Skip to main content
PMC home page
Journal of Virology logoLink to Journal of Virology
. 1997 Nov;71(11):8204–8212. doi: 10.1128/jvi.71.11.8204-8212.1997

Collectin-mediated antiviral host defense of the lung: evidence from influenza virus infection of mice.

P C Reading 1, L S Morey 1, E C Crouch 1, E M Anders 1
PMCID: PMC192277  PMID: 9343171

Abstract

Collagenous lectins (collectins) present in mammalian serum and pulmonary fluids bind to influenza virus and display antiviral activity in vitro, but their role in vivo has yet to be determined. We have used early and late isolates of H3N2 subtype influenza viruses that differ in their degree of glycosylation to examine the relationship between sensitivity to murine serum and pulmonary lectins in vitro and the ability of a virus to replicate in the respiratory tract of mice. A marked inverse correlation was found between these two parameters. Early H3 isolates (1968 to 1972) bear 7 potential glycosylation sites on hemagglutinin (HA), whereas later strains carry 9 or 10. Late isolates were shown to be much more sensitive than early strains to neutralization by the mouse serum mannose-binding lectin (MBL) and rat lung surfactant protein D (SP-D) and bound greater levels of these lectins in enzyme-linked immunosorbent assays and Western blot analyses. They also replicated very poorly in mouse lungs compared to the earlier strains. Growth in the lungs was greatly enhanced, however, if saccharide inhibitors of the collectins were included in the virus inoculum. The level of SP-D in bronchoalveolar lavage fluids increased on influenza virus infection. MBL was absent from lavage fluids of normal mice but could be detected in fluids from mice 3 days after infection with the virulent strain A/PR/8/34 (H1N1). The results implicate SP-D and possibly MBL as important components of the innate defense of the respiratory tract against influenza virus and indicate that the degree or pattern of glycosylation of a virus can be an important factor in its virulence.

Full Text

The Full Text of this article is available as a PDF (1.0 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anders E. M., Hartley C. A., Jackson D. C. Bovine and mouse serum beta inhibitors of influenza A viruses are mannose-binding lectins. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4485–4489. doi: 10.1073/pnas.87.12.4485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Anders E. M., Hartley C. A., Reading P. C., Ezekowitz R. A. Complement-dependent neutralization of influenza virus by a serum mannose-binding lectin. J Gen Virol. 1994 Mar;75(Pt 3):615–622. doi: 10.1099/0022-1317-75-3-615. [DOI] [PubMed] [Google Scholar]
  3. Baum L. G., Paulson J. C. The N2 neuraminidase of human influenza virus has acquired a substrate specificity complementary to the hemagglutinin receptor specificity. Virology. 1991 Jan;180(1):10–15. doi: 10.1016/0042-6822(91)90003-t. [DOI] [PubMed] [Google Scholar]
  4. Benne C. A., Benaissa-Trouw B., van Strijp J. A., Kraaijeveld C. A., van Iwaarden J. F. Surfactant protein A, but not surfactant protein D, is an opsonin for influenza A virus phagocytosis by rat alveolar macrophages. Eur J Immunol. 1997 Apr;27(4):886–890. doi: 10.1002/eji.1830270413. [DOI] [PubMed] [Google Scholar]
  5. Benne C. A., Kraaijeveld C. A., van Strijp J. A., Brouwer E., Harmsen M., Verhoef J., van Golde L. M., van Iwaarden J. F. Interactions of surfactant protein A with influenza A viruses: binding and neutralization. J Infect Dis. 1995 Feb;171(2):335–341. doi: 10.1093/infdis/171.2.335. [DOI] [PubMed] [Google Scholar]
  6. Both G. W., Sleigh M. J., Cox N. J., Kendal A. P. Antigenic drift in influenza virus H3 hemagglutinin from 1968 to 1980: multiple evolutionary pathways and sequential amino acid changes at key antigenic sites. J Virol. 1983 Oct;48(1):52–60. doi: 10.1128/jvi.48.1.52-60.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brown L. E., Ward C. W., Jackson D. C. Antigenic determinants of influenza virus hemagglutinin--IX. The carbohydrate side chains from an Asian strain. Mol Immunol. 1982 Feb;19(2):329–338. doi: 10.1016/0161-5890(82)90347-9. [DOI] [PubMed] [Google Scholar]
