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IFITM proteins inhibit entry driven by the MERS-coronavirus spike protein: evidence for cholesterol-independent
Florian Wrensch1, Michael Winkler2, Stefan Pöhlmann3
1Infection Biology Unit, German Primate Center, 37077 Göttingen, Germany. fwrensch@dpz.eu.
Abstract:
The interferon-inducible transmembrane (IFITM) proteins 1, 2 and 3 inhibit the host cell entry of several enveloped viruses, potentially by promoting the accumulation of cholesterol in endosomal compartments. IFITM3 is essential for control of influenza virus infection in mice and humans. In contrast, the role of IFITM proteins in coronavirus infection is less well defined. Employing a retroviral vector system for analysis of coronavirus entry, we investigated the susceptibility of human-adapted and emerging coronaviruses to inhibition by IFITM proteins. We found that entry of the recently emerged Middle East respiratory syndrome coronavirus (MERS-CoV) is sensitive to inhibition by IFITM proteins. In 293T cells, IFITM-mediated inhibition of cellular entry of the emerging MERS- and SARS-CoV was less efficient than blockade of entry of the globally circulating human coronaviruses 229E and NL63. Similar differences were not observed in A549 cells, suggesting that cellular context and/or IFITM expression levels can impact inhibition efficiency. The differential IFITM-sensitivity of coronaviruses observed in 293T cells afforded the opportunity to investigate whether efficiency of entry inhibition by IFITMs and endosomal cholesterol accumulation correlate. No such correlation was observed. 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. Collectively, these results show that the emerging MERS-CoV is a target of the antiviral activity of IFITM proteins and demonstrate that mechanisms other than accumulation of endosomal cholesterol can contribute to viral entry inhibition by IFITMs.
Insights
Interferon-inducible transmembrane (IFITM) proteins inhibit MERS-CoV entry. Their antiviral activity against coronaviruses is not solely dependent on endosomal cholesterol accumulation, suggesting alternative mechanisms are involved.
Area of Science:
- Virology
- Cell Biology
- Immunology
Background:
- Interferon-inducible transmembrane (IFITM) proteins 1, 2, and 3 are known to restrict enveloped virus entry.
- IFITM3 is crucial for controlling influenza virus infections.
- The role of IFITM proteins in coronavirus infection remains less understood.
Purpose of the Study:
- To investigate the susceptibility of emerging and human-adapted coronaviruses to IFITM protein-mediated inhibition.
- To explore the correlation between IFITM-mediated viral entry inhibition and endosomal cholesterol accumulation.
- To elucidate the mechanisms underlying IFITM antiviral activity against coronaviruses.
Main Methods:
- Utilized a retroviral vector system to analyze coronavirus entry.
- Assessed the inhibition efficiency of IFITM proteins on MERS-CoV, SARS-CoV, 229E, and NL63 entry in 293T and A549 cells.
- Investigated the relationship between IFITM-mediated inhibition and endosomal cholesterol levels.
Main Results:
- Entry of Middle East respiratory syndrome coronavirus (MERS-CoV) is sensitive to IFITM protein inhibition.
- IFITM-mediated inhibition was less efficient for MERS-CoV and SARS-CoV compared to 229E and NL63 in 293T cells, but not in A549 cells, indicating cell-context dependency.
- No correlation was observed between the efficiency of IFITM-mediated entry inhibition and endosomal cholesterol accumulation.
- Influenza virus hemagglutinin-mediated entry was inhibited by IFITM3 but not affected by endosomal cholesterol modulation.
Conclusions:
- Emerging MERS-CoV is a target of IFITM protein antiviral activity.
- Mechanisms beyond endosomal cholesterol accumulation contribute to IFITM-mediated viral entry inhibition.
- Cellular context and IFITM expression levels influence the efficiency of coronavirus entry inhibition.
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