, J., Regidor-Cerrillo, J., Ortega-Mora, L. M., Hemphill, A. (2015). Dose-dependent effects of experimental infection with the virulent Neospora caninum Nc-Spain7 isolate in a pregnant mouse model. Veterinary Parasitology 211, 133–140.CrossRefGoogle Scholar
Basto, A. P. and Leitao, A. (2014). Targeting TLR2 for vaccine development. Journal of Immunology Research 2014, 619410. doi: 10.1155/2014/619410.Google ScholarPubMed
Basto, A. P., Badenes, M., Almeida, S. C., Martins, C., Duarte, A., Santos, D. M. and Leitao, A. (2015). Immune response profile elicited by the model antigen ovalbumin expressed in fusion with the bacterial OprI lipoprotein. Molecular Immunology 64, 36–45.CrossRefGoogle ScholarPubMed
Basto, A. P., Morais, J., Marcelino, E., Leitao, A. and Santos, D. M. (2014). An efficient depyrogenation method for recombinant bacterial outer membrane lipoproteins. Protein Expression and Purification 98, 10–17.CrossRefGoogle ScholarPubMed
Basto, A. P., Piedade, J., Ramalho, R., Alves, S., Soares, H., Cornelis, P., Martins, C. and Leitao, A. (2012). A new cloning system based on the OprI lipoprotein for the production of recombinant bacterial cell wall-derived immunogenic formulations. Journal of Biotechnology 157, 50–63.CrossRefGoogle ScholarPubMed
Beagley, K. W. and Gockel, C. M. (2003). Regulation of innate and adaptive immunity by the female sex hormones oestradiol and progesterone. FEMS Immunology and Medical Microbiology 38, 13–22.CrossRefGoogle Scholar
Canton, G. J., Konrad, J. L., Moore, D. P., Caspe, S. G., Palarea-Albaladejo, J., Campero, C. M. and Chianini, F. (2014). Characterization of immune cell infiltration in the placentome of water buffaloes (Bubalus bubalis) infected with Neospora caninum during pregnancy. Journal of Comparative Pathology 150, 463–468.CrossRefGoogle ScholarPubMed
Cote-Sierra, J., Bredan, A., Toldos, C. M., Stijlemans, B., Brys, L., Cornelis, P., Segovia, M., de Baetselier, P. and Revets, H. (2002). Bacterial lipoprotein-based vaccines induce tumor necrosis factor-dependent type 1 protective immunity against Leishmania major. Infection and Immunity 70, 240–248.CrossRefGoogle ScholarPubMed
Debache, K. and Hemphill, A. (2013). Differential effects of intranasal vaccination with recombinant NcPDI in different mouse models of Neospora caninum infection. Parasite Immunology 35, 11–20.CrossRefGoogle ScholarPubMed
Debache, K., Guionaud, C., Alaeddine, F. and Hemphill, A. (2010). Intraperitoneal and intra-nasal vaccination of mice with three distinct recombinant Neospora caninum antigens results in differential effects with regard to protection against experimental challenge with Neospora caninum tachyzoites. Parasitology 137, 229–240.CrossRefGoogle ScholarPubMed
Dellarupe, A., Regidor-Cerrillo, J., Jimenez-Ruiz, E., Schares, G., Unzaga, J. M., Venturini, M. C. and Ortega-Mora, L. M. (2014). Comparison of host cell invasion and proliferation among Neospora caninum isolates obtained from oocysts and from clinical cases of naturally infected dogs. Experimental Parasitology 145, 22–28.CrossRefGoogle ScholarPubMed
Dillon, S., Agrawal, S., Banerjee, K., Letterio, J., Denning, T. L., Oswald-Richter, K., Kasprowicz, D. J., Kellar, K., Pare, J., van Dyke, T., Ziegler, S., Unutmaz, D. and Pulendran, B. (2006). Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immunological tolerance. Journal of Clinical Investigation 116, 916–928.CrossRefGoogle ScholarPubMed
Fiorentino, D. F., Zlotnik, A., Vieira, P., Mosmann, T. R., Howard, M., Moore, K. W. and O'Garra, A. (1991). IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. Journal of Immunology 146, 3444–3451.CrossRefGoogle ScholarPubMed
Gartner, T., Baeten, M., Otieno, S., Revets, H., De Baetselier, P. and Huygen, K. (2007). Mucosal prime-boost vaccination for tuberculosis based on TLR triggering OprI lipoprotein from Pseudomonas aeruginosa fused to mycolyl-transferase Ag85A. Immunology Letters 111, 26–35.CrossRefGoogle ScholarPubMed
Innes, E. A., Bartley, P. M., Maley, S. W., Wright, S. E. and Buxton, D. (2007). Comparative host-parasite relationships in ovine toxoplasmosis and bovine neosporosis and strategies for vaccination. Vaccine 25, 5495–5503.CrossRefGoogle ScholarPubMed
Kano, R., Masukata, Y., Omata, Y., Kobayashi, Y., Maeda, R. and Saito, A. (2005). Relationship between type 1/type 2 immune responses and occurrence of vertical transmission in BALB/c mice infected with Neospora caninum . Veterinary Parasitology 129, 159–164.CrossRefGoogle ScholarPubMed
Kano, R., Kudo, A., Kamiya, H., Kobayashi, Y., Maeda, R. and Omata, Y. (2007). C57BL/6 mice infected with Neospora caninum during administration of progesterone show bias toward type 2 immune response. The Journal of Veterinary Medical Science 69, 1095–1097.CrossRefGoogle ScholarPubMed
