Mammalian Innate Resistance to Highly Pathogenic Avian Influenza H5N1 Virus Infection Is Mediated through Reduced Proinflammation and Infectious Virus Release

Respiratory epithelial cells andmacrophages are the key innate immune cells that play an important role in the pathogenesis of influenza A virus infection. We found that these two cell types from both human and pig showed comparable susceptibilities to initial infection with a highly pathogenic avian influenza (HPAI) H5N1 virus (A/turkey/Turkey/1/05) and a moderately patho-genic human influenza H1N1 virus (A/USSR/77), but there were contrasting differences in host innate immune responses. Hu-man cells mounted vigorous cytokine (tumor necrosis factor alpha [TNF-] and interleukin-6 [IL-6]) and chemokine (CXCL9, CXCL10, and CXCL11) responses to H5N1 virus infection. However, pig epithelial cells andmacrophages showed weak or no TNF- and chemokine induction with the same infections. The apparent lack of a strong proinflammatory response, corrobo-rated by the absence of TNF- induction in H5N1 virus-challenged pigs, coincided with greater cell death and the reduced re-lease of infectious virus from infected pig epithelial cells. Suppressor of cytokine signaling 3 (SOCS3), a protein suppressor of the JAK-STAT pathway, was constitutively highly expressed and transcriptionally upregulated in H5N1 virus-infected pig epithelial cells andmacrophages, in contrast to the corresponding human cells. The overexpression of SOCS3 in infected humanmacro-phages dampened TNF- induction. In summary, we found that the reported low susceptibility of pigs to contemporary Eur-asian HPAI H5N1 virus infections coincides at the level of innate immunity of respiratory epithelial cells andmacrophages with a reduced output of viable virus and an attenuated proinflammatory response, possibly mediated in part by SOCS3, which coul