  8. Caton A. J., Brownlee G. G., Yewdell J. W., Gerhard W. The antigenic structure of the influenza virus A/PR/8/34 hemagglutinin (H1 subtype). Cell. 1982 Dec;31(2 Pt 1):417–427. doi: 10.1016/0092-8674(82)90135-0. [DOI] [PubMed] [Google Scholar]
  9. Crouch E., Chang D., Rust K., Persson A., Heuser J. Recombinant pulmonary surfactant protein D. Post-translational modification and molecular assembly. J Biol Chem. 1994 Jun 3;269(22):15808–15813. [PubMed] [Google Scholar]
  10. Deom C. M., Caton A. J., Schulze I. T. Host cell-mediated selection of a mutant influenza A virus that has lost a complex oligosaccharide from the tip of the hemagglutinin. Proc Natl Acad Sci U S A. 1986 Jun;83(11):3771–3775. doi: 10.1073/pnas.83.11.3771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Ezekowitz R. A., Kuhlman M., Groopman J. E., Byrn R. A. A human serum mannose-binding protein inhibits in vitro infection by the human immunodeficiency virus. J Exp Med. 1989 Jan 1;169(1):185–196. doi: 10.1084/jem.169.1.185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fischer P. B., Ellermann-Eriksen S., Thiel S., Jensenius J. C., Mogensen S. C. Mannan-binding protein and bovine conglutinin mediate enhancement of herpes simplex virus type 2 infection in mice. Scand J Immunol. 1994 May;39(5):439–445. doi: 10.1111/j.1365-3083.1994.tb03398.x. [DOI] [PubMed] [Google Scholar]
  13. Hartley C. A., Jackson D. C., Anders E. M. Two distinct serum mannose-binding lectins function as beta inhibitors of influenza virus: identification of bovine serum beta inhibitor as conglutinin. J Virol. 1992 Jul;66(7):4358–4363. doi: 10.1128/jvi.66.7.4358-4363.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hartley C. A., Reading P. C., Ward A. C., Anders E. M. Changes in the hemagglutinin molecule of influenza type A (H3N2) virus associated with increased virulence for mice. Arch Virol. 1997;142(1):75–88. doi: 10.1007/s007050050060. [DOI] [PubMed] [Google Scholar]
  15. Hartshorn K. L., Crouch E. C., White M. R., Eggleton P., Tauber A. I., Chang D., Sastry K. Evidence for a protective role of pulmonary surfactant protein D (SP-D) against influenza A viruses. J Clin Invest. 1994 Jul;94(1):311–319. doi: 10.1172/JCI117323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hartshorn K. L., Reid K. B., White M. R., Jensenius J. C., Morris S. M., Tauber A. I., Crouch E. Neutrophil deactivation by influenza A viruses: mechanisms of protection after viral opsonization with collectins and hemagglutination-inhibiting antibodies. Blood. 1996 Apr 15;87(8):3450–3461. [PubMed] [Google Scholar]
  17. Hartshorn K. L., Sastry K., Brown D., White M. R., Okarma T. B., Lee Y. M., Tauber A. I. Conglutinin acts as an opsonin for influenza A viruses. J Immunol. 1993 Dec 1;151(11):6265–6273. [PubMed] [Google Scholar]
  18. Hartshorn K. L., Sastry K., White M. R., Anders E. M., Super M., Ezekowitz R. A., Tauber A. I. Human mannose-binding protein functions as an opsonin for influenza A viruses. J Clin Invest. 1993 Apr;91(4):1414–1420. doi: 10.1172/JCI116345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Haurum J. S., Thiel S., Jones I. M., Fischer P. B., Laursen S. B., Jensenius J. C. Complement activation upon binding of mannan-binding protein to HIV envelope glycoproteins. AIDS. 1993 Oct;7(10):1307–1313. doi: 10.1097/00002030-199310000-00002. [DOI] [PubMed] [Google Scholar]
  20. Holmskov U., Malhotra R., Sim R. B., Jensenius J. C. Collectins: collagenous C-type lectins of the innate immune defense system. Immunol Today. 1994 Feb;15(2):67–74. doi: 10.1016/0167-5699(94)90136-8. [DOI] [PubMed] [Google Scholar]
  21. Holt P., Holmskov U., Thiel S., Teisner B., Højrup P., Jensenius J. C. Purification and characterization of mannan-binding protein from mouse serum. Scand J Immunol. 1994 Feb;39(2):202–208. doi: 10.1111/j.1365-3083.1994.tb03361.x. [DOI] [PubMed] [Google Scholar]
  22. Honda Y., Takahashi H., Kuroki Y., Akino T., Abe S. Decreased contents of surfactant proteins A and D in BAL fluids of healthy smokers. Chest. 1996 Apr;109(4):1006–1009. doi: 10.1378/chest.109.4.1006. [DOI] [PubMed] [Google Scholar]
