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Journal of Virology, December 2005, p. 14933-14944, Vol. 79, No. 23
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.23.14933-14944.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Terrence M. Tumpey,1* Adolfo García-Sastre,2 Jeffery K. Taubenberger,3 Peter Palese,2 David E. Swayne,4 Mary J. Pantin-Jackwood,4 Stacey Schultz-Cherry,5 Alicia Solórzano,2 Nico Van Rooijen,6 Jacqueline M. Katz,1 and Christopher F. Basler2

Influenza Branch, Mail Stop G-16, DVRD, NCID, Centers for Disease Control and Prevention, 1600 Clifton Road, N.E., Atlanta, Georgia,1 Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029,2 Department of Molecular Pathology, Armed Forces Institute of Pathology, Rockville, Maryland 20850,3 Southeast Poultry Research Laboratory, Agricultural Research Service, U.S. Department of Agriculture, 934 College Station Road, Athens, Georgia 30606,4 Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin 53706,5 Department of Molecular Cell Biology, Vrije University, Amsterdam, The Netherlands6

Received 25 July 2005/ Accepted 7 September 2005

The Spanish influenza pandemic of 1918 to 1919 swept the globe and resulted in the deaths of at least 20 million people. The basis of the pulmonary damage and high lethality caused by the 1918 H1N1 influenza virus remains largely unknown. Recombinant influenza viruses bearing the 1918 influenza virus hemagglutinin (HA) and neuraminidase (NA) glycoproteins were rescued in the genetic background of the human A/Texas/36/91 (H1N1) (1918 HA/NA:Tx/91) virus. Pathogenesis experiments revealed that the 1918 HA/NA:Tx/91 virus was lethal for BALB/c mice without the prior adaptation that is usually required for human influenza A H1N1 viruses. The increased mortality of 1918 HA/NA:Tx/91-infected mice was accompanied by (i) increased (>200-fold) viral replication, (ii) greater influx of neutrophils into the lung, (iii) increased numbers of alveolar macrophages (AMs), and (iv) increased protein expression of cytokines and chemokines in lung tissues compared with the levels seen for control Tx/91 virus-infected mice. Because pathological changes in AMs and neutrophil migration correlated with lung inflammation, we assessed the role of these cells in the pathogenesis associated with 1918 HA/NA:Tx/91 virus infection. Neutrophil and/or AM depletion initiated 3 or 5 days after infection did not have a significant effect on the disease outcome following a lethal 1918 HA/NA:Tx/91 virus infection. By contrast, depletion of these cells before a sublethal infection with 1918 HA/NA:Tx/91 virus resulted in uncontrolled virus growth and mortality in mice. In addition, neutrophil and/or AM depletion was associated with decreased expression of cytokines and chemokines. These results indicate that a human influenza H1N1 virus possessing the 1918 HA and NA glycoproteins can induce severe lung inflammation consisting of AMs and neutrophils, which play a role in controlling the replication and spread of 1918 HA/NA:Tx/91 virus after intranasal infection of mice.

* Corresponding author. Mailing address: Influenza Branch, Mail Stop G-16, DVRD, NCID, Centers for Disease Control and Prevention, 1600 Clifton Road, N.E., Atlanta, GA 30333. Phone: (404) 639-5444. Fax: (404) 639-2334. E-mail: tft9{at}cdc.gov.

Journal of Virology, December 2005, p. 14933-14944, Vol. 79, No. 23
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.23.14933-14944.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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