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IFITM3 variants point to a critical role in emergent virus infections
Parker J Denz1,2, Jacob S Yount1,2
1Department of Microbial Infection and Immunity, The Ohio State University College of Medicine, Columbus, Ohio, USA.
Abstract:
Interferon-induced transmembrane protein 3 (IFITM3) is a cellular protein that restricts numerous viral infections by blocking virus-host membrane fusion. In humans, there are two IFITM3 single nucleotide polymorphisms (SNPs), rs12252-C and rs34481144-A, that decrease IFITM3 activity and have been associated with severe illness following influenza virus infections. Mice lacking IFITM3 show increased influenza severity, supporting this association. However, some studies do not find a consistent link between IFITM3 SNPs and infection severity, causing uncertainty about its role in vivo. Review of the literature indicates that IFITM3 SNPs are primarily associated with increased viral disease in infections with emergent influenza viruses, such as the 2009 H1N1 pandemic virus and zoonotic H7N9 virus. Similarly, IFITM3 SNPs are reported to be risk factors for increased severity in other emergent infections, including SARS-CoV-2, Hantaan virus, and HIV. In contrast, most studies that failed to find an association examined seasonal influenza. We posit that adaptive immune mechanisms, including pre-existing antibodies and memory T cells against seasonally circulating viruses, compensate for IFITM3 deficiencies, therefore masking its role in seasonal influenza. We propose that IFITM3 is most critical in defending against emergent viruses and should be a key focus of public health strategies to prevent the emergence and spread of novel pathogens, with individuals carrying IFITM3 SNPs potentially benefiting from broadened vaccine coverage, avoidance of animal reservoirs, or enhanced masking to protect themselves and the wider population.
Insights
Interferon-induced transmembrane protein 3 (IFITM3) plays a key role in restricting viral infections. Specific IFITM3 genetic variations are linked to severe illness from emergent viruses, but not seasonal ones, suggesting a critical role in novel pathogen defense.
Area of Science:
- Virology
- Immunology
- Genetics
Background:
- Interferon-induced transmembrane protein 3 (IFITM3) is crucial for cellular defense against viral entry.
- Specific IFITM3 single nucleotide polymorphisms (SNPs) are associated with reduced protein activity and increased susceptibility to severe viral diseases.
- The precise role of IFITM3 and its associated SNPs in varying viral infection contexts remains under investigation.
Purpose of the Study:
- To review and synthesize existing literature on the association between IFITM3 SNPs and viral infection severity.
- To elucidate the differential impact of IFITM3 SNPs on emergent versus seasonal viral infections.
- To propose a hypothesis explaining the discrepancy in findings regarding IFITM3's role in vivo.
Main Methods:
- Literature review and synthesis of studies investigating IFITM3 SNPs and viral disease outcomes.
- Analysis of associations between IFITM3 SNPs and infections caused by emergent influenza viruses (e.g., 2009 H1N1, H7N9), SARS-CoV-2, Hantaan virus, and HIV.
- Comparison of findings from studies on emergent viruses versus those on seasonal influenza.
Main Results:
- IFITM3 SNPs are consistently linked to increased severity in infections with emergent viruses.
- Studies examining seasonal influenza often fail to find a significant association between IFITM3 SNPs and disease severity.
- Evidence suggests that adaptive immunity may compensate for IFITM3 deficiency in seasonal infections.
Conclusions:
- IFITM3 is critically important for defense against emergent viral threats.
- The role of IFITM3 in seasonal influenza may be masked by pre-existing adaptive immunity.
- IFITM3 warrants focus in public health strategies for novel pathogen preparedness, with potential benefits for SNP carriers from targeted interventions.
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