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. 2023 Apr 19;22(6):449–475. doi: 10.1038/s41573-023-00672-y

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© Springer Nature Limited 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

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Fig. 2 — a, Entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells. The viral spike protein binds to angiotensin-converting enzyme 2 (ACE2) (in complex with the sodium-dependent neutral-amino-acid transporter B⁰AT1) on the membrane surface. Spike is cleaved by furin at the S1/S2 cleavage site and subsequently cleaved at the S2′ site by transmembrane protease serine subfamily (TMPRSS) proteases in the cell surface entry pathway, or cathepsins in the endosomal entry pathway¹⁷² (see Fig. 7 for further details). b, Viral uncoating. The (+ss) genomic RNA is released from the viral particle into the host cell. The genomic RNA is translated into open reading frame 1a (ORF1a) and ORF1ab polyproteins (pp1a and pp1ab), which are subsequently cleaved by papain-like protease (PL^pro) and the main protease (M^pro) to release 16 non-structural proteins (NSPs). c, Viral RNA synthesis. Several NSPs assemble into the replication–transcription complex (RTC) that replicates and translates viral genomic RNA in replication organelles. d, Viral mRNA translation. Structural proteins are sorted into the endoplasmic reticulum (ER) and Golgi apparatus for maturation. Accessory proteins modulate virus−host interactions and viral pathogenesis. e, Viral assembly. The genomic RNA is packed with viral nucleocapsid (N) for viral assembly, along with structural proteins. f, Viral release by exocytosis. g, Viral RNA triggers host immune signalling pathways, which involve activation of transcription factors to produce cytokines such as interleukin (IL)-6, chemokines such as C–C motif chemokine ligand 2 (CCL2) and C–X–C motif chemokine ligand 10 (CXCL10), and interferons such as interferon-α (IFNα). h, Excessive production and secretion may result in cytokine-induced damage, multiorgan failure, thrombosis or death (see reviews elsewhere^11,280,281). Immune cells also provide positive feedback to release more cytokines, chemokines and interferons¹⁸⁷. Ps in red circles denote phosphorylation sites. dsRNA, double-stranded RNA; E, envelope protein; IRF, interferon regulatory factor; ISG, interferon-stimulated gene; ISRE, interferon-stimulated response element; JAK, Janus kinase; M, membrane protein; NF-κB, nuclear factor-κB; ssRNA, single-stranded RNA; STAT, signal transducer and activator of transcription; UU...UU, polyuridines. The electron micrograph image of SARS-CoV-2 (contributed by C.S. Goldsmith and A. Tamin) was retrieved from the CDC Public Health Image Library.