Volume 78, Issue 4
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645


Mice infected with Dhori virus (DHOV) develop a fulminant, systemic, and uniformly fatal illness that has many of the clinical and pathologic findings seen in H5N1 influenza A virus infection. However, the role of host’s immune response in DHOV infection remains unclear. In this study, the concentrations of 23 inflammatory cytokines and chemokines were measured in the liver, lungs, and sera of mice during the course of DHOV infection. Liver function, level of viremia, and hematologic response were also monitored. Infected animals exhibited significant leucopenia and lymphopenia, which directly correlated with the disease progression. High yields of infectious virus along with strikingly elevated expression of various inflammatory mediators, including tumor necrosis factor (TNF)-α, inter-leukin (IL)-1, IL-6, IL-10, macrophage inflammatory protein (MIP)-1α, manocyte chemoattractant protein (MCP)-1, and interferon (IFN)- α, indicate that these responses play an important role in the observed disease and pathology. The overall clinical, pathologic, and immunologic responses of ICR mice to DHOV infection closely resemble those described for highly virulent influenza A virus infection in humans, thereby offering a realistic, safe, and alternative animal model for studying the pathogenesis and treatment of highly pathogenic avian influenza virus.


Article metrics loading...

The graphs shown below represent data from March 2017
Loading full text...

Full text loading...



