Skip to main content
SpringerLink
Log in

Pathological lesions and viral localization of Influenza A (H5N1) virus in experimentally infected Chinese rhesus macaques: implications for pathogenesis and viral transmission

  • Original Article
  • Published:
Archives of Virology Aims and scope Submit manuscript

Abstract

Chinese rhesus macaques infected with influenza virus A/Tiger/Harbin/01/2002 (H5N1) developed acute interstitial pneumonia with diffuse alveolar damage. The results of virus isolation, reverse transcriptase polymerase chain reaction, immunohistochemistry, and in situ hybridization showed that the lung was the major target organ of the H5N1 virus infection. No virus was detected in the extrapulmonary organs. The results of immunohistochemistry and in situ hybridization also showed that pneumocytes and macrophages of the lower airway, not the ciliary epithelium of the trachea and bronchi, were the chief target cells in the lung tissue of the infected Chinese rhesus macaque. Our data indicate that the Chinese rhesus macaque is suitable as a new primate model for H5N1 virus research, especially for the study of H5N1 virus transmission. The predilection of the H5N1 virus to infect the lower airway suggests that the failure of the virus to attach to the ciliary epithelium of the trachea and bronchi may be a limiting factor in human-to-human transmissibility of the H5N1 virus.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Keawcharoen J, Oraveerakul K, Kuiken T, Fouchier RA, Amonsin A, Payungporn S, Noppornpanth S, Wattanodorn S, Theambooniers A, Tantilertcharoen R, Pattanarangsan R, Arya N, Ratanakorn P, Osterhaus DM, Poovorawan Y (2004) Avian influenza H5N1 in tigers and leopards. Emerg Infect Dis 10:2189–2191

    PubMed  Google Scholar 

  2. Kuiken T, Rimmelzwaan G, Van Riel D, Van Amerongen G, Baars M, Fouchier R, Osterhaus A (2004) Avian H5N1 influenza in cats. Science 306:241

    Article  PubMed  CAS  Google Scholar 

  3. Li KS, Guan Y, Wang J, Smith GJ, Xu KM, Duan L, Rahardjo AP, Puthavathana P, Buranathai C, Nguyen TD, Estoepangestie AT, Chaisingh A, Auewarakul P, Long HT, Hanh NT, Webby RJ, Poon LL, Chen H, Shortridge KF, Yuen KY, Webster RG, Peiris JS (2004) Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia. Nature 430:209–213

    Article  PubMed  CAS  Google Scholar 

  4. Mase M, Tsukamoto K, Imada T, Imai K, Tanimura N, Nakamura K, Yamamoto Y, Hitomi T, Kira T, Nakai T, Kiso M, Horimoto T, Kawaoka Y, Yamaguchi S (2005) Characterization of H5N1 influenza A viruses isolated during the 2003–2004 influenza outbreaks in Japan. Virology 332:167–176

    Article  PubMed  CAS  Google Scholar 

  5. Yuen KY, Chan PK, Peiris M (1998) Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus. Lancet 351:467–471

    Article  PubMed  CAS  Google Scholar 

  6. Lu X, Tumpey TM, Morken T, Zaki SR, Cox NJ, Katz JM (1999) A mouse model for the evaluation of pathogenesis and immunity to influenza A (H5N1) viruses isolated from humans. J Virol 73:5903–5911

    PubMed  CAS  Google Scholar 

  7. Rimmelzwaan GF, van Riel D, Baars M, Bestebroer TM, van Amerongen G, Fouchier RA, Osterhaus AD, Kuiken T (2006) Influenza A virus (H5N1) infection in cats causes systemic disease with potential novel routes of virus spread within and between hosts. Am J Pathol 168:176–183

    Article  PubMed  Google Scholar 

  8. Zitzow LA, Rowe T, Morken T, Shieh WJ, Zaki S, Katz JM (2002) Pathogenesis of avian influenza A (H5N1) viruses in ferrets. J Virol 76:4420–4429

    Article  PubMed  CAS  Google Scholar 

  9. Kuiken T, Rimmelzwaan GF, Van Amerongen G, Osterhaus AD (2003) Pathology of human influenza (H5N1) virus infection in cynomolgus macaques (Macaca fascicularis). Vet Pathol 40:304–310

    Article  PubMed  CAS  Google Scholar 

  10. Rimmelzwaan GF, Kuiken T, van Amerongen G, Bestebroer TM, Fouchier RA, Osterhaus AD (2001) Pathogenesis of influenza A (H5N1) virus infection in a primate model. J Virol 75:6687–6691

    Article  PubMed  CAS  Google Scholar 

  11. Trichel AM, Rajakumar PA, Murphey-Corb M (2002) Species-specific variation in SIV disease progression between Chinese and Indian subspecies of rhesus macaque. J Med Primatol 31:171–178

    Article  PubMed  CAS  Google Scholar 

  12. Uiprasertkul M, Puthavathana P, Sangsiriwut K, Pooruk P, Srisook K, Peiris M, Nicholls JM, Chokephaibulkit K, Vanprapar N, Auewarakul P (2005) Influenza A H5N1 replication sites in humans. Emerg Infect Dis 11:1036–1041

