Abstract
Ficolins are serum complement lectins, with a structure similar to mannose-binding lectin (MBL) and lung surfactant protein (SP)-A and SP-D. Ficolins activate the lectin complement system and play important roles in host innate immunity. Ficolins are members of the collectin family of proteins, which act as pattern recognition receptors (PRRs). They are soluble oligomeric defense proteins with lectin-like activity, and are able to recognize pathogen-associated molecular patterns (PAMPs), which are carbohydrate molecules on the surface of pathogens, and of apoptotic, necrotic, and malignant cells. Upon binding to their specific PAMPs, ficolins may trigger activation of the immune system either (1) by initiating activation of complement via the lectin pathway, (2) by a primitive type of opsonophagocytosis, or (3) by stimulating secretion of the inflammatory cytokines interferon (IFN)-Γ, interleukin (IL)-17, IL-6, and tumor necrosis factor (TNF)-α, and production of nitric oxide (NO) by macrophages, thus limiting the infection and concurrently orchestrating the subsequent adaptive immune response. Recently, a number of reports have shown that dysfunction or abnormal expression of ficolins may play crucial roles in viral and bacterial diseases and in inflammation. This review summarizes the reports on the roles of ficolins in the infectious diseases, and provides insight into ficolins as novel innate immune therapeutic options to treat these diseases.
Keywords: L-ficolin, H-ficolin, M-ficolin, virus, bacteria
References
- Akaiwa M, Yae Y, Sugimoto R, Suzuki S O, Iwaki T, Izuhara K, Hamasaki N. Hakata antigen, a new member of the ficolin/opsonin p35 family, is a novel human lectin secreted into bronchus/alveolus and bile. J Histochem Cytochem. 1999;47:777–786. doi: 10.1177/002215549904700607. [DOI] [PubMed] [Google Scholar]
- Ammitzboll C G, Thiel S, Ellingsen T, Deleuran B, Jorgensen A, Jensenius J C, Stengaard-Pedersen K. Levels of lectin pathway proteins in plasma and synovial fluid of rheumatoid arthritis and osteoarthritis. Rheumatol Int. 2012;32:1457–1463. doi: 10.1007/s00296-011-1879-x. [DOI] [PubMed] [Google Scholar]
- Aoyagi Y, Adderson E E, Min J G, Matsushita M, Fujita T, Takahashi S, Okuwaki Y, Bohnsack J F. Role of L-ficolin/mannose-binding lectin-associated serine protease complexes in the opsonophagocytosis of type III group B streptococci. J Immunol. 2005;174:418–425. doi: 10.4049/jimmunol.174.1.418. [DOI] [PubMed] [Google Scholar]
- Chang W C, Hartshorn K L, White M R, Moyo P, Michelow I C, Koziel H, Kinane B T, Schmidt E V, Fujita T, Takahashi K. Recombinant chimeric lectins consisting of mannose-binding lectin and L-ficolin are potent inhibitors of influenza A virus compared with mannose-binding lectin. Biochem Pharmacol. 2011;81:388–395. doi: 10.1016/j.bcp.2010.10.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dommett R M, Klein N, Turner M W. Mannose-binding lectin in innate immunity: past, present and future. Tissue Antigens. 2006;68:193–209. doi: 10.1111/j.1399-0039.2006.00649.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Egli A, Schafer J, Osthoff M, Thiel S, Mikkelsen C, Rauch A, Hirsch H H, Bucher H C, Young J, Jensenius J C, Battegay M, Trendelenburg M. Low levels of mannan-binding lectin or ficolins are not associated with an increased risk of cytomegalovirus disease in HIV-infected patients. PLoS One. 2013;8:e51983. doi: 10.1371/journal.pone.0051983. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Endo Y, Matsushita M, Fujita T. The role of ficolins in the lectin pathway of innate immunity. Int J Biochem Cell Biol. 2011;43:705–712. doi: 10.1016/j.biocel.2011.02.003. [DOI] [PubMed] [Google Scholar]
