[en] The pestivirus bovine viral diarrhea virus (BVDV) is known to bind to the CD46 molecule, which subsequently promotes entry of the virus. Mapping of the BVD-virion-binding site has shown that two peptides, 66EQIV69 and 82GQVLAL87, located on antiparallel beta sheets in the most distal complement control protein module (CCP1), provide the attachment platform. In the present study, we reveal new CD46-encoding transcripts that are predicted to encode CCP1-containing soluble forms. Further, we show that the serum of most adult cattle contains soluble CD46 (sCD46) and that a recombinant soluble isoform neutralizes BVDV infectivity in an in vitro assay. We have then established an ELISA for determination of plasma sCD46 in a large cohort of animals. Overall, serum sCD46 amounts to 8 ± 18 ng/mL (mean ± SD, n = 440), with a IC [95-105] ranging from 6,4 to 9,8 ng/mL and extreme values between 0 and 178 ng/mL. We found that sCD46 is not detectable in fetal and neonatal sera and that its plasma concentration increases progressively up to adulthood. We also detected high- and low-sCD46 performers and show that this phenotype does not depend of environment. As modern rearing techniques make it possible to disseminate genetically-determined phenotypes very quickly in a population, a large-scale study examining whether high-sCD46 animals provide epidemiological protection against BVDV infection and transmission should be undertaken.
[1] ICTV (International Committee on taxonomy of Viruses), 2014. Virus taxonomy: 2014 release. Accessible at http://www.ictvonline.org/virustaxonomy.asp.
[2] Thiel, H.J., Meyers, G., Stark, R., Tautz, N., Rumenapf, T., Unger, G., Conzelmann, K.K., Molecular characterization of positive-strand RNA viruses: pestiviruses and the porcine reproductive and respiratory syndrome virus (PRRSV). Arch. Virol. Suppl. 7 (1993), 41–52.
[3] Ronecker, S., Zimmer, G., Herrler, G., Greiser-Wilke, I., Grummer, B., Formation of bovine viral diarrhea virus E1-E2 heterodimers is essential for virus entry and depends on charged residues in the transmembrane domains. J. Gen. Virol. 89 (2008), 2114–2121.
[4] Maurer, K., Krey, T., Moennig, V., Thiel, H.J., Rumenapf, T., CD46 is a cellular receptor for bovine viral diarrhea virus. J. Virol. 78 (2004), 1792–1799.
[5] Marie, J.C., Astier, A.L., Rivailler, P., Rabourdin-Combe, C., Wild, T.F., Horvat, B., Linking innate and acquired immunity: divergent role of CD46 cytoplasmic domains in T cell induced inflammation. Nat. Immunol. 3 (2002), 659–666.
[6] Liszewski, M.K., Post, T.W., Atkinson, J.P., Membrane cofactor protein (MCP or CD46): newest member of the regulators of complement activation gene cluster. Annu. Rev. Immunol. 9 (1991), 431–455.
[7] Cattaneo, R., Four viruses two bacteria, and one receptor: membrane cofactor protein (CD46) as pathogens' magnet. J. Virol. 78 (2004), 4385–4388.
[8] Buchholz, C.J., Koller, D., Devaux, P., Mumenthaler, C., Schneider-Schaulies, J., Braun, W., Gerlier, D., Cattaneo, R., Mapping of the primary binding site of measles virus to its receptor CD46. J. Biol. Chem. 272 (1997), 22072–22079.
[9] Mori, Y., Seya, T., Huang, H.L., Akkapaiboon, P., Dhepakson, P., Yamanishi, K., Human herpesvirus 6 variant A but not variant B induces fusion from without in a variety of human cells through a human herpesvirus 6 entry receptor, CD46. J. Virol. 76 (2002), 6750–6761.
[10] Santoro, F., Greenstone, H.L., Insinga, A., Liszewski, M.K., Atkinson, J.P., Lusso, P., Berger, E.A., Interaction of glycoprotein H of human herpesvirus 6 with the cellular receptor CD46. J. Biol. Chem. 278 (2003), 25964–25969.
[11] Segerman, A., Atkinson, J.P., Marttila, M., Dennerquist, V., Wadell, G., Arnberg, N., Adenovirus type 11 uses CD46 as a cellular receptor. J. Virol. 77 (2003), 9183–9191.
[12] Wu, E., Trauger, S.A., Pache, L., Mullen, T.M., Von Seggern, D.J., Siuzdak, G., Nemerow, G.R., Membrane cofactor protein is a receptor for adenoviruses associated with epidemic keratoconjunctivitis. J. Virol. 78 (2004), 3897–3905.
[13] Kallstrom, H., Blackmer Gill, D., Albiger, B., Liszewski, M.K., Atkinson, J.P., Jonsson, A.B., Attachment of Neisseria gonorrhoeae to the cellular pilus receptor CD46: identification of domains important for bacterial adherence. Cell. Microbiol. 3 (2001), 133–143.
[14] Krey, T., Himmelreich, A., Heimann, M., Menge, C., Thiel, H.J., Maurer, K., Rumenapf, T., Function of bovine CD46 as a cellular receptor for bovine viral diarrhea virus is determined by complement control protein 1. J. Virol. 80 (2006), 3912–3922.
[15] Zezafoun, H., Decreux, A., Desmecht, D., Genetic and splice variations of Bos taurus CD46 shift cell permissivity to BVDV the bovine pestivirus. Vet. Microbiol. 152 (2011), 315–327.
