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Journal of Virology, May 2008, p. 4265-4274, Vol. 82, No. 9
0022-538X/08/$08.00+0     doi:10.1128/JVI.02602-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Alveolar Macrophages Are Indispensable for Controlling Influenza Viruses in Lungs of Pigs

Laboratory of Influenza Research,¹ Section of Diagnostic Imaging,² Laboratory of Public Health,³ Laboratory of Pathology, College of Veterinary Medicine, Chungnam National University, Yuseong-Gu, Daejeon 305-764, Korea,⁴ Department of Cell Biology and Immunology, Free University, Amsterdam, The Netherlands,⁵ Department of Microbiology, The University of Hong Kong, Pokfulam, Hong Kong SAR, China⁶

Received 6 December 2007/ Accepted 6 February 2008

Alveolar macrophages constitutively reside in the respiratory tracts of pigs and humans. An in vivo role of alveolar macrophages in defending against influenza viruses in mice infected with a reassorted influenza virus, 1918 HA/NA:Tx/91, was reported, but there has been no report on an in vivo role of alveolar macrophages in a natural host such as a pig using currently circulating human influenza virus. Here we show that in vivo depletion of alveolar macrophages in pigs by dichloromethylene diphosphonate (MDPCL2) treatment results in 40% mortality when pigs are infected with currently circulating human H1N1 influenza viruses, while none of the infected control pigs died. All infected pigs depleted of alveolar macrophages suffered from more severe respiratory signs than infected control pigs. Induction of tumor necrosis factor alpha in the infected pigs depleted of alveolar macrophages was significantly lower than that in the lungs of infected control pigs, and the induction of interleukin-10, an immunosuppressive cytokine, significantly increased in the lungs of infected pigs depleted of alveolar macrophages compared to infected control pigs. When we measured antibody titers and CD8⁺ T lymphocytes expressing gamma interferon (IFN-), lower antibody titers and a lower percentage of CD8⁺ T lymphocytes expressing IFN- were detectable in MDPCL2-treated infected pigs than in phosphate-buffered saline- and liposome-treated and infected pigs. Taken together, our findings suggest that alveolar macrophages are essential for controlling H1N1 influenza viruses in pigs.

Published ahead of print on 20 February 2008.