The antiviral restriction factor IFN-induced transmembrane protein 3 prevents cytokine-driven CMV pathogenesis

Stacey, Maria A.; Clare, Simon; Clement, Mathew; Marsden, Morgan; Abdul-Karim, Juneid; Kane, Leanne; Brandt, Cordelia; Fielding, Ceri Alan; Smith, Sarah E.; Wash, R.; Brias, Silvia Gimeno; Stack, Gabrielle; Notley, George; Cambridge, Emma L.; Isherwood, Christopher; Speak, Anneliese O.; Johnson, Zoë; Ferlin, Walter; Jones, Simon A.; Kellam, Paul; Humphreys, Ian R.

doi:10.1172/jci84889

Cited by 45 publications

(64 citation statements)

References 58 publications

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“…In this case, IFITM3 does not limit virus entry into cells (the protein was previously shown to facilitate CMV virion morphogenesis [ 68 ]). Rather, CMV infection in IFITM3-deficient mice led to much higher production of the pro-inflammatory cytokine interleukin-6 (IL-6) [ 69 ]. The result was dysregulation of cellular immunity and impaired control of virus replication, suggesting that murine IFITM3 plays a part in regulating cytokine production important for resolution of virus infection.…”

Section: The Extended Immunological Impact Of Ifitm: Beyond the Endosmentioning

confidence: 99%

More than meets the I: the diverse antiviral and cellular functions of interferon-induced transmembrane proteins

2017

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The first responders of human antiviral immunity are components of the intrinsic immune response that reside within each and every one of our cells. This cell-autonomous arsenal consists of nucleic acid sensors and antiviral effectors strategically placed by evolution to detect and restrict invading viruses. While some factors are present at baseline to allow for constant surveillance of the cell interior, others are upregulated by cytokines (such as interferons) that signal a viral infection underway in neighboring cells. In this review, we highlight the multiple roles played by the interferon-induced transmembrane (IFITM) proteins during viral infection, with focuses on IFITM3 and HIV-1. Moreover, we discuss the cellular pathways in which IFITM proteins are intertwined and the various functions they have been ascribed outside the context of infection. While appreciated as broadly-acting, potent restriction factors that prevent virus infection and pathogenesis in cell culture and in vivo, questions remain regarding their precise mode of action and importance in certain viral contexts. Continued efforts to study IFITM protein function will further cement their status as critical host determinants of virus susceptibility and prioritize them in the development of new antiviral therapies.

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Section: The Extended Immunological Impact Of Ifitm: Beyond the Endosmentioning

confidence: 99%

More than meets the I: the diverse antiviral and cellular functions of interferon-induced transmembrane proteins

2017

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“…Single nucleotide polymorphisms (SNPs) in the IFITM3 gene or its promoter are among the only genetic defects that have been reproducibly associated with severe influenza in humans (18)(19)(20)(21)(22)(23)(24). IFITM3 directly restricts influenza virus infection by inhibiting virus entry into cells, and it also provides a secondary function in dampening tissue-damaging inflammatory cytokine responses (25)(26)(27)(28)(29)(30). The rs12252-C SNP has been suggested to cause IFITM3 mislocalization and thus an inability to inhibit influenza virus infections (19,31).…”

mentioning

confidence: 99%

IFITM3 protects the heart during influenza virus infection

Kenney

McMichael

Imas

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Influenza virus can disseminate from the lungs to the heart in severe infections and can induce cardiac pathology, but this has been difficult to study due to a lack of small animal models. In humans, polymorphisms in the gene encoding the antiviral restriction factor IFN-induced transmembrane protein 3 (IFITM3) are associated with susceptibility to severe influenza, but whether IFITM3 deficiencies contribute to cardiac dysfunction during infection is unclear. We show that IFITM3 deficiency in a new knockout (KO) mouse model increases weight loss and mortality following influenza virus infections. We investigated this enhanced pathogenesis with the A/PR/8/34 (H1N1) (PR8) influenza virus strain, which is lethal in KO mice even at low doses, and observed increased replication of virus in the lungs, spleens, and hearts of KO mice compared with wild-type (WT) mice. Infected IFITM3 KO mice developed aberrant cardiac electrical activity, including decreased heart rate and irregular, arrhythmic RR (interbeat) intervals, whereas WT mice exhibited a mild decrease in heart rate without irregular RR intervals. Cardiac electrical dysfunction in PR8-infected KO mice was accompanied by increased activation of fibrotic pathways and fibrotic lesions in the heart. Infection with a sublethal dose of a less virulent influenza virus strain (A/WSN/33 [H1N1]) resulted in a milder cardiac electrical dysfunction in KO mice that subsided as the mice recovered. Our findings reveal an essential role for IFITM3 in limiting influenza virus replication and pathogenesis in heart tissue and establish IFITM3 KO mice as a powerful model for studying mild and severe influenza virus-induced cardiac dysfunction.

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“…Other than viral restriction, IFITM3 has additional roles in cytokine production. It has been shown to restrict cytokine production in murine cytomegalovirus infection to prevent overt pathology caused by infection (26). In this setting, IFITM3 was most apparent in reducing IL-6 release from myeloid cells.…”

Section: Discussionmentioning

confidence: 99%

Low basal expression and slow induction of IFITM3 puts immune cells at risk of influenza A infection

Wellington

Yin

Zhang

et al. 2019

Preprint

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The interferon-induced transmembrane protein, IFITM3, has been shown to restrict influenza virus infection in murine and in vitro settings for ten years, but no explanation has been found to explain why this virus infection is so highly contagious and infects most individuals it comes in contact with. We confirm that the expression level of IFITM3 plays a role in determining the level of viral infection through manipulation of IFITM3 levels with interferon (IFN) stimulation and overexpression systems. Low basal expression may put some immune cells, including lymphocytes and lung-resident macrophages, at risk of influenza virus infection. Investigating the induction of IFITM3 by IFN, we find a strong preference for Type I IFN in IFITM3 induction in both cell lines and primary human cells. While myeloid cells can increase expression following stimulation by Type I IFN, lymphocytes show minimal induction of IFITM3 following IFN stimulation, suggesting that they are always at risk of viral infection. Surprisingly, we found that the time it takes for maximal induction of IFITM3 is relatively slow for an interferon-stimulated gene at around 36 hours. Low basal expression and slow induction of IFITM3 could increase the risk of influenza virus infection in selected immune cells.ImportanceInfluenza virus infection remains one of the top ten threats to global health, causing significant deaths and hospitalisations across the world each year. Understanding mechanisms for controlling influenza virus infection remain a priority. The interferon-induced transmembrane protein IFITM3 can restrict influenza infection by limiting replication of the virus. The precise mechanisms of how IFITM3 reduced replication of influenza are unknown, although it is predicted to prevent release of viral contents into the cytosol by preventing pore formation on the endosomal compartments where it is suggested to reside. Here we have shown that the expression level of IFITM3 is important in determining the control of influenza virus infection. We find an expression pattern for IFITM3 that varies based on cell type, tissue locality, differentiation state and cell naivety, all of which highlights cells that may be at the highest risk of influenza infection.

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The antiviral restriction factor IFN-induced transmembrane protein 3 prevents cytokine-driven CMV pathogenesis

Cited by 45 publications

References 58 publications

More than meets the I: the diverse antiviral and cellular functions of interferon-induced transmembrane proteins

More than meets the I: the diverse antiviral and cellular functions of interferon-induced transmembrane proteins

IFITM3 protects the heart during influenza virus infection

Low basal expression and slow induction of IFITM3 puts immune cells at risk of influenza A infection

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