Leitao, A., Malur, A., Cartaxeiro, C., Vasco, G., Cruz, B., Cornelis, P. and Martins, C. L. (2000). Bacterial lipoprotein based expression vectors as tools for the characterisation of African swine fever virus (ASFV) antigens. Archives of Virology 145, 1639–1657.Google ScholarPubMed
Manicassamy, S., Ravindran, R., Deng, J., Oluoch, H., Denning, T. L., Kasturi, S. P., Rosenthal, K. M., Evavold, B. D. and Pulendran, B. (2009). Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity. Nature Medicine 15, 401–409.CrossRefGoogle ScholarPubMed
Mineo, T. W., Oliveira, C. J., Gutierrez, F. R. and Silva, J. S. (2010). Recognition by Toll-like receptor 2 induces antigen-presenting cell activation and Th1 programming during infection by Neospora caninum . Immunology and Cell Biology 88, 825–833.CrossRefGoogle ScholarPubMed
Monney, T. and Hemphill, A. (2014). Vaccines against neosporosis: what can we learn from the past studies? Experimental Parasitology 140, 52–70.CrossRefGoogle ScholarPubMed
Monney, T., Debache, K., Grandgirard, D., Leib, S. L. and Hemphill, A. (2012). Vaccination with the recombinant chimeric antigen recNcMIC3-1-R induces a non-protective Th2-type immune response in the pregnant mouse model for N. caninum infection. Vaccine 30, 6588–6594.CrossRefGoogle ScholarPubMed
Monney, T., Grandgirard, D., Leib, S. L. and Hemphill, A. (2013). Use of a Th1 stimulator adjuvant for vaccination against Neospora caninum infection in the pregnant mouse model. Pathogens 2, 193–208.CrossRefGoogle ScholarPubMed
Monney, T., Rutti, D., Schorer, M., Debache, K., Grandgirard, D., Leib, S. L. and Hemphill, A. (2011). RecNcMIC3-1-R is a microneme- and rhoptry-based chimeric antigen that protects against acute neosporosis and limits cerebral parasite load in the mouse model for Neospora caninum infection. Vaccine 29, 6967–6975.CrossRefGoogle ScholarPubMed
Muller, J., Sterk, M., Hemphill, A. and Muller, N. (2007). Characterization of Giardia lamblia WB C6 clones resistant to nitazoxanide and to metronidazole. The Journal of Antimicrobial Chemotherapy 60, 280–287.CrossRefGoogle ScholarPubMed
Muller, N., Vonlaufen, N., Gianinazzi, C., Leib, S. L. and Hemphill, A. (2002). Application of real-time fluorescent PCR for quantitative assessment of Neospora caninum infections in organotypic slice cultures of rat central nervous system tissue. Journal of Clinical Microbiology 40, 252–255.CrossRefGoogle ScholarPubMed
Quinn, H. E., Miller, C. M. and Ellis, J. T. (2004). The cell-mediated immune response to Neospora caninum during pregnancy in the mouse is associated with a bias towards production of interleukin-4. International Journal for Parasitology 34, 723–732.CrossRefGoogle ScholarPubMed
Regidor-Cerrillo, J., Gomez-Bautista, M., Pereira-Bueno, J., Aduriz, G., Navarro-Lozano, V., Risco-Castillo, V., Fernandez-Garcia, A., Pedraza-Diaz, S. and Ortega-Mora, L. M. (2008). Isolation and genetic characterization of Neospora caninum from asymptomatic calves in Spain. Parasitology 135, 1651–1659.CrossRefGoogle ScholarPubMed
Reichel, M. P., McAllister, M. M., Pomroy, W. E., Campero, C., Ortega-Mora, L. M. and Ellis, J. T. (2014). Control options for Neospora caninum–is there anything new or are we going backwards? Parasitology 141, 1455–1470.CrossRefGoogle ScholarPubMed
Roberts, C. W., Walker, W. and Alexander, J. (2001). Sex-associated hormones and immunity to protozoan parasites. Clinical Microbiology Reviews 14, 476–488.CrossRefGoogle ScholarPubMed
Rocchi, M. S., Bartley, P. M., Inglis, N. F., Collantes-Fernandez, E., Entrican, G., Katzer, F. and Innes, E. A. (2011). Selection of Neospora caninum antigens stimulating bovine CD4+ve T cell responses through immuno-potency screening and proteomic approaches. Veterinary Research 42, 91.CrossRefGoogle ScholarPubMed
Rowe, J. H., Ertelt, J. M., Aguilera, M. N., Farrar, M. A. and Way, S. S. (2011). Foxp3(+) regulatory T cell expansion required for sustaining pregnancy compromises host defense against prenatal bacterial pathogens. Cell Host & Microbe 10, 54–64.CrossRefGoogle ScholarPubMed
Wang, S., Villablanca, E. J., De Calisto, J., Gomes, D. C., Nguyen, D. D., Mizoguchi, E., Kagan, J. C., Reinecker, H. C., Hacohen, N., Nagler, C., Xavier, R. J., Rossi-Bergmann, B., Chen, Y. B., Blomhoff, R., Snapper, S. B. and Mora, J. R. (2011). MyD88-dependent TLR1/2 signals educate dendritic cells with gut-specific imprinting properties. Journal of Immunology 187, 141–150.CrossRefGoogle ScholarPubMed
Whitten, M. K. (1957). Effect of exteroceptive factors on the oestrous cycle of mice. Nature 180, 1436.CrossRefGoogle ScholarPubMed
Yang, D. M., Rogers, M. V. and Liew, F. Y. (1991). Identification and characterization of host-protective T-cell epitopes of a major surface glycoprotein (gp63) from Leishmania major. Immunology 72, 3–9.Google Scholar