Oral Presentation Lorne Infection and Immunity 2013

Exploring the patterns of viral restriction of IFITM proteins across primate species (#9)

Sarah E Smith 1 , Rachael S Wash 1 , Paul Kellam 1 2
  1. Wellcome Trust Sanger Institute, Cambridge, United Kingdom
  2. UCL, London, UK

Evolution of host effector proteins of the innate or intrinsic immune system is thought to be driven mainly by the pathogens that they encounter. Interferon inducible transmembrane protein 3 (IFITM3) is one such effector and has been shown to confer potent resistance to a number of enveloped viruses both in vitro and in vivo, including influenza virus, West Nile virus and dengue virus.

Although the function of IFITM3 is thought to involve denying cytosolic entry to the viruses, the precise mechanism of its action is not known. Here we aim to further characterise IFITM3 by investigating its function and the consequence of sequence variation. IFITM3 is conserved through mammalian evolution and duplication events have led to paralogous genes arising in many species. Thus we have investigated the consequence of IFITM1, 2 and 3 sequence variation across several primate species.

Stable cells lines were established by transducing A549 lung epithelial cells with lentiviruses expressing different IFITM proteins. The potency of their viral restriction was tested against a panel of pseudotyped viruses including subtypes of influenza A and lyssaviruses. Focusing on human IFITMs (H-IFITM), it is clear that whilst H-IFITM3 is able to potently restrict all pseudotyped viruses tested, H-IFITM1 restricts some subtypes of influenza equally well but is much less effective against others compared to paralogous H-IFITM3.

This supports the theory that increasing the copy number of a restriction factor allows the host to match the evolution of rapidly evolving RNA viruses leading to large families of related restriction factors. Elucidating the functions of IFITM 1, 2 and 3 proteins will help explain the differential susceptibilities of enveloped viruses and provides further insights into understanding host-pathogen interactions.

  1. Feeley, E. M. et al. (2011) IFITM3 inhibits influenza A virus infection by preventing cytosolic entry. PlosPathogens. Vol7, issue 10.
  2. Everitt, A. R. et al. (2012) IFITM3 restrict the morbidity and mortality associated with influenza. Nature. Vol 484