IFITM

• IFITMs

  Interferon-induced transmembrane family proteins
• Major Targets of IFITMs

  • Influenza A virus
  • Dengue virus
  • West Nile virus
  • Ebola Virus
• Pathway activation

  • Pathogen associated molecular patterns (PAMPS) interact with PRRs in host cell, activating IFNs 1&2 expression
  • IFNs 1&2 recruit Janus Kinases (JAK), leading to activation of the JAK-STAT signaling pathways i.e., phosphorylation and activation of STAT1, STAT2
  • IFITMs undergo post-translational modifications, regulating its antiviral effects
• Influenza A Virus


  • Found to promote cho
• IFITM localizations

  • IFITM-1: Cell surface
  • IFITM-2 &3: Endosomes & lysosomes
• IFITMs' Key functions

  • Prevents viral entry by altering host cell membrane properties to block membrane fusion
  • Inhibits viral replication
  • Aids activation of adaptive immune responses
  • Enhances IFN signalling pathways
• IFITMs


  • Transmembrane proteins
  • 5 types: IFITM-1, 2, 3, 5 & 10 with different functions and localizations in the cell
  • IFITM 1-3 are most prominent in antiviral immunity
  • IFITM1, IFITM2 & IFITM3 genes are highly homologous
  • Expression induced by interferon (IFN) upregulation
• IFITM activation

  • IFITM expression is induced by interferons (IFNs) type 1 & 2
  • IFITMs are one of the interferon stimulated genes (ISGs) and expression is increased when IFN binds to corresponding interferon receptor, activating the JAK-STAT signaling pathways
• Contribution to antiviral immunity

  • IFITMs change endosome and lysosome characteristics to inhibit virus entry
  • IFITM blocks formation of fusion pores following virus-endosome hemifusion
  • Function independently to inhibit virus infection
• Dengue Virus and West Nile Virus (Jiang et al. 2010)


  • IFITMs 2&3 and related ISGs are found to block viral entry into host cells
  • IFN-induced enzymes, viperin, ISG20 and double stranded RNA activated protein kinase inhibited RNA synthesis hence viral replication
  • Evident from reduced viral colony formation in in vitro infected cells
• Virus examples

  • Influenza A Virus (Desai et al. 2014)
  • Dengue Virus and West Nile Virus (Jiang et al. 2010)
  • Ebola Virus (Wrensch et al. 2015)
• Evidence that viruses evade IFITM response


  • Influenza Virus: Some strains encode the M2 protein to counteract IFITMs
  • Influenza virus repurposes the antiviral protein IFIT2 to promote translation of viral mRNAs
  • Hepatitis C Virus (HCV): Can induce microRNA-130a to downregulate IFITM proteins
• Ebola Virus (Wrensch et al. 2015)


  • Found to inhibit glycoprotein-mediated viral entry primarily by IFITMs 2&3
  • IFITM3 and neutralising antibodies might synergistically inhibit viral entry -> the potential to enhance adaptive immune responses
• IFITMs function

  1. Preventing its association with oxysterol-binding proteins which disrupts intracellular cholesterol homeostasis

  2. Function independently to inhibit virus infection

  3. Alters cell membrane structure

  4. Stimulating effective immune response through promoting T helper differentiation, regulating cytokine signalling
• Influenza A Virus (Desai et al. 2014)

  • Found to promote cholesterol synthesis in endosomes by IFITM-3
  • The cholesterol acts as a physical barrier blocking viral release into the cytoplasm
• Hepatitis C Virus (HCV)


  • Many types of microRNAs are involved in modulating viral entry, IFN signalling pathways, viral replication
  • HCV can induce microRNA-130a to downregulate IFITM proteins
• Influenza Virus

  • Some strains encode the M2 protein to counteract IFITMs
  • Influenza virus repurposes the antiviral protein IFIT2 to promote translation of viral mRNAs
  • The virus mediates lysosomal degradation of Eukaryotic Translation Initiation factor 4B