- Endo Y, Sato Y, Matsushita M, Fujita T. Cloning and characterization of the human lectin P35 gene and its related gene. Genomics. 1996;36:515–521. doi: 10.1006/geno.1996.0497. [DOI] [PubMed] [Google Scholar]
- Frederiksen P D, Thiel S, Larsen C B, Jensenius J C. M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement. Scand J Immunol. 2005;62:462–473. doi: 10.1111/j.1365-3083.2005.01685.x. [DOI] [PubMed] [Google Scholar]
- Fujimori Y, Harumiya S, Fukumoto Y, Miura Y, Yagasaki K, Tachikawa H, Fujimoto D. Molecular cloning and characterization of mouse ficolin-A. Biochem Biophys Res Commun. 1998;244:796–800. doi: 10.1006/bbrc.1998.8344. [DOI] [PubMed] [Google Scholar]
- Gokudan S, Muta T, Tsuda R, Koori K, Kawahara T, Seki N, Mizunoe Y, Wai S N, Iwanaga S, Kawabata S. Horseshoe crab acetyl group-recognizing lectins involved in innate immunity are structurally related to fibrinogen. Proc Natl Acad Sci U S A. 1999;96:10086–10091. doi: 10.1073/pnas.96.18.10086. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hoang T V, Toan N L, Songle H, Ouf E A, Bock C T, Kremsner P G, Kun J F, Velavan T P. Ficolin-2 levels and FCN2 haplotypes influence hepatitis B infection outcome in Vietnamese patients. PLoS One. 2011;6:e28113. doi: 10.1371/journal.pone.0028113. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Holmskov U, Thiel S, Jensenius J C. Collections and ficolins: humoral lectins of the innate immune defense. Annu Rev Immunol. 2003;21:547–578. doi: 10.1146/annurev.immunol.21.120601.140954. [DOI] [PubMed] [Google Scholar]
- Hu Y L, Luo F L, Fu J L, Chen T L, Wu S M, Zhou Y D, Zhang X L. Early increased ficolin-2 oncentrations are associated with severity of liver inflammation and efficacy of anti-viral therapy in chronic hepatitis C patients. Scand J Immunol. 2013;77:144–150. doi: 10.1111/sji.12014. [DOI] [PubMed] [Google Scholar]
- Ichijo H, Hellman U, Wernstedt C, Gonez L J, Claesson-Welsh L, Heldin C H, Miyazono K. Molecular cloning and characterization of ficolin, a multimeric protein with fibrinogen- and collagen-like domains. J Biol Chem. 1993;268:14505–14513. [PubMed] [Google Scholar]
- Jack D L, Dodds A W, Anwar N, Ison C A, Law A, Frosch M, Turner M W, Klein N J. Activation of complement by mannose-binding lectin on isogenic mutants of Neisseria meningitidis serogroup B. J Immunol. 1998;160:1346–1353. [PubMed] [Google Scholar]
- Keirstead N D, Lee C, Yoo D, Brooks A S, Hayes M A. Porcine plasma ficolin binds and reduces infectivity of porcine reproductive and respiratory syndrome virus (PRRSV) in vitro. Antiviral Res. 2008;77:28–38. doi: 10.1016/j.antiviral.2007.08.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kilpatrick D C, Chalmers J D. Human L-ficolin (ficolin-2) and its clinical significance. J Biomed Biotechnol. 2012;2012:138797. doi: 10.1155/2012/138797. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kilpatrick D C, Chalmers J D, MacDonald S L, Murray M, Mohammed A, Hart S P, Matsushita M, Hill A. Stable bronchiectasis is associated with low serum L-ficolin concentrations. Clin Respir J. 2009;3:29–33. doi: 10.1111/j.1752-699X.2008.00105.x. [DOI] [PubMed] [Google Scholar]
- Kjaer T R, Hansen A G, Sorensen U B, Nielsen O, Thiel S, Jensenius J C. Investigations on the pattern recognition molecule M-ficolin: quantitative aspects of bacterial binding and leukocyte association. J Leukoc Biol. 2011;90:425–437. doi: 10.1189/jlb.0411201. [DOI] [PubMed] [Google Scholar]
