Skip to main content

Advertisement

SpringerLink
Log in

Influenza-B-virus-induced eye and brain malformations during early chick embryogenesis and localization of the viral RNA in specific areas

  • Original Paper
  • Published:
Journal of Biomedical Science

Abstract

Influenza is prevalent worldwide, and the teratogenic effects of influenza infection have been suspected to occur within the developing central nervous system. We herein report the sequelae of influenza B viral infection during early chick embryogenesis. Chick embryos at Hamburger-Hamilton stage 9 were infected by an in ovo injection under the blastoderm of influenza B virus (B/Taiwan/25/99). At 48 h after infection, gross malformations of the eye and brain, ranging from 25 to 58% of 168 infected embryos, were observed, in contrast to 3–6% among 71 mock-infected controls (p < 0.0001 for both eye and brain malformations). Histological analyses showed extensive tissue degeneration and aggregates of cells in the head mesenchyme, suggesting cell death and heterotopia. Influenza B viral RNA was directly localized by in situ hybridization with probes specific for the HA segment. Viral RNA was extensively detected in the head surface ectoderm and in the lung bud. In the developing brain, viral RNA was specifically located in the anterior neural retina, habenular area, mid-thalamus, and rhombencephalon. Our data show that influenza B virus can be a teratogenic agent in neural and nonneural embryonic tissues, raising concern for transplacental infection during early pregnancy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Barr CE, Mednick SA, Munk-Jorgensen P. Exposure to influenza epidemics during gestation and adult schizophrenia: A 4-year study. Arch Genet Psychiatr 47:869–874;1990.

    Google Scholar 

  2. Burton GJ, Watson AL. The structure of the human placenta: implications for initiating and defending against virus infections. Rev Med Virol 7:219–228;1997.

    Article  PubMed  Google Scholar 

  3. Campen HV, Easterday BC, Hinshaw VS. Destruction of lymphocytes by a virulent avian influenza A virus. J Gen Virol 70:467–472;1989.

    PubMed  Google Scholar 

  4. Cox B, Hadjantonakis A-K, Collins JA, Magee, AI. Cloning and expression throughout mouse development ofmfat1, a homologue of the Drosophila tumor suppressor genefat. Develop Dynam 217:233–240;2000.

    Google Scholar 

  5. Davis LE, Cole LL, Lockwood SJ, Kornfeld M. Experimental influenza B virus toxicity in mice: a possible model for Reye's syndrome. Lab Invest 48:140–147;1983.

    PubMed  Google Scholar 

  6. Davis LE, Kornfeld M. Mouse influenza B virus model of Reye's syndrome. Am J Pathol 122:190–192;1986.

    PubMed  Google Scholar 

  7. Delorme L, Middleton PJ. Influenza A virus associated with acute encephalopathy. Am J Dis Child 133:822–824;1979.

    PubMed  Google Scholar 

  8. Frankova V, Jirasek A, Tumova B. Type A influenza: Postmortem virus isolations from different organs in human lethal cases. Arch Virol 53:265–268;1977.

    PubMed  Google Scholar 

  9. Gamboa ET, Harter DH, Wolf A, Benitez HH, Takahata N, Duffy PE, Hsu KC. Replication of neurotropic influenza virus in organotypic cultures of embryonic mouse hypothalamus. J Neuropathol Exp Neurol 33:571–581;1974.

    PubMed  Google Scholar 

  10. Graham A, Lumsden A. Patterning the neural crest. Biochem Soc Symp 62:77–83;1996.

    PubMed  Google Scholar 

  11. Hamburger V, Hamilton HL. A series of normal stages in the development of the chick embryo. J Morph 88:49–92;1951.

    Article  Google Scholar 

  12. Hayden FG, Fritz R, Lobo MC, Alvord W, Strober W, Straus SE. Local and systemic cytokine responses during experimental human influenza A virus infection: Relation to symptom formation and host defense. J Clin Invest 101:643–649;1998.

