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.
Highlights
Intrinsic cellular defense molecules are able to detect and restrict invading pathogens at the level of the infected cell and constitute an initial repertoire of proteins that prevent infection
We show a novel role for Ifitm3 in vivo in restriction of respiratory syncytial virus (RSV): a virus that does not enter cells through the endosomal pathway, adding further to the role of interferon-inducible transmembrane 3 (IFITM3) as a central antiviral restriction factor that targets cellular entry
The role of IFITM3 in restricting virus infections, where the virus enters the cell through the acidic endosomal pathway, is well established [5,15,29]
Summary
Intrinsic cellular defense molecules are able to detect and restrict invading pathogens at the level of the infected cell and constitute an initial repertoire of proteins that prevent infection Such intrinsic defenses have the ability to detect the pathogen, and either directly block a component of the pathogen’s life cycles and / or signal to the innate and adaptive immune system to further control the infection. In certain cases, these intrinsic restriction factors recognise non-self pathogenassocated molecular patterns, such as lipids, proteins and nucleic acids, from a broad range of pathogens through pathogen recognition receptors. Restriction factors that work in defined cellular locations against a common pathogen feature of infection may have broad anti-influenza properties
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