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Review
. 2018:419:1-42.
doi: 10.1007/82_2017_25.

Host Factors in Coronavirus Replication

Adriaan H de Wilde  1 , Eric J Snijder  1 , Marjolein Kikkert  1 , Martijn J van Hemert  2
Affiliations
Review

Host Factors in Coronavirus Replication

Adriaan H de Wilde et al. Curr Top Microbiol Immunol. 2018.

Abstract

Coronaviruses are pathogens with a serious impact on human and animal health. They mostly cause enteric or respiratory disease, which can be severe and life threatening, e.g., in the case of the zoonotic coronaviruses causing severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) in humans. Despite the economic and societal impact of such coronavirus infections, and the likelihood of future outbreaks of additional pathogenic coronaviruses, our options to prevent or treat coronavirus infections remain very limited. This highlights the importance of advancing our knowledge on the replication of these viruses and their interactions with the host. 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.

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Figures

Fig. 1
Fig. 1
Outline of the coronavirus replicative cycle and replicase polyprotein organization, based on SARS-CoV. a Schematic overview of the coronavirus replicative cycle. Following entry by receptor-mediated endocytosis and release of the genome into the cytosol, genome translation yields the pp1a and pp1ab replicase polyproteins. Following polyprotein cleavage by multiple internal proteases, the viral nsps assemble into an RTC that engages in minus-strand RNA synthesis. Both full-length and subgenome (sg)-length minus strands are produced, with the latter templating the synthesis of the sg mRNAs required to express the structural and accessory protein genes residing in the 3′-proximal quarter of the genome. Ultimately, novel genomes are packaged into nucleocapsids that become enveloped by budding from smooth intracellular membranes, after which the new virions leave the cell by following the exocytic pathway. See text for more details. b The 14 open reading frames in the genome are indicated, i.e., the replicase ORFs 1a and 1b, the four common CoV structural protein genes (S, E, M, and N) and the ORFs encoding so-called ‘accessory proteins.’ The bottom panel explains the organization and proteolytic processing of the pp1a and pp1ab replicase polyproteins, the latter being produced by −1 ribosomal frameshifting. The nsp3 (PLpro) and nsp5 (3CLpro) proteases and their cleavage sites are indicated in matching colors. The resulting 16 cleavage products [nonstructural proteins (nsps)] are indicated, as are the conserved replicase domains. Domain abbreviations and corresponding nsp numbers: PLpro, papain-like proteinase (nsp3); 3CLpro, 3C-like protease (nsp5); TM, transmembrane domain (nsp3, nsp4, and nsp6); NiRAN, nidovirus RdRp-associated nucleotidyl transferase (nsp12); RdRp, RNA-dependent RNA polymerase (nsp12); ZBD, zinc-binding domain (nsp13); HEL1, superfamily 1 helicase (nsp13); ExoN, exoribonuclease (nsp14); N7-MT, N7-methyl transferase (nsp14); endoU, uridylate-specific endoribonuclease (nsp15); 2′-O-MT, 2′-O-methyl transferase (nsp16). Adopted with permission from (Snijder et al. 2016)
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