    PubMed  Google Scholar 

  13. Hennet T, Ziltener HJ, Frei K, Peterhans E. A kinetic study of immune mediators in the lungs of mice infected with influenza A virus. J Immunol 149:932–939;1992.

    PubMed  Google Scholar 

  14. Hinshaw VS, Olsen CW, Dybdahl-Sissoko N, Evans D. Apoptosis: A mechanism of cell killing by influenza A and B viruses. J Virol 68:3667–3673;1994.

    PubMed  Google Scholar 

  15. Janerich DT. Influenza and neural tube defects. Lancet ii:551–552;1971.

    Google Scholar 

  16. Karkinen-Jääskeläinen M, Saxén L. Maternal influenza, drug consumption, and congenital defects of the central nervous system. Am J Obstet Gynecol 118:815–818;1974.

    PubMed  Google Scholar 

  17. Kendell RE, Kemp IW. Maternal influenza in the aetiology of schizophrenia. Arch Gen Psychiatr 46:878–882;1989.

    PubMed  Google Scholar 

  18. Kunugi H, Nanko S, Takei N. Influenza and schizophrenia in Japan. Br J Psychiatr 161:274–275;1992.

    PubMed  Google Scholar 

  19. Lin C, Zimmer SG, Holland RE Jr, Dong Q, Chambers TM. The involvement of a stress-activated pathway in equine influenza virus-mediated apoptosis. Virol 287:202–213;2001.

    Google Scholar 

  20. Lipska BK, Luu S, Halim ND, Weinberger DR. Behavioral effects of neonatal and adult excitotoxic lesions of the mediodorsal thalamus in the adult rat. Behav Brain Res 141:105–111;2003.

    Article  PubMed  Google Scholar 

  21. Lynberg MC, Khoury MJ, Lu X, Cocian T. Maternal flu, fever, and the risk of neural tube defects: A population-based case-control study. Am J Epidemiol 140:244–255;1994.

    PubMed  Google Scholar 

  22. McGregor JA, Burns JC, Levin MJ, Burlington B, Meiklejohn G. Transplacental passage of influenza A/Bangkok (H3N2) mimicking amniotic fluid infection syndrome. Am J Obstet Gynecol 149:856–859;1984.

    PubMed  Google Scholar 

  23. Mednick SA, Machon RA, Huttenen MO, Bonet D. Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch Gen Psychiatr 45:189–192;1988.

    PubMed  Google Scholar 

  24. Monteiro JM, Harvey C, Trinchieri G. Role of interleukin-12 in primary influenza virus infection. J Virol 72:4825–4831;1998.

    PubMed  Google Scholar 

  25. Mori I, Diehl AD, Chauhan A, Ljunggren H-G, Kristensson K. Selective targeting of habenular, thalamic midline and monoaminergic brainstem neurons by neurotropic influenza A virus in mice. J Neurovirol 5:355–362;1999.

    PubMed  Google Scholar 

  26. Morris SJ, Smith H, Sweet C. Exploitation of the Herpes simplex virus translocating protein VP22 to carry influenza virus proteins into cells for studies of apoptosis: Direct confirmation that neuraminidase induces apoptosis and indications that other proteins may have a role. Arch Virol 147:961–979;2002.

    Article  PubMed  Google Scholar 

  27. Moses HL, Serra R. Regulation of differentiation by TGFβ. Curr Opin Genet Develop 6:581–596;1996.

    Article  Google Scholar 

  28. Nagata S. Apoptosis by death factor. Cell 88:355–365;1997.

    Article  PubMed  Google Scholar 

  29. O'Callaghan E, Sham P, Takei N, Glover G, Murray RM. Schizophrenia after prenatal exposure to 1957 A2 influenza epidemic. Lancet 337:1248–1250;1991.

    Article  PubMed  Google Scholar 

  30. Oda Y. Choline acetyltransferase: the structure, distribution and pathologic changes in the central nervous system. Pathol Int 49:921–937;1999.

