IFITM3 polymorphism rs12252-C restricts influenza A viruses

Area of Science:

• Virology
• Immunology
• Genetics

Background:

• The IFITM3 polymorphism rs12252-C, encoding a truncated IFITM3 isoform (Δ21 IFITM3), is controversially linked to severe H1N1 influenza A virus (IAV) outcomes.
• Previous in vitro studies suggested Δ21 IFITM3 lacks anti-IAV activity, and tyrosine 20 was identified as crucial for IFITM3's antiviral function via endocytic trafficking.

Purpose of the Study:

• To re-evaluate the functional impact of the Δ21 IFITM3 isoform and the role of tyrosine 20 in IFITM3's restriction of influenza A virus.
• To investigate the subcellular localization and antiviral activity of Δ21 IFITM3 and a Y20A IFITM3 variant against various IAV subtypes.

Main Methods:

• In vitro assays assessing viral entry restriction mediated by full-length IFITM3, Δ21 IFITM3, and Y20A IFITM3 variants using IAV H1, H3, H5, and H7 proteins.
• Analysis of viral replication suppression for H1N1 and H3N2 IAV.
• Subcellular localization studies using microscopy to compare IFITM3 variants with full-length IFITM3.

Main Results:

• Both Δ21 IFITM3 and Y20A IFITM3 variants strongly restricted entry of H1, H3, H5, and H7 IAV proteins, contradicting previous findings.
• Δ21 IFITM3 demonstrated efficient suppression of H1N1 and moderate suppression of H3N2 IAV replication.
• While exhibiting broader subcellular distributions, both variants retained significant localization to late endosomes and lysosomes.

Conclusions:

• Tyrosine 20 partially influences IFITM3's subcellular localization but is not essential for its ability to restrict IAV entry.
• Mechanisms beyond viral entry restriction likely contribute to the observed clinical outcome variations in H1N1 influenza associated with the rs12252-C polymorphism.