    PubMed  CAS  Google Scholar 

  13. Qin C, Wang J, Wei Q, She M, Marasco WA, Jiang Tu X, Zhu H, Ren L, Gao H, Guo L, Huang L, Yang R, Cong Z, Guo L, Wang Y, Liu Y, Sun Y, Duan S, Qu J, Chen L, Tong W, Ruan L, Liu P, Zhang H, Zhang J, Zhang H, Liu D, Liu Q, Hong T, He W (2005) An animal model of SARS produced by infection of Macaca mulatta with SARS coronavirus. J Pathol 206:251–259

    Article  PubMed  Google Scholar 

  14. Yang XH, Deng W, Tong Z, Liu YX, Zhang LF, Zhu H, Gao H, Huang L, Liu YL, Ma CM, Xu YF, Ding MX, Deng HK, Qin C (2007) Mice transgenic for human angiotensin-converting enzyme 2 provide a model for SARS coronavirus infection. Comp Med 57:450–459

    PubMed  CAS  Google Scholar 

  15. Zhang B, Zheng J, Gong EC, Gao ZF, Zhong YF, Hou L, Zhong HH, Xie ZG, Shao HQ, Gao DX (2003) Detection of SARS coronavirus in human tissues by in situ hybridization. Appl Immunohistochem Mol Morphol 11:285–286

    Google Scholar 

  16. Baskin CR, García-Sastre A, Tumpey TM, Bielefeldt-Ohmann H, Carter VS, Nistal-Villán E, Katze MG (2004) Integration of clinical data, pathology, and cDNA microarrays in influenza virus-infected pigtailed macaques (Macaca nemestrina). J Virol 78:10420–10432

    Article  PubMed  CAS  Google Scholar 

  17. Nishimura H, Itamura S, Iwasaki T, Kurata T, Tashiro M (2000) Characterization of human influenza A (H5N1) virus infection in mice: neuro-, pneumo- and adipotropic infection. J Gen Virol 81:2503–2510

    PubMed  CAS  Google Scholar 

  18. Zhao WB, Huang R, Zhang Y, Min FG, Wang J, Liu XM, Liu ZH (2007) Observation on rhesus monkeys infected second time with H5N1 avian influenza virus. Bing Du Xue Bao 23:282–286

    PubMed  Google Scholar 

  19. Cheung CY, Poon LL, Lau AS, Luk W, Lau YL, Shortridge KF (2002) Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? Lancet 360:1831–1837

    Article  PubMed  CAS  Google Scholar 

  20. Chan MC, Cheung CY, Chui WH, Tsao SW, Nicholls JM, Chan YO, Chan RW, Long HT, Poon LL, Guan Y, Peiris JS (2005) Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells. Respir Res 6:135

    Article  PubMed  CAS  Google Scholar 

  21. Mok CK, Lee DC, Cheung CY, Peiris M, Lau AS (2007) Differential onset of apoptosis in influenza A virus H5N1- and H1N1-infected human blood macrophages. J Gen Virol 88:1275–1280

    Article  PubMed  CAS  Google Scholar 

  22. Ling B, Veazey RS, Luckay A, Penedo C, Xu K, Lifson JD, Marx PA (2002) SIV(mac) pathogenesis in rhesus macaques of Chinese and Indian origin compared with primary HIV infections in humans. AIDS 16:1489–1496

    Article  PubMed  Google Scholar 

  23. To KF, Chan PK, Chan KF, Lee WK, Lam WY, Wong KF, Tang NL, Tsang DN, Sung RY, Buckley TA, Tam JS, Cheng AF (2001) Pathology of fatal human infection associated with avian influenza A H5N1 virus. J Med Virol 63:242–246

    Article  PubMed  CAS  Google Scholar 

  24. Lipatov AS, Andreansky S, Webby RJ, Hulse DJ, Rehg JE, Krauss S, Perez DR, Doherty PC, Webster RG, Sangster MY (2005) Pathogenesis of Hong Kong H5N1 influenza virus NS gene reassortants in mice: the role of cytokines and B- and T-cell responses. J Gen Virol 86:1121–1130

    Article  PubMed  CAS  Google Scholar 

  25. Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka Y (2006) Avian flu: influenza virus receptors in the human airway. Nature 440:435–436

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr. Huan Zhao for technical support. This study was supported by the National Key Science and Technology Project (2004BA519A34). We also thank The Chinese Public Fund Project of Institute of Laboratory Animal Science (DWS 200701), The Chinese Academy of Medical Sciences, and The Peking Union Medical College, for financial support.

Author information

Authors and Affiliations

  1. Department of Pathology, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 5, Panjiayuan, Nanli, Chaoyang District, 100021, Beijing, People’s Republic of China

    Yunxin Chen, Wei Deng, Chunshi Jia, Xiaowei Dai, Hua Zhu, Qi Kong, Lan Huang, Yali Liu, Chunmei Ma, Jiamei Li, Chong Xiao, Ying Liu & Chuan Qin

  2. Department of Virology, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, People’s Republic of China

    Qiang Wei

Authors
  1. Yunxin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wei Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chunshi Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaowei Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hua Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qi Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yali Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chunmei Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jiamei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Chong Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ying Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Qiang Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Chuan Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chuan Qin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, Y., Deng, W., Jia, C. et al. Pathological lesions and viral localization of Influenza A (H5N1) virus in experimentally infected Chinese rhesus macaques: implications for pathogenesis and viral transmission. Arch Virol 154, 227–233 (2009). https://doi.org/10.1007/s00705-008-0277-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00705-008-0277-5

Keywords

Search

Navigation