Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

SARS-CoV-2 biology and host interactions

Abstract

The zoonotic emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the ensuing coronavirus disease 2019 (COVID-19) pandemic have profoundly affected our society. The rapid spread and continuous evolution of new SARS-CoV-2 variants continue to threaten global public health. Recent scientific advances have dissected many of the molecular and cellular mechanisms involved in coronavirus infections, and large-scale screens have uncovered novel host-cell factors that are vitally important for the virus life cycle. In this Review, we provide an updated summary of the SARS-CoV-2 life cycle, gene function and virus–host interactions, including recent landmark findings on general aspects of coronavirus biology and newly discovered host factors necessary for virus replication.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: SARS-CoV-2 genome organization, virion architecture and intracellular life cycle.
Fig. 2: Conventional and unconventional capping mechanism.
Fig. 3: Viral immune evasion.
Fig. 4: SARS-CoV-2 host factors and interactome during the viral life cycle.

Similar content being viewed by others

References

  1. Gorbalenya, A. E. et al. The species severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat. Microbiol. 5, 536–544 (2020).

    Google Scholar 

  2. Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  3. Zhu, N. et al. A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med. 382, 727–733 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Coronavirus (COVID-19) Dashboard. WHO https://covid19.who.int/ (2022).

  5. Telenti, A., Hodcroft, E. B. & Robertson, D. L. The evolution and biology of SARS-CoV-2 variants. Cold Spring Harb. Persp. Med. 12, a041390 (2022).

    CAS  Google Scholar 

  6. Harvey, W. T. et al. SARS-CoV-2 variants, spike mutations and immune escape. Nat. Rev. Microbiol. 19, 409–424 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Grant, R. et al. When to update COVID-19 vaccine composition. Nat. Med. 29, 776–780 (2023).

    CAS  PubMed  Google Scholar 

  8. Jungreis, I., Sealfon, R. & Kellis, M. SARS-CoV-2 gene content and COVID-19 mutation impact by comparing 44 Sarbecovirus genomes. Nat. Commun. 12, 2642 (2021).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  9. Jungreis, I. et al. Conflicting and ambiguous names of overlapping ORFs in the SARS-CoV-2 genome: a homology-based resolution. Virology 558, 145–151 (2021).

    CAS  PubMed  Google Scholar 

  10. Finkel, Y. et al. The coding capacity of SARS-CoV-2. Nature 589, 125–130 (2020).

    PubMed  ADS  Google Scholar 

  11. Gordon, D. E. et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 583, 459–468 (2020).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  12. Kim, D. et al. The architecture of SARS-CoV-2 transcriptome. Cell 181, 914–921.e10 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Huston, N. C. et al. Comprehensive in vivo secondary structure of the SARS-CoV-2 genome reveals novel regulatory motifs and mechanisms. Mol. Cell 81, 584–598.e5 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Lan, T. C. T. et al. Secondary structural ensembles of the SARS-CoV-2 RNA genome in infected cells. Nat. Commun. 13, 1128 (2022).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  15. Ziv, O. et al. The short- and long-range RNA–RNA interactome of SARS-CoV-2. Mol. Cell 80, 1067–1077.e5 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Madhugiri, R., Fricke, M., Marz, M. & Ziebuhr, J. Coronavirus cis-acting RNA elements. Adv. Virus Res. 96, 127–163 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Tidu, A. et al. The viral protein NSP1 acts as a ribosome gatekeeper for shutting down host translation and fostering SARS-CoV-2 translation. RNA 27, 253–264 (2021). This publication demonstrated that SARS-CoV-2 relies on stem loop 1 in the 5′ UTR to evade the nsp1-induced translational shutoff of its own genes.

    CAS  PubMed Central  Google Scholar 

  18. Bujanic, L. et al. The key features of SARS-CoV-2 leader and NSP1 required for viral escape of NSP1-mediated repression. RNA 28, 766–779 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Iserman, C. et al. Genomic RNA elements drive phase separation of the SARS-CoV-2 nucleocapsid. Mol. Cell 80, 1078–1091.e6 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Bhatt, P. R. et al. Structural basis of ribosomal frameshifting during translation of the SARS-CoV-2 RNA genome. Science 372, 1306–1313 (2021). In-depth structural and biochemical analysis into the mechanism of the programmed ribosomal frameshift for SARS-CoV-2.

