In recent years a single nucleotide polymorphism, interferon-induced transmembrane protein 3 (IFITM3) rs12252, has been shown to alter the severity of influenza infection in Asian populations.
High Level Antibody Response to Pandemic Influenza H1N1/09 Virus Is Associated With Interferon-Induced Transmembrane Protein-3rs12252-CC in Young Adults.
We analyzed the population genetics of IFITM3 variants in the Portuguese general population (n = 200) and Central Africans (largely Angolan) (n = 148) as well as its association to influenza severity in Portuguese patients (n = 41).
By performing high-throughput RNA sequencing on primary dendritic cells and peripheral blood mononuclear cells isolated from pandemic H1N1 influenza and human immunodeficiency virus-1 (HIV-1) infected patients we show that full-length IFITM3 mRNA is dominantly expressed (>99%) across all rs12252 genotypes.
Recent studies suggested, the rs12252 T > C polymorphism in the interferon-inducible transmembrane protein 3 (IFITM3) gene might be associated with susceptibility to severe influenza.
To further understand the association between the SNP of IFITM3 and the risk of influenza, we searched related studies in five databases including PubMed published earlier than 9 November 2017.
IFITM3 was sequenced in patients and parents were genotyped for specific variants for family-based association testing. rs12252 was genotyped in 54 African-American pediatric outpatients with influenza (FLU09), included in the population-based comparisons with 1000 genomes.
Consistent with the known ability of amphipathic helices to alter membrane properties, we show that this helix and its amphipathicity are required for the IFITM3-dependent inhibition of influenza virus, Zika virus, vesicular stomatitis virus, Ebola virus, and human immunodeficiency virus infections.
Stratification analysis of ethnicity and severity revealed a significant increase in influenza susceptibility by IFITM3-SNP rs12252 among both Asian and Caucasian population.
Clustering of gene expression profiles suggests IFITM1 and 2 have an anti-viral response and IFITM3 may restrict avian influenza virus through cell membrane fusion.
Furthermore, entry mediated by the influenza virus hemagglutinin was robustly inhibited by IFITM3 but was insensitive to accumulation of endosomal cholesterol, indicating that modulation of cholesterol synthesis/transport did not account for the antiviral activity of IFITM3.
We have genotyped a possible splice-site altering single-nucleotide polymorphism (rs12252) in the IFITM3 gene in 34 patients with H1N1 influenza and severe pneumonia, and >5000 individuals comprising patients with community-acquired mild lower respiratory tract infection and matched controls of Caucasian ancestry.
Interferon-induced transmembrane protein-3 genetic variants could, therefore, have a strong effect of the epidemiology of influenza in China and in people of Chinese descent.
One study does however present convincing functional evidence for an important role for IFITM3 in susceptibility to severe influenza in mice, and some evidence that this may also be important in human A/H1N1/pdm2009 infection.
Together these data reveal that the action of a single intrinsic immune effector, IFITM3, profoundly alters the course of influenza virus infection in mouse and humans.
S-palmitoylation and ubiquitination differentially regulate interferon-induced transmembrane protein 3 (IFITM3)-mediated resistance to influenza virus.
Collectively, these findings establish a central role for Ifitm3 in limiting acute influenza in vivo, and provide further insight into Ifitm3 expression and regulation.
Tetherin and IFITM3 are recently identified interferon-induced cellular proteins that restrict infections by retroviruses and filoviruses and of influenza virus and flaviviruses, respectively.