Compared to other +RNA viruses, coronaviruses have an exceptionally large genome and employ a complex genome expression strategy. Next to a role in basic virus replication or virus assembly, many of the coronavirus proteins expressed in the infected cell contribute to the coronavirus-host interplay. For example, by interacting with the host cell to create an optimal environment for coronavirus replication, by altering host gene expression or by counteracting the host's antiviral defenses. These coronavirus-host interactions are key to viral pathogenesis and will ultimately determine the outcome of infection. Due to the complexity of the coronavirus proteome and replication cycle, our knowledge of host factors involved in coronavirus replication is still in an early stage compared to what is known for some other +RNA viruses. This review summarizes our current understanding of coronavirus-host interactions at the level of the infected cell, with special attention for the assembly and function of the viral RNA-synthesising machinery and the evasion of cellular innate immune responses.
Insight into coronavirus-host interactions, obtained, e.g., using systematic screening approaches, does not only yield valuable information on the molecular details of the replicative cycle and pathogenesis, but can also be a starting point for the development of antiviral strategies. Virus binding and entry are the first steps of the replication cycle that can be targeted with inhibitors. Several well-known inhibitors of endosomal acidification, like ammonium chloride and the FDA-approved anti-malaria drug chloroquine, have been shown to block entry of coronaviruses (Takano et al. 2013; Keyaerts et al. 2009; Krzystyniak and Dupuy 1984; Payne et al. 1990; Kono et al. 2008), including SARS-CoV and MERS-CoV (Keyaerts et al. 2004; de Wilde et al. 2014). In addition, peptides have been developed that block fusion by interfering with the interaction between the HR1 and HR2 domains of the S protein, preventing the formation of a fusogenic complex or blocking S protein oligomerisation [reviewed in (Du et al. 2009)]. Interferon (IFN) was shown to trigger the innate immune response in coronavirus-infected cells, leading to transcription of many ISGs that have a role in controlling infection (Schoggins and Rice 2011). Treatment with type-I IFNs inhibits coronavirus replication in cell culture (Garlinghouse et al. 1984; Taguchi and Siddell 1985; Haagmans et al. 2004; Paragas et al. 2005; Zheng et al. 2004; de Wilde et al. 2013b) and, for example, protected type-I pneumocytes against SARS-CoV infection in macaques (Haagmans et al. 2004). Despite the potency of IFN as an antiviral agent, its side effects like fatigue, malaise, apathy, and cognitive changes (Dusheiko 1997) emphasize the need for developing IFN-free therapeutic strategies. Besides inhibitors directed at viral enzymes (Kim et al. 2016), such therapeutic strategies could also involve host-directed approaches, based on the knowledge obtained on coronavirus–host interactions. The host-directed approach might lower the chance of development of antiviral resistance and could yield a broad-spectrum therapeutic strategy to treat infections with currently problematic coronaviruses and new variants that will undoubtedly emerge in the future.
Reference & source information: https://europepmc.org/
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