Early control of H5N1 influenza virus replication by the type I interferon response in mice.
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 cases. Although the pathogenic mechanism(s) of H5N1 influenza viruses has 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 that type I interferons (alpha/beta interferon [IFN-alpha/beta]) might play in H5N1 pathogenicity in vivo, by comparing the kinetics and outcomes of H5N1 virus infection in IFN-alpha/beta receptor (IFN-alpha/betaR)-deficient and SvEv129 wild-type 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), which exhibit high and low lethality in mice, respectively. IFN-alpha/betaR-deficient mice experienced significantly more weight loss and more rapid time to death than did wild-type mice. HK/486 virus caused a systemic infection similar to that with 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 IFN-alpha/beta. These results suggest a role for the IFN-alpha/beta response in the control of H5N1 virus replication both in vivo and in vitro, and as such it may provide some degree of protection to the host in the early stages of infection.
Szretter
Kristy J
KJ
Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 303331, USA.
Gangappa
Shivaprakash
S
Belser
Jessica A
JA
Zeng
Hui
H
Chen
Hualan
H
Matsuoka
Yumiko
Y
Sambhara
Suryaprakash
S
Swayne
David E
DE
Tumpey
Terrence M
TM
Katz
Jacqueline M
JM
D000818:Animals; D045744:Cell Line, Tumor; D002645:Chickens; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects* / Q000502:physiology*; D007370:Interferon Type I / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000378:metabolism*; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D013997:Time Factors; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
D007370:Interferon Type I; C057027:PB2 protein, Influenzavirus A; D014764:Viral Proteins; D053633:Receptor, Interferon alpha-beta; D012324:RNA-Dependent RNA Polymerase