- Liu J, Ali M A, Shi Y, Zhao Y, Luo F, Yu J, Xiang T, Tang J, Li D, Hu Q, Ho W, Zhang X. Specifically binding of L-ficolin to N-glycans of HCV envelope glycoproteins E1 and E2 leads to complement activation. Cell Mol Immunol. 2009;6:235–244. doi: 10.1038/cmi.2009.32. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Liu Y, Endo Y, Iwaki D, Nakata M, Matsushita M, Wada I, Inoue K, Munakata M, Fujita T. Human M-ficolin is a secretory protein that activates the lectin complement pathway. J Immunol. 2005;175:3150–3156. doi: 10.4049/jimmunol.175.5.3150. [DOI] [PubMed] [Google Scholar]
- Lu J, Tay P N, Kon O L, Reid K B. Human ficolin: cDNA cloning, demonstration of peripheral blood leucocytes as the major site of synthesis and assignment of the gene to chromosome 9. Biochem J. 1996;313(Pt2):473–478. doi: 10.1042/bj3130473. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Luo F, Sun X, Wang Y, Wang Q, Wu Y, Pan Q, Fang C, Zhang X L. Ficolin-2 defends against virulent Mycobacteria tuberculosis infection in vivo, and its insufficiency is associated with infection in humans. PLoS One. 2013;8:e73859. doi: 10.1371/journal.pone.0073859. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lynch N J, Roscher S, Hartung T, Morath S, Matsushita M, Maennel D N, Kuraya M, Fujita T, Schwaeble W J. L-ficolin specifically binds to lipoteichoic acid, a cell wall constituent of Gram-positive bacteria, and activates the lectin pathway of complement. J Immunol. 2004;172:1198–1202. doi: 10.4049/jimmunol.172.2.1198. [DOI] [PubMed] [Google Scholar]
- Matsushita M. Ficolins: complement-activating lectins involved in innate immunity. J Innate Immun. 2010;2:24–32. doi: 10.1159/000228160. [DOI] [PubMed] [Google Scholar]
- Matsushita M, Endo Y, Fujita T. Cutting edge: complement-activating complex of ficolin and mannose-binding lectin-associated serine protease. J Immunol. 2000;164:2281–2284. doi: 10.4049/jimmunol.164.5.2281. [DOI] [PubMed] [Google Scholar]
- Matsushita M, Endo Y, Hamasaki N, Fujita T. Activation of the lectin complement pathway by ficolins. Int Immunopharmacol. 2001;1:359–363. doi: 10.1016/S1567-5769(00)00045-X. [DOI] [PubMed] [Google Scholar]
- Matsushita M, Endo Y, Taira S, Sato Y, Fujita T, Ichikawa N, Nakata M, Mizuochi T. A novel human serum lectin with collagen- and fibrinogen-like domains that functions as an opsonin. J Biol Chem. 1996;271:2448–2454. doi: 10.1074/jbc.271.23.13770. [DOI] [PubMed] [Google Scholar]
- Medzhitov R. Recognition of microorganisms and activation of the immune response. Nature. 2007;449:819–826. doi: 10.1038/nature06246. [DOI] [PubMed] [Google Scholar]
- Medzhitov R, Janeway C A., Jr. Decoding the patterns of self and nonself by the innate immune system. Science. 2002;296:298–300. doi: 10.1126/science.1068883. [DOI] [PubMed] [Google Scholar]
- Michelow I C, Dong M, Mungall B A, Yantosca L M, Lear C, Ji X, Karpel M, Rootes C L, Brudner M, Houen G, Eisen D P, Kinane T B, Takahashi K, Stahl G L, Olinger G G, Spear G T, Ezekowitz R A, Schmidt E V. A novel L-ficolin/mannose-binding lectin chimeric molecule with enhanced activity against Ebola virus. J Biol Chem. 2010;285:24729–24739. doi: 10.1074/jbc.M110.106260. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Munthe-Fog L, Hummelshoj T, Honore C, Madsen H O, Permin H, Garred P. Immunodeficiency associated with FCN3 mutation and ficolin-3 deficiency. N Engl J Med. 2009;360:2637–2644. doi: 10.1056/NEJMoa0900381. [DOI] [PubMed] [Google Scholar]
- Nahid A M, Sugii S. Binding of porcine ficolin-alpha to lipopolysaccharides from Gram-negative bacteria and lipoteichoic acids from Gram-positive bacteria. Dev Comp Immunol. 2006;30:335–343. doi: 10.1016/j.dci.2005.04.002. [DOI] [PubMed] [Google Scholar]
