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.
Highlights
Coronaviruses are enveloped, positive-sense RNA viruses, which infect birds and mammals [1].The human coronaviruses 229E, OC43, NL63, and HKU1 are adapted to spread in the human population and circulate globally [1,2]
Similar results were obtained when cells transduced to express untagged interferon-inducible transmembrane (IFITM) proteins were analyzed, employing an IFITM1-specific antibody and an antiserum raised against IFITM2, which is cross-reactive with IFITM3 (Figure 1B)
In order to test if the IFITM proteins unfold the expected antiviral activity, the IFITM-positive cells were transduced with retroviral vectors bearing the hemagglutinin (HA) of influenza A virus (FLUAV), the glycoprotein of the vesicular stomatitis virus (VSV-G), the envelope protein (Env) of murine leukemia virus (MLV) or the glycoproteins of Machupo virus (MACV-GPC) and Lassa virus (LASV-GPC)
Summary
The human coronaviruses (hCoV) 229E, OC43, NL63, and HKU1 are adapted to spread in the human population and circulate globally [1,2]. These viruses cause the common cold, immunocompromised patients and the elderly occasionally develop more severe disease [3,4,5,6,7,8]. The emerging coronaviruses severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) and Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) were relatively recently transmitted from bats via intermediate hosts to humans, and can induce severe disease in afflicted patients [9,10,11]. The SARS outbreak in 2002/2003 was associated with 8096 infections and 774 deaths (case-fatality rate of 9.6%) [12], and the ongoing MERS epidemic, far, entails 837 laboratory confirmed infections of which 291 were fatal (as of 23 July 2014), resulting in a case-fatality rate of 35% [13].
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