title: Novel mode of ISG15-mediated protection against influenza A virus and Sendai virus in mice.
abstract: ISG15 is a diubiquitin-like modifier and one of the most rapidly induced genes upon type I interferon stimulation. Hundreds of host proteins and a number of viral proteins have been shown to be ISGylated, and understanding how these modifications affect the interferon response and virus replication has been of considerable interest. ISG15(-/-) mice exhibit increased susceptibility to viral infection, and in the case of influenza B virus and vaccinia virus, ISG15 conjugation has been shown to restrict virus replication in vivo. A number of studies have also found that ISG15 is capable of antagonizing replication of some viruses in tissue culture. However, recent findings have demonstrated that ISG15 can protect mice from Chikungunya virus infection without affecting the virus burden. In order to better understand the function of ISG15 in vivo, we characterized the pathogenesis of influenza A virus and Sendai virus in ISG15(-/-) mice. We found that ISG15 protects mice from virus induced lethality by a conjugation-dependent mechanism in both of these models. However, surprisingly, we found that ISG15 had minimal effect on virus replication and did not have an obvious role in the modulation of the acute immune response to infection. Instead, we observed an increase in the number of diseased small airways in mice lacking ISG15. This ability of ISG15 to protect mice in a conjugation-dependent, but nonantiviral, manner from respiratory virus infection represents a previously undescribed role for ISG15 and demonstrates the importance of further characterization of ISG15 in vivo.
  
  
  OBJECTIVE
  It has previously been demonstrated that ISG15(-/-) mice are more susceptible to a number of viral infections. Since ISG15 is one of the most strongly induced genes after type I interferon stimulation, analysis of ISG15 function has largely focused on its role as an antiviral molecule during acute infection. Although a number of studies have shown that ISG15 does have a small effect on virus replication in tissue culture, few studies have confirmed this mechanism of protection in vivo. In these studies we have found that while ISG15(-/-) mice are more susceptible to influenza A virus and Sendai virus infections, ISGylation does not appear to mediate this protection through the direct inhibition of virus replication or the modulation of the acute immune response. Thus, in addition to showing a novel mode of ISG15 mediated protection from virus infection, this study demonstrates the importance of studying the role of ISG15 in vivo.
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Morales
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Monte
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Lulu
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Struckhoff
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Agapov
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA Department of Cell Biology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Holtzman
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Thaddeus S
authors.initials: TS
authors.lastname: Stappenbeck
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA dlenscho@dom.wustl.edu.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Lenschow
mesh_terms: D000818:Animals; D016207:Cytokines / Q000172:deficiency / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D009980:Influenza A virus / Q000276:immunology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000821:virology; D010253:Respirovirus Infections / Q000276:immunology* / Q000821:virology; D029082:Sendai virus / Q000276:immunology*; D016019:Survival Analysis; D014452:Ubiquitins / Q000172:deficiency / Q000378:metabolism
chemical_list: D016207:Cytokines; C489550:G1p2 protein, mouse; D014452:Ubiquitins