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  21. Sun, L. et al. In vivo structural characterization of the SARS-CoV-2 RNA genome identifies host proteins vulnerable to repurposed drugs. Cell 184, 1865–1883.e20 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Jackson, C. B., Farzan, M., Chen, B. & Choe, H. Mechanisms of SARS-CoV-2 entry into cells. Nat. Rev. Mol. Cell Biol. 23, 3–20 (2021). Comprehensive review on SARS-CoV-2 entry mechanism.

    PubMed  PubMed Central  Google Scholar 

  23. Hoffmann, M., Kleine-Weber, H. & Pöhlmann, S. A multibasic cleavage site in the spike protein of SARS-CoV-2 is essential for infection of human lung cells. Mol. Cell 78, 779–784.e5 (2020). This article highlights the presence of a multibasic S1/S2 cleavage site in the SARS-CoV-2 spike protein that can be cut by furin and is a prerequisite for viral entry into lung cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Hansen, J. et al. Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail. Science 369, 1010–1014 (2020).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  25. Robbiani, D. F. et al. Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Nature 584, 437–442 (2020).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  26. Pinto, D. et al. Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature 583, 290–295 (2020).

    CAS  PubMed  ADS  Google Scholar 

  27. Yuan, M. et al. A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV. Science 368, 630–633 (2020).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  28. Liu, L. et al. Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike. Nature 584, 450–456 (2020). This is one of the first publications to report the receptor-binding domain (RBD) and N-terminal domain (NTD) epitopes as the two main neutralization targets on the SARS-CoV-2 spike protein.

    CAS  PubMed  Google Scholar 

  29. Chi, X. et al. A neutralizing human antibody binds to the N-terminal domain of the spike protein of SARS-CoV-2. Science 369, 650–655 (2020).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  30. Meng, B. et al. SARS-CoV-2 spike N-terminal domain modulates TMPRSS2-dependent viral entry and fusogenicity. Cell Rep. 40, 111220 (2022). Here, it was shown that the SARS-CoV-2 spike protein’s NTD can modulate S1/S2 cleavage and influence TMPRSS2 usage and fusogenicity.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Hoffmann, M. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181, 271–280.e8 (2020). The first publication to confirm that, similar to SARS-CoV, the processing of the SARS-CoV-2 spike protein is mediated by TMPRSS2.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhao, M. M. et al. Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development. Signal. Transduct. Target. Ther. 6, 134 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Ziegler, C. G. K. et al. SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell 181, 1016–1035.e19 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Su, M. C. et al. An atypical RNA pseudoknot stimulator and an upstream attenuation signal for −1 ribosomal frameshifting of SARS coronavirus. Nucleic Acids Res. 33, 4265–4275 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhang, K. et al. Cryo-EM and antisense targeting of the 28-kDa frameshift stimulation element from the SARS-CoV-2 RNA genome. Nat. Struct. Mol. Biol. 28, 747–754 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Brierley, I., Digard, P. & Inglis, S. C. Characterization of an efficient coronavirus ribosomal frameshifting signal: requirement for an RNA pseudoknot. Cell 57, 537–547 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Sun, Y. et al. Restriction of SARS-CoV-2 replication by targeting programmed –1 ribosomal frameshifting. Proc. Natl Acad. Sci. USA 118, e2023051118 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Osipiuk, J. et al. Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors. Nat. Commun. 12, 743 (2021).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  39. Jin, Z. et al. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature 582, 289–293 (2020).

    CAS  PubMed  ADS  Google Scholar 

  40. Ziebuhr, J., Snijder, E. J. & Gorbalenya, A. E. Virus-encoded proteinases and proteolytic processing in the Nidovirales. J. Gen. Virol. 81, 853–879 (2000).

    CAS  PubMed  Google Scholar 

  41. Thoms, M. et al. Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2. Science 369, 1249–1256 (2020). Thoms et al. (2020) and Schubert et al. (2020) elucidate the binding of SARS-CoV-2 nsp1 to the ribosome and cause translational shutdown.

