|Tumpey, Terrence - CDC - ATLANTA, GA|
|Garcia-Sastre, Garcia - MT SANAI -NEW YORK, NY|
|Taubenberger, Jeffery - ARMED FORCES INST- MD|
|Palese, Peter - MT SANAI -NEW YORK, NY|
|Schultz-Cherry, Stacey - UNIV OF WI-MADISON, WI|
|Solorzano, Alicia - MT SINAI-NEW YORK, NY|
|Van Rooijen, Nico - VRIJE UNIV-THE NETHERLAND|
|Katz, Jacqueline - CDC - ATLANTA, GA|
|Basler, Christopher - MT SANAI-NEW YORK, NY|
Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: October 1, 2005
Publication Date: December 1, 2005
Citation: Tumpey, T.M., Garcia-Sastre, G., Taubenberger, J.K., Palese, P., Swayne, D.E., Pantin Jackwood, M.J., Schultz-Cherry, S., Solorzano, A., Van Rooijen, N., Katz, J.M., Basler, C.F. 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. Journal of Virology. 79:14933-14944. Interpretive Summary: The human H1N1 Spanish influenza pandemic of 1918-1919 caused 20 million deaths. How it caused high lethality and severe lung damage is unknown. Using a mouse model, we determined that white blood cells recruited into infected lungs played an important role in reducing virus growth and preventing virus spread. This indicates the natural host defense systems played a role in reducing the severity of the disease.
Technical Abstract: The Spanish influenza pandemic of 1918-1919 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 (1918 HA/NA:Tx/91) H1N1 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 to control Tx/91 virus-infected mice. Because pathologic changes of 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 affect 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. Additionally, 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 is able to induce severe lung inflammation consisting of AMs and neutrophils, which play a role in helping control the replication and spread of 1918 HA/NA:Tx/91 virus after intranasal infection of mice.