  1. Kawaoka Y, Cox NJ, Haller O, Hongo S, Kaverin N, Klenk H-D, Lamb RA, McCauley J, Palese P, Rimstad E, Webster RG, 2005. Family Orthomyxoviridae. Virus taxonomy. Classification and nomenclature of virus. Fauquet CM, Mayo MA, Maniloff J, Desselberger U, Ball LA, eds Eighth Report of the International Committee on the Taxonomy of Viruses. San Diego, CA: Elsevier Academic Press; 681–693.
  2. Felipe AR, Peleteiro MC, Rebedo DAH, 1990. Dhori virus induced lesions in mice. Acta Viro 34 : 578–581. [Google Scholar]
  3. Mateo RI, Xiao SY, Lei H, Da Rosa AP, Tesh RB, 2007. Dhori virus (Orthomyxoviridae: Thogotovirus) infection in mice: a model of the pathogenesis of severe orthomyxovirus infection. Am J Trop Med Hyg 76 : 785–790. [Google Scholar]
  4. 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) virus isolated from humans. J Virol 73 : 5903–5911. [Google Scholar]
  5. Xu T, Qiao J, Zhao L, Wang G, He G, Li K, Tian Y, Gao M, Wang J, Wang H, Dong C, 2006. Acute respiratory distress syndrome induced by avian influenza A (H5N1) virus in mice. Am J Respir Crit Care Med 174 : 1011–1017. [Google Scholar]
  6. Maher JA, DeStefano J, 2004. The ferret: an animal model to study influenza virus. Lab Anim (NY) 33 : 50–53. [Google Scholar]
  7. Osterholm MT, 2005. Preparing for the next pandemic. N Engl J Med 352 : 1839–1842. [Google Scholar]
  8. The writing committee of the WHO consultation on human influenza A/H5, 2005. Avian influenza A (H5N1) infection in humans. N Engl J Med 353 : 1374–1385. [Google Scholar]
  9. Angela L, Petroshino MPH, CHES (Northwest Ohio Consortium for Public Health), Cytokine storm and the influenza pandemic. Available at: http://www.cytokinestorm.com Accessed September 22, 2001.
  10. 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. [Google Scholar]
  11. CDC/NIH, 2006. Biosafety in Microbiological and Biomedical Laboratories. Fifth edition. Washington, DC: US Government Printing Office.
  12. Anderson CR, Casals J, 1973. Dhori virus, a new agent isolated from Hyalomma dromedarii in India. Indian J Med Res 61 : 1416–1420. [Google Scholar]
  13. Tesh RB, Guzman H, da Rosa AP, Vasconcelos PF, Dias LB, Bunnell JE, Zhang H, Xiao SY, 2001. Experimental yellow fever virus infection in the golden hamster (Mesocricetus auratus). I. virologic, biochemical, and immunologic studies. J Infect Dis 183 : 1431–1436. [Google Scholar]
  14. Maines TR, Lu XH, Erb SM, Edwards L, Guarner J, Greer PW, Nguyen DC, Szretter KJ, Chen LM, Thawatsupha P, Chittaganpitch M, Waicharoen S, Nguyen DT, Nguyen HH, Kim JH, Hoang LT, Kang C, Phuong LS, Lim W, Zaki S, Donis RO, Cox NJ, Katz JM, Tumpey TM, 2005. Avian influenza (H5N1) viruses isolated from humans in Asia in 2004 exhibit increased virulence in mammals. J Virol 79 : 11788–11800. [Google Scholar]
  15. Szretter KJ, Gangappa S, Lu X, Smith C, Shieh WJ, Zaki SR, Sambhara S, Tumpey TM, Katz JM, 2007. Role of host cytokine responses in the pathogenesis of avian H5N1 influenza viruses in mice. J Virol 81 : 2736–2744. [Google Scholar]
  16. Chotpitayasunondh T, Ungchusak K, Hanshaoworakul W, Chunsuthiwat S, Sawanpanyalert P, Kijphati R, Lochindarat S, Srisan P, Suwan P, Osotthanakorn Y, Anantasetagoon T, Kanjanawasyi S, Tanupattarachai S, Weerakul J, Chaiwirattana K, Maneerattanaporn M, Poolsavathitikool R, Chokephaibulkit K, Apisarnthanarak A, Dowell SF, 2005. Human disease from influenza A (H5N1), Thailand, 2004. Emerg Infect Dis 11 : 201–209. [Google Scholar]
  17. 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 Viro. 632 : 242–246. [Google Scholar]
  18. Peiris JS, Yu WC, Leung CW, Cheung CY, Ng WF, Nicholls JM, Ng TK, Chan KH, Lai ST, Lim WL, Yuen KY, Guan Y, 2004. Re-emergence of fatal human influenza A subtype H5N1 disease. Lancet 363 : 617–619. [Google Scholar]
  19. Yuen KY, Chan PK, Peiris M, Tsang DN, Que TL, Shortridge KF, Cheung PT, To WK, Ho ET, Sung R, Cheng AF, 1998. Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus. Lancet 351 : 467–471. [Google Scholar]
  20. Fisman DN, 2000. Hemophagocytic syndromes and infection. Emerg Infect Dis 6 : 601–608. [Google Scholar]
  21. Headley AS, Tolley E, Meduri GU, 1997. Infections and the inflammatory response in acute respiratory distress syndrome. Chest 111 : 1306–1321. [Google Scholar]
  22. Tumpey TM, Garcia SA, Taubenberger JK, Palese P, Swayne DE, Pantin JMJ, Schultz CS, Solorzano A, Van RN, Katz JM, Basler CF, 2005. Pathogenicity of influenza viruses with genes from the 1918 pandemic virus: functional roles of alveolar macrophages and neutrophils in limiting virus replication and mortality in mice. J Virol 79 : 14933–14944. [Google Scholar]
  23. Tumpey TM, Lu X, Morken T, Zaki SR, Katz JM, 2000. Depletion of lymphocytes and diminished cytokine production in mice infected with a highly virulent influenza A (H5N1) virus isolated from humans. J Virol 74 : 6105–6116. [Google Scholar]
  24. Chaudhri G, Panchanathan V, Buller RML, Van DE, Alfons JM, Claassen E, Zhou J, De Chazal R, Laman JD, Karupiah G, 2004. Polarized type I cytokine response and cell-mediated immunity determine genetic resistance to mousepox. Proc Natl Acad Sci USA 101 : 9057–9062. [Google Scholar]
  25. Mosmann TR, Sad S, 1996. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today 17 : 138–146. [Google Scholar]
  26. Yssel H, Groux H, 2000. Characterization of T cell subpopulations involved in the pathogenesis of asthma and allergic diseases. Int Arch Allergy Immunol 121 : 10–18. [Google Scholar]
  27. Marone G, 1998. Asthma: recent advances. Immunol Today 19 : 5–9. [Google Scholar]
  28. Kaminuma O, Mori A, Ogawa K, Nakatu A, Kikkawa H, Ikezawa K, Okudaira H, 1999. Cloned Th cells confer eosinophilic inflammation and bronchial hyperresponsiveness. Int Arch Allergy Immunol 118 : 136–139. [Google Scholar]
  29. Klein A, Dijkstra MD, Boks SS, Severijnen LA, Mulder PG, Fokken WJ, 1999. Increase in IL-18, IL-10, IL-13, and RANTES mRNA levels (in situ hybridization) in the nasal mucosa after nasal allergen provocation. J Allergy Clin Immunol 103 : 441–450. [Google Scholar]
  30. Adachi M, Matsukrua S, Tokunaga H, Kokubu F, 1997. Expression of cytokines on human bronchial epithelial cells induced by influenza virus A. Int Arch Allergy Immunol 113 : 307–311. [Google Scholar]
  31. Openshaw PJ, 2004. What does the peripheral blood tell you in SARS? Clin Exp Immunol 136 : 11–12. [Google Scholar]
  32. De Jong MD, Simmons CP, Thanh TT, Hien VM, Smith GJ, Chau TN, Hoang DM, Van Vinh Chau N, Khanh TH, Dong VC, Qui PT, Van Cam B, Ha Do Q, Guan Y, Peiris JS, Chinh NT, Hien TT, Farrar J, 2006. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hyper-cytokinemia. Nat Med 12 : 1203–1207. [Google Scholar]
  33. Kash JC, Tumpey TM, Proll SC, Carter V, Perwitasari O, Thomas MJ, Basler CF, Palese P, Taubenberger JK, Garcia SA, Swayne DE, Katze MG, 2006. Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus. Nature 443 : 578–581. [Google Scholar]

Data & Media loading...

  • Received : 04 Oct 2007
  • Accepted : 18 Jan 2008

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error