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  42. Schubert, K. et al. SARS-CoV-2 Nsp1 binds the ribosomal mRNA channel to inhibit translation. Nat. Struct. Mol. Biol. 27, 959–966 (2020).

    CAS  PubMed  Google Scholar 

  43. Fisher, T. et al. Parsing the role of NSP1 in SARS-CoV-2 infection. Cell Rep. 39, 110954 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Snijder, E. J., Decroly, E. & Ziebuhr, J. The nonstructural proteins directing coronavirus RNA synthesis and processing. In Advances in Virus Research Vol. 96 (ed. Ziebuhr, J.) 59–126 (Academic Press, 2016).

  45. Cortese, M. et al. Integrative imaging reveals SARS-CoV-2-induced reshaping of subcellular morphologies. Cell Host Microbe 28, 853–866.e5 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Snijder, E. J. et al. A unifying structural and functional model of the coronavirus replication organelle: tracking down RNA synthesis. PLoS Biol. 18, e3000715 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Wolff, G., Melia, C. E., Snijder, E. J. & Bárcena, M. Double-membrane vesicles as platforms for viral replication. Trends Microbiol. 28, 1022–1033 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Klein, S. et al. SARS-CoV-2 structure and replication characterized by in situ cryo-electron tomography. Nat. Commun. 11, 5885 (2020).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  49. Ricciardi, S. et al. The role of NSP6 in the biogenesis of the SARS-CoV-2 replication organelle. Nature 606, 761–768 (2022).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  50. Twu, W. I. et al. Contribution of autophagy machinery factors to HCV and SARS-CoV-2 replication organelle formation. Cell Rep. 37, 110049 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Tabata, K. et al. Convergent use of phosphatidic acid for hepatitis C virus and SARS-CoV-2 replication organelle formation. Nat. Commun. 12, 7276 (2021).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  52. Ji, M. et al. VMP1 and TMEM41B are essential for DMV formation during β-coronavirus infection. J. Cell Biol. 221, e202112081 (2022).

    PubMed  PubMed Central  Google Scholar 

  53. Wolff, G. et al. A molecular pore spans the double membrane of the coronavirus replication organelle. Science 369, 1395–1398 (2020).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  54. Zimmermann, L. et al. SARS-CoV-2 nsp3 and nsp4 are minimal constituents of a pore spanning replication organelle. Nat. Commun. 14, 7894 (2023).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  55. da Silva Gomes Dias, S. et al. Lipid droplets fuel SARS-CoV-2 replication and production of inflammatory mediators. PLoS Pathog. 16, e1009127 (2020).

    Google Scholar 

  56. Malone, B., Urakova, N., Snijder, E. J. & Campbell, E. A. Structures and functions of coronavirus replication–transcription complexes and their relevance for SARS-CoV-2 drug design. Nat. Rev. Mol. Cell Biol. 23, 21–39 (2021).

    PubMed  PubMed Central  Google Scholar 

  57. Gao, Y. et al. Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science 368, 779–782 (2020).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  58. Wang, Q. et al. Structural basis for RNA replication by the SARS-CoV-2 polymerase. Cell 23, 182–417.e13 (2020).

    Google Scholar 

  59. Hillen, H. S. et al. Structure of replicating SARS-CoV-2 polymerase. Nature 584, 154–156 (2020).

    CAS  PubMed  ADS  Google Scholar 

  60. Mickolajczyk, K. J. et al. Force-dependent stimulation of RNA unwinding by SARS-CoV-2 nsp13 helicase. Biophys. J. 120, 1020–1030 (2021).

    CAS  PubMed  ADS  Google Scholar 

  61. Chen, J. et al. Structural basis for helicase-polymerase coupling in the SARS-CoV-2 replication–transcription complex. Cell 182, 1560–1573.e13 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Yan, L. et al. Architecture of a SARS-CoV-2 mini replication and transcription complex. Nat. Commun. 11, 5874 (2020).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  63. Malone, B. et al. Structural basis for backtracking by the SARS-CoV-2 replication–transcription complex. Proc. Natl Acad. Sci. USA 118, e2102516118 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Chen, J. et al. Ensemble cryo-EM reveals conformational states of the nsp13 helicase in the SARS-CoV-2 helicase replication–transcription complex. Nat. Struct. Mol. Biol. 29, 250–260 (2022).