- Pan Q, Chen H, Wang F, Jeza V T, Hou W, Zhao Y, Xiang T, Zhu Y, Endo Y, Fujita T, Zhang X L. L-ficolin binds to the glycoproteins hemagglutinin and neuraminidase and inhibits influenza A virus infection both in vitro and in vivo. J Innate Immun. 2012;4:312–324. doi: 10.1159/000335670. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rorvig S, Honore C, Larsson L I, Ohlsson S, Pedersen C C, Jacobsen L C, Cowland J B, Garred P, Borregaard N. Ficolin-1 is present in a highly mobilizable subset of human neutrophil granules and associates with the cell surface after stimulation with fMLP. J Leukoc Biol. 2009;86:1439–1449. doi: 10.1189/jlb.1008606. [DOI] [PubMed] [Google Scholar]
- Schaffer T, Flogerzi B, Schoepfer A M, Seibold F, Muller S. Increased titers of anti-Saccharomyces cerevisiae antibodies in Crohn’s disease patients with reduced H-ficolin levels but normal MASP-2 activity. J Crohns Colitis. 2013;7:e1–10. doi: 10.1016/j.crohns.2012.02.013. [DOI] [PubMed] [Google Scholar]
- Schlapbach L J, Aebi C, Hansen A G, Hirt A, Jensenius J C, Ammann R A. H-ficolin serum concentration and susceptibility to fever and neutropenia in paediatric cancer patients. Clin Exp Immunol. 2009;157:83–89. doi: 10.1111/j.1365-2249.2009.03957.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sugimoto R, Yae Y, Akaiwa M, Kitajima S, Shibata Y, Sato H, Hirata J, Okochi K, Izuhara K, Hamasaki N. Cloning and characterization of the Hakata antigen, a member of the ficolin/opsonin p35 lectin family. J Biol Chem. 1998;273:20721–20727. doi: 10.1074/jbc.273.33.20721. [DOI] [PubMed] [Google Scholar]
- Taira S, Kodama N, Matsushita M, Fujita T. Opsonic function and concentration of human serum ficolin/P35. Fukushima J Med Sci. 2000;46:13–23. doi: 10.5387/fms.46.13. [DOI] [PubMed] [Google Scholar]
- Takahashi K, Moyo P, Chigweshe L, Chang W C, White M R, Hartshorn K L. Efficacy of recombinant chimeric lectins, consisting of mannose binding lectin and L-ficolin, against influenza A viral infection in mouse model study. Virus Res. 2013;178:495–501. doi: 10.1016/j.virusres.2013.10.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Teh C, Le Y, Lee S H, Lu J. M-ficolin is expressed on monocytes and is a lectin binding to N-acetyl-D-glucosamine and mediates monocyte adhesion and phagocytosis of Escherichia coli. Immunology. 2000;101:225–232. doi: 10.1046/j.1365-2567.2000.00099.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tsujimura M, Ishida C, Sagara Y, Miyazaki T, Murakami K, Shiraki H, Okochi K, Maeda Y. Detection of serum thermolabile beta-2 macroglycoprotein (Hakata antigen) by enzyme-linked immunosorbent assay using polysaccharide produced by Aerococcus viridans. Clin Diagn Lab Immunol. 2001;8:454–459. doi: 10.1128/CDLI.8.2.454-459.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Verma A, White M, Vathipadiekal V, Tripathi S, Mbianda J, Ieong M, Qi L, Taubenberger J K, Takahashi K, Jensenius J C, Thiel S, Hartshorn K L. Human H-ficolin inhibits replication of seasonal and pandemic influenza A viruses. J Immunol. 2012;189:2478–2487. doi: 10.4049/jimmunol.1103786. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wang C C, Yim K W, Poon T C, Choy K W, Chu C Y, Lui W T, Lau T K, Rogers M S, Leung T N. Innate immune response by ficolin binding in apoptotic placenta is associated with the clinical syndrome of preeclampsia. Clin Chem. 2007;53:42–52. doi: 10.1373/clinchem.2007.074401. [DOI] [PubMed] [Google Scholar]
- Zhang X L, Ali M A. Ficolins: structure, function and associated diseases. Adv Exp Med Biol. 2008;632:105–115. [PubMed] [Google Scholar]