Distinct patterns of IFITM-mediated restriction of filoviruses, SARS coronavirus, and influenza A virus.
Interferon-inducible transmembrane proteins 1, 2, and 3 (IFITM1, 2, and 3) are recently identified viral restriction factors that inhibit infection mediated by the influenza A virus (IAV) hemagglutinin (HA) protein. Here we show that IFITM proteins restricted infection mediated by the entry glycoproteins (GP(1,2)) of Marburg and Ebola filoviruses (MARV, EBOV). Consistent with these observations, interferon-β specifically restricted filovirus and IAV entry processes. IFITM proteins also inhibited replication of infectious MARV and EBOV. We observed distinct patterns of IFITM-mediated restriction: compared with IAV, the entry processes of MARV and EBOV were less restricted by IFITM3, but more restricted by IFITM1. Moreover, murine Ifitm5 and 6 did not restrict IAV, but efficiently inhibited filovirus entry. We further demonstrate that replication of infectious SARS coronavirus (SARS-CoV) and entry mediated by the SARS-CoV spike (S) protein are restricted by IFITM proteins. The profile of IFITM-mediated restriction of SARS-CoV was more similar to that of filoviruses than to IAV. Trypsin treatment of receptor-associated SARS-CoV pseudovirions, which bypasses their dependence on lysosomal cathepsin L, also bypassed IFITM-mediated restriction. However, IFITM proteins did not reduce cellular cathepsin activity or limit access of virions to acidic intracellular compartments. Our data indicate that IFITM-mediated restriction is localized to a late stage in the endocytic pathway. They further show that IFITM proteins differentially restrict the entry of a broad range of enveloped viruses, and modulate cellular tropism independently of viral receptor expression.
Department of Microbiology and Molecular Genetics, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts, United States of America. I-Chueh_Huang@hms.harvard.edu
I-Chueh
IC
Huang
Charles C
CC
Bailey
Jessica L
JL
Weyer
Sheli R
SR
Radoshitzky
Michelle M
MM
Becker
Jessica J
JJ
Chiang
Abraham L
AL
Brass
Asim A
AA
Ahmed
Xiaoli
X
Chi
Lian
L
Dong
Lindsay E
LE
Longobardi
Dutch
D
Boltz
Jens H
JH
Kuhn
Stephen J
SJ
Elledge
Sina
S
Bavari
Mark R
MR
Denison
Hyeryun
H
Choe
Michael
M
Farzan
D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004730:Endothelium, Vascular; D005260:Female; D016563:Filoviridae / Q000254:growth & development / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions; D006801:Humans; D009980:Influenza A virus / Q000254:growth & development / Q000472:pathogenicity*; D051379:Mice; D045473:Severe acute respiratory syndrome-related coronavirus / Q000254:growth & development / Q000472:pathogenicity*; D014709:Vero Cells; D014777:Virus Diseases / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D053586:Virus Internalization; D014779:Virus Replication
D000943:Antigens, Differentiation; C062010:leu-13 antigen
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