Defining the range of pathogens susceptible to Ifitm3 restriction using a knockout mouse model

• Published in: PloS one 2013-11, Vol.8 (11), p.e80723-e80723
• Main Authors: Everitt, Aaron R, Clare, Simon, McDonald, Jacqueline U, Kane, Leanne, Harcourt, Katherine, Ahras, Malika, Lall, Amar, Hale, Christine, Rodgers, Angela, Young, Douglas B, Haque, Ashraful, Billker, Oliver, Tregoning, John S, Dougan, Gordon, Kellam, Paul
• Format: Article
• Language: English
• Subjects: Animal; Animals; Antiviral activity; Bacteria; Bacteria - metabolism; Biological response modifiers; Citrobacter; Citrobacter rodentium - growth & development; Citrobacter rodentium - physiology; Citrobacter rodentium/growth & development/physiology; College campuses; Disease control; Ethics; Gene expression; Genetic aspects; Genomes; Health aspects; Homeostasis; Immunology; In vivo methods and tests; Inbred C57BL; Infection; Infections; Infectious diseases; Influenza; Influenza viruses; Interferon; Kinetics; Knockout; Laboratories; Malaria - parasitology; Medical research; Membrane Proteins - deficiency; Membrane Proteins - metabolism; Membrane Proteins/deficiency/metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Animal; Mycobacterium tuberculosis - growth & development; Mycobacterium tuberculosis - physiology; Mycobacterium tuberculosis/growth & development/physiology; Pathogenesis; Pathogenic microorganisms; Pathogens; Phenotype; Plasmodium berghei; Plasmodium berghei - growth & development; Plasmodium berghei - physiology; Plasmodium berghei/growth & development/physiology; Proteins; Protozoa; Respiratory syncytial virus; Respiratory Syncytial Viruses - growth & development; Respiratory Syncytial Viruses - physiology; Respiratory Syncytial Viruses/growth & development/physiology; Salmonella; Salmonella typhimurium - physiology; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Tuberculosis; Viral infections; Virology; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0080723

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.