  23. Hoppe H. J., Reid K. B. Collectins--soluble proteins containing collagenous regions and lectin domains--and their roles in innate immunity. Protein Sci. 1994 Aug;3(8):1143–1158. doi: 10.1002/pro.5560030801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kilbourne E. D. Future influenza vaccines and the use of genetic recombinants. Bull World Health Organ. 1969;41(3):643–645. [PMC free article] [PubMed] [Google Scholar]
  25. Kilbourne E. D., Laver W. G., Schulman J. L., Webster R. G. Antiviral activity of antiserum specific for an influenza virus neuraminidase. J Virol. 1968 Apr;2(4):281–288. doi: 10.1128/jvi.2.4.281-288.1968. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kilbourne E. D., Schulman J. L., Schild G. C., Schloer G., Swanson J., Bucher D. Related studies of a recombinant influenza-virus vaccine. I. Derivation and characterization of virus and vaccine. J Infect Dis. 1971 Nov;124(5):449–462. doi: 10.1093/infdis/124.5.449. [DOI] [PubMed] [Google Scholar]
  27. Kuan S. F., Rust K., Crouch E. Interactions of surfactant protein D with bacterial lipopolysaccharides. Surfactant protein D is an Escherichia coli-binding protein in bronchoalveolar lavage. J Clin Invest. 1992 Jul;90(1):97–106. doi: 10.1172/JCI115861. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lambré C. R., Terzidis H., Greffard A., Webster R. G. Measurement of anti-influenza neuraminidase antibody using a peroxidase-linked lectin and microtitre plates coated with natural substrates. J Immunol Methods. 1990 Dec 31;135(1-2):49–57. doi: 10.1016/0022-1759(90)90255-t. [DOI] [PubMed] [Google Scholar]
  29. Malhotra R., Haurum J. S., Thiel S., Sim R. B. Binding of human collectins (SP-A and MBP) to influenza virus. Biochem J. 1994 Dec 1;304(Pt 2):455–461. doi: 10.1042/bj3040455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Malhotra R., Thiel S., Reid K. B., Sim R. B. Human leukocyte C1q receptor binds other soluble proteins with collagen domains. J Exp Med. 1990 Sep 1;172(3):955–959. doi: 10.1084/jem.172.3.955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Muster T., Ferko B., Klima A., Purtscher M., Trkola A., Schulz P., Grassauer A., Engelhardt O. G., García-Sástre A., Palese P. Mucosal model of immunization against human immunodeficiency virus type 1 with a chimeric influenza virus. J Virol. 1995 Nov;69(11):6678–6686. doi: 10.1128/jvi.69.11.6678-6686.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Naeve C. W., Hinshaw V. S., Webster R. G. Mutations in the hemagglutinin receptor-binding site can change the biological properties of an influenza virus. J Virol. 1984 Aug;51(2):567–569. doi: 10.1128/jvi.51.2.567-569.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Nakajima S., Takeuchi Y., Nakajima K. Location on the evolutionary tree of influenza H3 haemagglutinin genes of Japanese strains isolated during 1985-6 season. Epidemiol Infect. 1988 Apr;100(2):301–310. doi: 10.1017/s0950268800067431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Newton S. E., Air G. M., Webster R. G., Laver W. G. Sequence of the hemagglutinin gene of influenza virus A/Memphis/1/71 and previously uncharacterized monoclonal antibody-derived variants. Virology. 1983 Jul 30;128(2):495–501. doi: 10.1016/0042-6822(83)90277-5. [DOI] [PubMed] [Google Scholar]
  35. Pyhälä R., Ikonen N., Forsten T., Alanko S., Kinnunen L. Evolution of the HA1 domain of human influenza A (H1N1) virus: loss of glycosylation sites and occurrence of herald and conserved strains. J Gen Virol. 1995 Jan;76(Pt 1):205–210. doi: 10.1099/0022-1317-76-1-205. [DOI] [PubMed] [Google Scholar]
  36. Pyhälä R., Ikonen N., Haanpä M., Kinnunen L. HA1 domain of influenza A (H3N2) viruses in Finland in 1989-1995: evolution, egg-adaptation and relationship to vaccine strains. Arch Virol. 1996;141(6):1033–1046. doi: 10.1007/BF01718607. [DOI] [PubMed] [Google Scholar]
  37. Reading P. C., Hartley C. A., Ezekowitz R. A., Anders E. M. A serum mannose-binding lectin mediates complement-dependent lysis of influenza virus-infected cells. Biochem Biophys Res Commun. 1995 Dec 26;217(3):1128–1136. doi: 10.1006/bbrc.1995.2886. [DOI] [PubMed] [Google Scholar]
  38. Rocha E. P., Xu X., Hall H. E., Allen J. R., Regnery H. L., Cox N. J. Comparison of 10 influenza A (H1N1 and H3N2) haemagglutinin sequences obtained directly from clinical specimens to those of MDCK cell- and egg-grown viruses. J Gen Virol. 1993 Nov;74(Pt 11):2513–2518. doi: 10.1099/0022-1317-74-11-2513. [DOI] [PubMed] [Google Scholar]