[16] Elvander, M., Baule, C., Persson, M., Egyed, L., Ballagi-Pordany, A., Belak, S., Alenius, S., An experimental study of a concurrent primary infection with bovine respiratory syncytial virus (BRSV) and bovine viral diarrhoea virus (BVDV) in calves. Acta Vet. Scand. 39 (1998), 251–264.
[17] Reed, L.J., Muench, H., A Simple method of estimating fifty per cent endpoints. Am. J. Epidemiol. 27 (1938), 493–497.
[18] Rozen, S., Skaletsky, H., Primer3 on the WWW for general users and for biologist programmers. Methods Mol. Biol. 132 (2000), 365–386.
[19] Altschul, S.F., Gish, W., Miller, W., Myers, E.W., Lipman, D.J., Basic local alignment search tool. J. Mol. Biol. 215 (1990), 403–410.
[20] Wang, M., Marin, A., Characterization and prediction of alternative splice sites. Gene 366 (2006), 219–227.
[21] Boyum, A., Separation of leukocytes from blood and bone marrow. Scand. J. Clin. Lab. Invest. Suppl. 97 (1968), 7–15.
[22] Garigliany, M.M., Cloquette, K., Leroy, M., Decreux, A., Goris, N., De Clercq, K., Desmecht, D., Modulating mouse innate immunity to RNA viruses by expressing the Bos taurus Mx system. Transgenic Res. 18 (2009), 719–732.
[23] Kemper, C., Leung, M., Stephensen, C.B., Pinkert, C.A., Liszewski, M.K., Cattaneo, R., Atkinson, J.P., Membrane cofactor protein (MCP; CD46) expression in transgenic mice. Clin. Exp. Immunol. 124 (2001), 180–189.
[25] Post, T.W., Liszewski, M.K., Adams, E.M., Tedja, I., Miller, E.A., Atkinson, J.P., Membrane cofactor protein of the complement system: alternative splicing of serine/threonine/proline-rich exons and cytoplasmic tails produces multiple isoforms that correlate with protein phenotype. J. Exp. Med. 174 (1991), 93–102.
[26] Pérez de la Lastra, J.M., Hanna, S.M., Morgan, B.P., Distribution of membrane cofactor protein (MCP/CD46) on pig tissues: relevance To xenotransplantation. Immunology 98 (1999), 144–151.
[27] Miwa, T., Nonaka, M., Okada, N., Wakana, S., Shiroishi, T., Okada, H., Molecular cloning of rat and mouse membrane cofactor protein (MCP: CD46): preferential expression in testis and close linkage between the mouse Mcp and Cr2 genes on distal chromosome 1. Immunogenetics 48 (1998), 363–371.
[28] Nomura, M., Tsujimura, A., Shida, K., Matsumoto, M., Matsuda, Y., Toyoshima, K., Seya, T., Membrane and secretory forms of mouse membrane cofactor protein (CD46) generated from a single gene through alternative splicing. Immunogenetics 50 (1999), 245–254.
[29] Tsujimura, A., Nunoue, K., Inoue, N., Shida, K., Kurita-Taniguchi, M., Matsumoto, M., Nomura, M., Takeya, T., Seya, T., Three soluble form messages of murine CD46 are produced through alternative mRNA splicing. J. Biochem. 130 (2001), 841–848.
[30] Hara, T., Kuriyama, S., Kiyohara, H., Nagase, Y., Matsumoto, M., Seya, T., Soluble forms of membrane cofactor protein (CD46 MCP) are present in plasma, tears, and seminal fluid in normal subjects. Clin. Exp. Immunol. 89 (1992), 490–494.
[31] Seya, T., Hirano, A., Matsumoto, M., Nomura, M., Ueda, S., Human membrane cofactor protein (MCP: CD46): multiple isoforms and functions. Int. J. Biochem. Cell. Biol. 31 (1999), 1255–1260.
[32] Seya, T., Kurita, M., Hara, T., Iwata, K., Semba, T., Hatanaka, M., Matsumoto, M., Yanagi, Y., Ueda, S., Nagasawa, S., Blocking measles virus infection with a recombinant soluble form of or monoclonal antibodies against, membrane cofactor protein of complement (CD46). Immunology 84 (1995), 619–625.
[33] Christiansen, D., Devaux, P., Réveil, B., Evlashev, A., Horvat, B., Lamy, J., Rabourdin-Combe, C., Cohen, J.H., Gerlier, D., Octamerization enables soluble CD46 receptor to neutralize measles virus in vitro and in vivo. J. Virol. 74 (2000), 4672–4678.
[34] Fogdell-Hahn, A., Soldan, S.S., Shue, S., Akhyani, N., Refai, H., Ahlqvist, J., Jacobson, S., Co-purification of soluble membrane cofactor protein (CD46) and human herpesvirus 6 variant A genome in serum from multiple sclerosis patients. Virus Res. 110 (2005), 57–63.
[35] Strong, R., La Rocca, S.A., Paton, D., Bensaude, E., Sandvik, T., Davis, L., Turner, J., Drew, T., Raue, R., Vangeel, I., Steinbach, F., Viral dose and immunosuppression modulate the progression of acute BVDV-1 infection in calves: evidence of long term persistence after intra-nasal infection. PLoS One, 10, 2015, e0124689.
[36] Sandvik, T., Selection and use of laboratory diagnostic assays in BVD control programmes. Prev. Vet. Med. 72 (2005), 3–16.
[37] Ballard, L., Seya, T., Teckman, J., Lublin, D.M., Atkinson, J.P., A polymorphism of the complement regulatory protein MCP (membrane cofactor protein or gp45-70). J. Immunol. 138 (1987), 3850–3855.