    Article  PubMed  Google Scholar 

  31. Protheroe SM, Mellor DH. Imaging in influenza A encephalitis. Arch Dis Child 66:702–705;1991.

    PubMed  Google Scholar 

  32. Reyhani F, Nazarian I, Shakibi J. The effects of two strains of influenza virus on cardiac development in the chick embryo. Jpn Hear J 24:607–614;1983.

    Google Scholar 

  33. Ruben FL, Thompson DS. Cord blood lymphocyte in vitro responses to influenza A antigens after an epidemic of influenza A/Port Chalmers/73 (H3N2). Am J Obstet Gynecol 141:443;1981.

    PubMed  Google Scholar 

  34. Schultz-Cherry S, Hinshaw VS. Influenza virus neuraminidase activates latent transforming growth factor β. J Virol 70:8624–8629;1996.

    PubMed  Google Scholar 

  35. Sever LE. Influenza and congenital malformations of the central nervous system. Lancet i:910–911;1972.

    Google Scholar 

  36. Sham P, O'Callaghan E, Takei N, Murray GK, Hare EH, Murray RM. Schizophrenia following prenatal exposure to influenza epidemics between 1939 and 1960. Br J Psychiatr 160:461–466;1992.

    PubMed  Google Scholar 

  37. Spence HA, O'Callaghan RJ. Induction of chick embryo feather malformations by an influenza C virus. Teratology 32:57–64;1985.

    PubMed  Google Scholar 

  38. Stevensen PG, Freeman S, Bangham CRM, Hawke S. Virus dissemination through the brain parenchyma without immunologic control. J Immunol 159:1876–1884;1997.

    PubMed  Google Scholar 

  39. Stevensen PG, Hawke S, Sloan DJ, Bangham CRM. The immunogenicity of intracerebral virus infection depends on anatomical site. J Virol 71;145–151;1997.

    PubMed  Google Scholar 

  40. Sulkava R, Rissanen A, Pyhala R. Post-influenzal encephalitis during the influenza A outbreak in 1979/1980. J Neurol Neurosurg Psychiatr 44:161–163;1981.

    PubMed  Google Scholar 

  41. Torrey EF, Rawlings R, Waldman IN. Schizophrenic births and viral diseases in two states. Schizophrenia Res 1:73–77;1988.

    Google Scholar 

  42. Volk DW, Lewis DA. Effects of a mediodorsal thalamus lesion on prefrontal inhibitory circuitry: Implications for schizophrenia. Biol Psychiatr 53:385–389;2003.

    Article  Google Scholar 

  43. Whitman M. Smads and early developmental signaling by the TGFβ superfamily. Gene Develop 12:2445–2462;1998.

    Google Scholar 

  44. Wright P, Gill M, Murray RM. Schizophrenia: genetics and the maternal immune response to viral infection. Am J Med Genet (Neuropsychiatr Genet) 48:40–46;1993.

    Google Scholar 

  45. Xu G, Horiike G, Suzuki T, Miyamoto D, Kumihashi H, Suzuki Y. A novel strain, B/Gifu/2/73, differs from other influenza B viruses in the receptor binding specificities toward sialo-sugar chain linkage. Biochem Biophys Res Commun 224:815–818;1996.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Biochemistry, Chung Shan Medical University, Taichung, Taiwan, ROC

    Bo-Yie Chen

  2. School of Nutrition, Chung Shan Medical University, Taichung, Taiwan, ROC

    Han-Hsin Chang

  3. School of Medical Technology, Chung Shan Medical University, No. 110, Chien-Kuo N. Road, 402, Taichung, Taiwan (ROC)

    Hui-Ling Chiou &  David Pei-Cheng Lin

Authors
  1. Bo-Yie Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Han-Hsin Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hui-Ling Chiou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David Pei-Cheng Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, BY., Chang, HH., Chiou, HL. et al. Influenza-B-virus-induced eye and brain malformations during early chick embryogenesis and localization of the viral RNA in specific areas. J Biomed Sci 11, 266–274 (2004). https://doi.org/10.1007/BF02256570

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02256570

Key Words

Search

Navigation