    MathSciNet  CAS  PubMed  PubMed Central  Google Scholar 

  65. Nudler, E. RNA polymerase backtracking in gene regulation and genome instability. Cell 149, 1438–1445 (2012).

    CAS  PubMed  Google Scholar 

  66. Shannon, A. et al. Rapid incorporation of Favipiravir by the fast and permissive viral RNA polymerase complex results in SARS-CoV-2 lethal mutagenesis. Nat. Commun. 11, 4682 (2020).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  67. Smith, E. C., Blanc, H., Vignuzzi, M. & Denison, M. R. Coronaviruses lacking exoribonuclease activity are susceptible to lethal mutagenesis: evidence for proofreading and potential therapeutics. PLoS Pathog. 9, e1003565 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Lin, S. et al. Crystal structure of SARS-CoV-2 nsp10 bound to nsp14–ExoN domain reveals an exoribonuclease with both structural and functional integrity. Nucleic Acids Res. 49, 5382–5392 (2021).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  69. Liu, C. et al. Structural basis of mismatch recognition by a SARS-CoV-2 proofreading enzyme. Science 373, 1142–1146 (2021).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  70. Yan, L. et al. Coupling of N7-methyltransferase and 3′-5′ exoribonuclease with SARS-CoV-2 polymerase reveals mechanisms for capping and proofreading. Cell 184, 3474–3485.e11 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Sawicki, S. G. & Sawicki, D. L. Coronaviruses use discontinuous extension for synthesis of subgenome-length negative strands. In Advances in Experimental Medicine and Biology Vol. 380 (eds Talbot, P. J. & Levy, G. A.) 499–506 (Springer, 1995).

  72. Wang, D. et al. The SARS-CoV-2 subgenome landscape and its novel regulatory features. Mol. Cell 81, 2135–2147.e5 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Sola, I., Almazán, F., Zúñiga, S. & Enjuanes, L. Continuous and discontinuous RNA synthesis in coronaviruses. Annu. Rev. Virol. 2, 265–288 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Zhang, Y. et al. In vivo structure and dynamics of the SARS-CoV-2 RNA genome. Nat. Commun. 12, 5695 (2021).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  75. Mendez, A. S. et al. The N-terminal domain of SARS-CoV-2 nsp1 plays key roles in suppression of cellular gene expression and preservation of viral gene expression. Cell Rep. 37, 109841 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Vora, S. M. et al. Targeting stem-loop 1 of the SARS-CoV-2 50 UTR to suppress viral translation and Nsp1 evasion. Proc. Natl Acad. Sci. USA 119, e2117198119 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Finkel, Y. et al. SARS-CoV-2 uses a multipronged strategy to impede host protein synthesis. Nature 594, 240–245 (2021).

    CAS  PubMed  ADS  Google Scholar 

  78. Walker, A. P. et al. The SARS-CoV-2 RNA polymerase is a viral RNA capping enzyme. Nucleic Acids Res. 49, 13019–13030 (2021). These authors identify the nidovirus RdRP-associated nucleotidyltransferase (NiRAN) domain of nsp12 as a capping enzyme involved in the formation of the cap core structure.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Pan, R. et al. N7-methylation of the coronavirus RNA cap is required for maximal virulence by preventing innate immune recognition. mBio 13, e0366221 (2022).

    PubMed  Google Scholar 

  80. Russ, A. et al. Nsp16 shields SARS–CoV-2 from efficient MDA5 sensing and IFIT1-mediated restriction. EMBO Rep. 23, e55648 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Decroly, E., Ferron, F., Lescar, J. & Canard, B. Conventional and unconventional mechanisms for capping viral mRNA. Nat. Rev. Microbiol. 10, 51–65 (2012).

    CAS  Google Scholar 

  82. Kikkert, M. Innate immune evasion by human respiratory RNA viruses. J. Innate Immun. 12, 4–20 (2020).

    CAS  PubMed  Google Scholar 

  83. Chen, Y. et al. Functional screen reveals SARS coronavirus nonstructural protein nsp14 as a novel cap N7 methyltransferase. Proc. Natl Acad. Sci. 106, 3484–3489 (2009).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  84. Bouvet, M. et al. In vitro reconstitution of SARS-coronavirus mRNA cap methylation. PLoS Pathog. 6, e1000863 (2010).

