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Title: Early control of H5N1 influenza virus replication by the Type I interferon response in mice

item ZENG, HUI
item Swayne, David

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/10/2009
Publication Date: 6/1/2009
Citation: Szretter, K.J., Gangappa, S., Zeng, H., Chen, H., Matsuoka, Y., Sambhara, S., Tumpey, T.M., Swayne, D.E., Katz, J.M. 2009. Early control of H5N1 influenza virus replication by the Type I interferon response in mice. Journal of Virology. 83(11):5825-5834.

Interpretive Summary: H5N1 high pathogenicity (HP) avian influenza (AI) has caused infection in humans. This study examined the role of interferon, a naturally produced antiviral substance in animals, in preventing severe disease in a mouse model for human infection. When infected with the H5N1 high pathogenicity avian influenza (HPAI) virus, mice that could not produce interferon lost weight, had multiple organs with lesions, and had more rapid time-to-death compared to mice that produced interferon. This suggests that correct interferon response in animals will reduce the severity of disease from H5N1 HPAI virus infections.

Technical Abstract: Widespread distribution of highly pathogenic avian H5N1 influenza viruses in domesticated and wild birds continues to pose a threat to public health as interspecies transmission of virus has resulted in increasing numbers of human disease. Although the pathogenic mechanism(s) of H5N1 influenza viruses have not been fully elucidated, it has been suggested that the ability to evade host innate responses, such as the type I interferon response may contribute to the virulence of these viruses in mammals. We investigated the role of type I interferons (IFN-alpha-beta) might play in H5N1 pathogenicity in vivo, by comparing the kinetics and outcome of H5N1 virus infection in IFN-alpha-betaR-deficient and SvEv129 wildtype mice using two avian influenza A viruses isolated from humans, A/Hong Kong/483/97 (HK/483) and A/Hong Kong/486/97 (HK/486) that exhibit high and low lethality in mice, respectively. IFN-alpha-betaR-deficient mice experienced significantly more weight-loss and more rapid time-to-death compared to wildtype mice. HK/486 virus caused a systemic infection similar to HK/483 virus in IFN-alpha-betaR-deficient mice, suggesting a role for IFN-alpha-beta in controlling the systemic spread of this H5N1 virus. HK/483 virus replicated more efficiently than HK/486 virus both in vivo and in vitro. However, replication of both viruses was significantly reduced following pretreatment with I IFN-alpha-beta. These results suggest a role for IFN-alpha-beta response in the control of H5N1 virus replication both in vivo and in vitro and as such may provide some degree of protection to the host in the early stages of infection.