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.