IFITM3 Restricts Human Metapneumovirus Infection

J Infect Dis. 2018 Oct 5;218(10):1582-1591. doi: 10.1093/infdis/jiy361.

Abstract

Human metapneumovirus (hMPV) utilizes a bifurcated cellular entry strategy, fusing either with the plasma membrane or, after endocytosis, with the endosome membrane. Whether cellular factors restrict or enhance either entry pathway is largely unknown. We found that the interferon-induced transmembrane protein 3 (IFITM3) inhibits hMPV infection to an extent similar to endocytosis-inhibiting drugs, and an IFITM3 variant that accumulates at the plasma membrane in addition to its endosome localization provided increased virus restriction. Mechanistically, IFITM3 blocks hMPV F protein-mediated membrane fusion, and inhibition of infection was reversed by the membrane destabilizing drug amphotericin B. Conversely, we found that infection by some hMPV strains is enhanced by the endosomal protein toll-like receptor 7 (TLR7), and that IFITM3 retains the ability to restrict hMPV infection even in cells expressing TLR7. Overall, our results identify IFITM3 as an endosomal restriction factor that limits hMPV infection of cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Chlorocebus aethiops
  • HEK293 Cells
  • Host-Pathogen Interactions / immunology*
  • Humans
  • Membrane Proteins / immunology*
  • Metapneumovirus / pathogenicity*
  • Paramyxoviridae Infections* / immunology
  • Paramyxoviridae Infections* / virology
  • RNA-Binding Proteins / immunology*
  • Toll-Like Receptor 7 / immunology
  • Vero Cells
  • Virus Internalization*

Substances

  • IFITM3 protein, human
  • Membrane Proteins
  • RNA-Binding Proteins
  • TLR7 protein, human
  • Toll-Like Receptor 7