    PubMed  PubMed Central  Google Scholar 

  85. Lehmann, K. C. et al. Discovery of an essential nucleotidylating activity associated with a newly delineated conserved domain in the RNA polymerase-containing protein of all nidoviruses. Nucleic Acids Res. 43, 8416–8434 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Slanina, H. et al. Coronavirus replication-transcription complex: vital and selective NMPylation of a conserved site in nsp9 by the NiRAN–RdRp subunit. Proc. Natl Acad. Sci. USA 118, e2022310118 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Yan, L. et al. Cryo-EM structure of an extended SARS-CoV-2 replication and transcription complex reveals an intermediate state in cap synthesis. Cell 184, 184–193.e10 (2021).

    CAS  PubMed  Google Scholar 

  88. Park, G. J. et al. The mechanism of RNA capping by SARS-CoV-2. Nature 609, 793–800 (2022). These authors show the RNAylation of nsp9 by NiRAN in vitro and hence propose an unconventional capping mechanism for SARS-CoV-2.

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  89. Yan, L. et al. A mechanism for SARS-CoV-2 RNA capping and its inhibition by nucleotide analog inhibitors. Cell 185, 4347–4360.e17 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Ogino, T. & Green, T. J. RNA synthesis and capping by non-segmented negative strand RNA viral polymerases: lessons from a prototypic virus. Front. Microbiol. 10, 1490 (2019).

    PubMed  PubMed Central  Google Scholar 

  91. Wang, B., Svetlov, D. & Artsimovitch, I. NMPylation and de-NMPylation of SARS-CoV-2 nsp9 by the NiRAN domain. Nucleic Acids Res. 49, 8822–8835 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Cong, Y. et al. Nucleocapsid protein recruitment to replication–transcription complexes plays a crucial role in coronaviral life cycle. J. Virol. 94, e01925–e02019 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Cubuk, J. et al. The SARS-CoV-2 nucleocapsid protein is dynamic, disordered, and phase separates with RNA. Nat. Commun. 12, 1936 (2021).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  94. Lu, S. et al. The SARS-CoV-2 nucleocapsid phosphoprotein forms mutually exclusive condensates with RNA and the membrane-associated M protein. Nat. Commun. 12, 502 (2021).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  95. Yao, H. et al. Molecular architecture of the SARS-CoV-2 virus. Cell 183, 730–738.e13 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Bracquemond, D. & Muriaux, D. Betacoronavirus assembly: clues and perspectives for elucidating SARS-CoV-2 particle formation and egress. mBio 12, e0237121 (2021).

    PubMed  Google Scholar 

  97. Cascarina, S. M. & Ross, E. D. Phase separation by the SARS-CoV-2 nucleocapsid protein: consensus and open questions. J. Biol. Chem. 298, 101677 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Boson, B. et al. The SARS-CoV-2 envelope and membrane proteins modulate maturation and retention of the spike protein, allowing assembly of virus-like particles. J. Biol. Chem. 296, 100111 (2021).

    CAS  PubMed  Google Scholar 

  99. de Haan, C. A. M. & Rottier, P. J. M. Molecular interactions in the assembly of coronaviruses. Adv. Virus Res. 64, 165–230 (2005).

    PubMed  PubMed Central  Google Scholar 

  100. Mandala, V. S. et al. Structure and drug binding of the SARS-CoV-2 envelope protein transmembrane domain in lipid bilayers. Nat. Struct. Mol. Biol. 27, 1202–1208 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Nieto-Torres, J. L. et al. Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome. Virology 485, 330–339 (2015).

