title: Defining the range of pathogens susceptible to Ifitm3 restriction using a knockout mouse model.
abstract: The interferon-inducible transmembrane (IFITM) family of proteins has been shown to restrict a broad range of viruses in vitro and in vivo by halting progress through the late endosomal pathway. Further, single nucleotide polymorphisms (SNPs) in its sequence have been linked with risk of developing severe influenza virus infections in humans. The number of viruses restricted by this host protein has continued to grow since it was first demonstrated as playing an antiviral role; all of which enter cells via the endosomal pathway. We therefore sought to test the limits of antimicrobial restriction by Ifitm3 using a knockout mouse model. We showed that Ifitm3 does not impact on the restriction or pathogenesis of bacterial (Salmonella typhimurium, Citrobacter rodentium, Mycobacterium tuberculosis) or protozoan (Plasmodium berghei) pathogens, despite in vitro evidence. However, Ifitm3 is capable of restricting respiratory syncytial virus (RSV) in vivo either through directly restricting RSV cell infection, or by exerting a previously uncharacterised function controlling disease pathogenesis. This represents the first demonstration of a virus that enters directly through the plasma membrane, without the need for the endosomal pathway, being restricted by the IFITM family; therefore further defining the role of these antiviral proteins.
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Everitt
authors.forename: Simon
authors.initials: S
authors.lastname: Clare
authors.forename: Jacqueline U
authors.initials: JU
authors.lastname: McDonald
authors.forename: Leanne
authors.initials: L
authors.lastname: Kane
authors.forename: Katherine
authors.initials: K
authors.lastname: Harcourt
authors.forename: Malika
authors.initials: M
authors.lastname: Ahras
authors.forename: Amar
authors.initials: A
authors.lastname: Lall
authors.forename: Christine
authors.initials: C
authors.lastname: Hale
authors.forename: Angela
authors.initials: A
authors.lastname: Rodgers
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Young
authors.forename: Ashraful
authors.initials: A
authors.lastname: Haque
authors.forename: Oliver
authors.initials: O
authors.lastname: Billker
authors.forename: John S
authors.initials: JS
authors.lastname: Tregoning
authors.forename: Gordon
authors.initials: G
authors.lastname: Dougan
authors.forename: Paul
authors.initials: P
authors.lastname: Kellam
mesh_terms: D000818:Animals; D001419:Bacteria / Q000378:metabolism*; D044082:Citrobacter rodentium / Q000254:growth & development / Q000502:physiology; D006706:Homeostasis; D007700:Kinetics; D008288:Malaria / Q000469:parasitology; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000502:physiology; D010641:Phenotype; D010962:Plasmodium berghei / Q000254:growth & development / Q000502:physiology*; D012136:Respiratory Syncytial Viruses / Q000254:growth & development / Q000502:physiology*; D012486:Salmonella typhimurium / Q000502:physiology
chemical_list: D008565:Membrane Proteins; C462181:fragilis protein, mouse