  39. Rocha E., Cox N. J., Black R. A., Harmon M. W., Harrison C. J., Kendal A. P. Antigenic and genetic variation in influenza A (H1N1) virus isolates recovered from a persistently infected immunodeficient child. J Virol. 1991 May;65(5):2340–2350. doi: 10.1128/jvi.65.5.2340-2350.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Sastry K., Zahedi K., Lelias J. M., Whitehead A. S., Ezekowitz R. A. Molecular characterization of the mouse mannose-binding proteins. The mannose-binding protein A but not C is an acute phase reactant. J Immunol. 1991 Jul 15;147(2):692–697. [PubMed] [Google Scholar]
  41. Schulman J. L. The role of antineuraminidase antibody in immunity to influenza virus infection. Bull World Health Organ. 1969;41(3):647–650. [PMC free article] [PubMed] [Google Scholar]
  42. Skehel J. J., Stevens D. J., Daniels R. S., Douglas A. R., Knossow M., Wilson I. A., Wiley D. C. A carbohydrate side chain on hemagglutinins of Hong Kong influenza viruses inhibits recognition by a monoclonal antibody. Proc Natl Acad Sci U S A. 1984 Mar;81(6):1779–1783. doi: 10.1073/pnas.81.6.1779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Sumiya M., Super M., Tabona P., Levinsky R. J., Arai T., Turner M. W., Summerfield J. A. Molecular basis of opsonic defect in immunodeficient children. Lancet. 1991 Jun 29;337(8757):1569–1570. doi: 10.1016/0140-6736(91)93263-9. [DOI] [PubMed] [Google Scholar]
  44. Summerfield J. A., Ryder S., Sumiya M., Thursz M., Gorchein A., Monteil M. A., Turner M. W. Mannose binding protein gene mutations associated with unusual and severe infections in adults. Lancet. 1995 Apr 8;345(8954):886–889. doi: 10.1016/s0140-6736(95)90009-8. [DOI] [PubMed] [Google Scholar]
  45. Super M., Thiel S., Lu J., Levinsky R. J., Turner M. W. Association of low levels of mannan-binding protein with a common defect of opsonisation. Lancet. 1989 Nov 25;2(8674):1236–1239. doi: 10.1016/s0140-6736(89)91849-7. [DOI] [PubMed] [Google Scholar]
  46. Thiel S., Reid K. B. Structures and functions associated with the group of mammalian lectins containing collagen-like sequences. FEBS Lett. 1989 Jun 19;250(1):78–84. doi: 10.1016/0014-5793(89)80689-1. [DOI] [PubMed] [Google Scholar]
  47. Turner M. W. Mannose-binding lectin: the pluripotent molecule of the innate immune system. Immunol Today. 1996 Nov;17(11):532–540. doi: 10.1016/0167-5699(96)10062-1. [DOI] [PubMed] [Google Scholar]
  48. Verhoeyen M., Fang R., Jou W. M., Devos R., Huylebroeck D., Saman E., Fiers W. Antigenic drift between the haemagglutinin of the Hong Kong influenza strains A/Aichi/2/68 and A/Victoria/3/75. Nature. 1980 Aug 21;286(5775):771–776. doi: 10.1038/286771a0. [DOI] [PubMed] [Google Scholar]
  49. Ward C. W., Brown L. E., Downie J. C., Jackson D. C. Antigenic determinants of influenza virus hemagglutinin. VII. The carbohydrate side chains of A/Memphis/102/72 hemagglutinin heavy chain which cross-react with host antigen. Virology. 1981 Jan 15;108(1):71–79. doi: 10.1016/0042-6822(81)90527-4. [DOI] [PubMed] [Google Scholar]
  50. Ward C. W., Dopheide T. A. Amino acid sequence and oligosaccharide distribution of the haemagglutinin from an early Hong Kong influenza virus variant A/Aichi/2/68 (X-31). Biochem J. 1981 Mar 1;193(3):953–962. doi: 10.1042/bj1930953. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Webster R. G., Kawaoka Y., Bean W. J., Jr Molecular changes in A/Chicken/Pennsylvania/83 (H5N2) influenza virus associated with acquisition of virulence. Virology. 1986 Mar;149(2):165–173. doi: 10.1016/0042-6822(86)90118-2. [DOI] [PubMed] [Google Scholar]
  52. Wilson I. A., Skehel J. J., Wiley D. C. Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 A resolution. Nature. 1981 Jan 29;289(5796):366–373. doi: 10.1038/289366a0. [DOI] [PubMed] [Google Scholar]
  53. Wong C. J., Akiyama J., Allen L., Hawgood S. Localization and developmental expression of surfactant proteins D and A in the respiratory tract of the mouse. Pediatr Res. 1996 Jun;39(6):930–937. doi: 10.1203/00006450-199606000-00002. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES