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Journal of Virology, July 2006, p. 6295-6304, Vol. 80, No. 13
0022-538X/06/$08.00+0     doi:10.1128/JVI.02381-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Influenza Virus Evades Innate and Adaptive Immunity via the NS1 Protein{dagger}

Ana Fernandez-Sesma,1 Svetlana Marukian,1 Barbara J. Ebersole,2 Dorothy Kaminski,1 Man-Seong Park,1 Tony Yuen,2 Stuart C. Sealfon,2 Adolfo García-Sastre,1 and Thomas M. Moran1*

Departments of Microbiology,1 Neurology, Mount Sinai School of Medicine, New York, New York 100292

Received 11 November 2005/ Accepted 20 March 2006

Both antibodies and T cells contribute to immunity against influenza virus infection. However, the generation of strong Th1 immunity is crucial for viral clearance. Interestingly, we found that human dendritic cells (DCs) infected with influenza A virus have lower allospecific Th1-cell stimulatory abilities than DCs activated by other stimuli, such as lipopolysaccharide and Newcastle disease virus infection. This weak stimulatory activity correlates with a suboptimal maturation of the DCs following infection with influenza A virus. We next investigated whether the influenza A virus NS1 protein could be responsible for the low levels of DC maturation after influenza virus infection. The NS1 protein is an important virulence factor associated with the suppression of innate immunity via the inhibition of type I interferon (IFN) production in infected cells. Using recombinant influenza and Newcastle disease viruses, with or without the NS1 gene from influenza virus, we found that the induction of a genetic program underlying DC maturation, migration, and T-cell stimulatory activity is specifically suppressed by the expression of the NS1 protein. Among the genes affected by NS1 are those coding for macrophage inflammatory protein 1ß, interleukin-12 p35 (IL-12 p35), IL-23 p19, RANTES, IL-8, IFN-{alpha}/ß, and CCR7. These results indicate that the influenza A virus NS1 protein is a bifunctional viral immunosuppressor which inhibits innate immunity by preventing type I IFN release and inhibits adaptive immunity by attenuating human DC maturation and the capacity of DCs to induce T-cell responses. Our observations also support the potential use of NS1 mutant influenza viruses as live attenuated influenza virus vaccines.

* Corresponding author. Mailing address: Department of Microbiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029. Phone: (212) 241-6927. Fax: (212) 987-3653. E-mail: Thomas.moran{at}mssm.edu.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, July 2006, p. 6295-6304, Vol. 80, No. 13
0022-538X/06/$08.00+0     doi:10.1128/JVI.02381-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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