J Vir. Parasite-Mediated Upregulation of NK Cell-Derived Gamma Interferon Protects against Severe Highly Pathogenic H5N1 Influenza Virus Infection

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http://jvi.asm.org/cgi/content/abstract/85/17/8680

Parasite-Mediated Upregulation of NK Cell-Derived Gamma Interferon Protects against Severe Highly Pathogenic H5N1 Influenza Virus Infection<sup>

</sup> Kevin B. O'Brien,¹^,2 Stacey Schultz-Cherry,¹^*, and Laura J. Knoll²^* Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105,¹ Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin 53706²
Received 17 May 2011/ Accepted 23 June 2011
Outbreaks of influenza A viruses are associated with significanthuman morbidity worldwide. Given the increasing resistance tothe available influenza drugs, new therapies for the treatmentof influenza virus infection are needed. An alternative approachis to identify products that enhance a protective immune response.In these studies, we demonstrate that infecting mice with theTh1-inducing parasite Toxoplasma gondii prior to highly pathogenicavian H5N1 influenza virus infection led to decreased lung viraltiters and enhanced survival. A noninfectious fraction of T.gondii soluble antigens (STAg) elicited an immune response similarto that elicited by live parasites, and administration of STAg2 days after H5N1 influenza virus infection enhanced survival,lowered viral titers, and reduced clinical disease. STAg administrationprotected H5N1 virus-infected mice lacking lymphocytes, suggestingthat while the adaptive immune response was not required forenhanced survival, it was necessary for STAg-mediated viralclearance. Mechanistically, we found that administration ofSTAg led to increased production of gamma interferon (IFN-

)from natural killer (NK) cells, which were both necessary andsufficient for survival. Further, administration of exogenousIFN-

alone enhanced survival from H5N1 influenza virus infection,although not to the same level as STAg treatment. These studiesdemonstrate that a noninfectious T. gondii extract enhancesthe protective immune response against severe H5N1 influenzavirus infections even when a single dose is administered 2 dayspostinfection.