    CAS  PubMed  Google Scholar 

  102. Ghosh, S. et al. β-Coronaviruses use lysosomes for egress instead of the biosynthetic secretory pathway. Cell 183, 1520–1535.e14 (2020). This paper first proposed and investigated the egress of SARS-CoV-2 and other betacoronaviruses via lysosomal trafficking.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Tancini, B. et al. Lysosomal exocytosis: the extracellular role of an intracellular organelle. Membranes 10, 406 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Pu, J. et al. BORC, a multisubunit complex that regulates lysosome positioning. Dev. Cell 33, 176–188 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Chen, D. et al. ORF3a of SARS-CoV-2 promotes lysosomal exocytosis-mediated viral egress. Dev. Cell 56, 3250–3263.e5 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Minkoff, J. M. & tenOever, B. Innate immune evasion strategies of SARS-CoV-2. Nat. Rev. Microbiol. 21, 178–194 (2023). Comprehensive review on SARS-CoV-2 innate immune evasion.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Gao, B. et al. Inhibition of anti-viral stress granule formation by coronavirus endoribonuclease nsp15 ensures efficient virus replication. PLoS Pathog. 17, e1008690 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Banerjee, A. K. et al. SARS-CoV-2 disrupts splicing, translation, and protein trafficking to suppress host defenses. Cell 183, 1325–1339.e21 (2020). They identified the viral proteins involved (nsp1, nap8, nsp9 and nsp16) in global inhibition of host mRNA splicing, protein translation and membrane protein trafficking.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Hayn, M. et al. Systematic functional analysis of SARS-CoV-2 proteins uncovers viral innate immune antagonists and remaining vulnerabilities. Cell Rep. 35, 109126 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Lei, X. et al. Activation and evasion of type I interferon responses by SARS-CoV-2. Nat. Commun. 11, 3812 (2020).

    ADS  Google Scholar 

  111. Li, J. Y. et al. The ORF6, ORF8 and nucleocapsid proteins of SARS-CoV-2 inhibit type I interferon signaling pathway. Virus Res. 286, 198074 (2020).

    CAS  PubMed  Google Scholar 

  112. Shemesh, M. et al. SARS-CoV-2 suppresses IFNβ production mediated by NSP1, 5, 6, 15, ORF6 and ORF7b but does not suppress the effects of added interferon. PLoS Pathog. 17, e1009800 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Stukalov, A. et al. Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 594, 246–252 (2021).

    CAS  PubMed  ADS  Google Scholar 

  114. Vazquez, C. et al. SARS-CoV-2 viral proteins NSP1 and NSP13 inhibit interferon activation through distinct mechanisms. PLoS One 16, e0253089 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Xia, H. et al. Evasion of type I interferon by SARS-CoV-2. Cell Rep. 33, 108234 (2020). One of the first papers to report the interferon antagonism of SARS-CoV-2.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Yuen, C. K. et al. SARS-CoV-2 nsp13, nsp14, nsp15 and orf6 function as potent interferon antagonists. Emerg. Microbes Infect. 9, 1418–1428 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Zheng, M. et al. TLR2 senses the SARS-CoV-2 envelope protein to produce inflammatory cytokines. Nat. Immunol. 22, 829–838 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Planès, R., Bert, J. B., Tairi, S., Benmohamed, L. & Bahraoui, E. SARS-CoV-2 envelope (E) protein binds and activates TLR2 pathway: a novel molecular target for COVID-19 interventions. Viruses 14, 999 (2022).

    PubMed  PubMed Central  Google Scholar 

  119. Moreno-Eutimio, M. A., López-Macías, C. & Pastelin-Palacios, R. Bioinformatic analysis and identification of single-stranded RNA sequences recognized by TLR7/8 in the SARS-CoV-2, SARS-CoV, and MERS-CoV genomes. Microbes Infect. 22, 226–229 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Choudhury, A. & Mukherjee, S. In silico studies on the comparative characterization of the interactions of SARS-CoV-2 spike glycoprotein with ACE-2 receptor homologs and human TLRs. J. Med. Virol. 92, 2105–2113 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Bortolotti, D. et al. Tlr3 and tlr7 RNA sensor activation during SARS-CoV-2 infection. Microorganisms 9, 1820 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Rebendenne, A. et al. SARS-CoV-2 triggers an MDA-5-dependent interferon response which is unable to control replication in lung epithelial cells. J. Virol. 95, e02415–e02420 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Thorne, L. G. et al. SARS‐CoV‐2 sensing by RIG‐I and MDA5 links epithelial infection to macrophage inflammation. EMBO J. 40, e107826 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Yang, D.-M., Geng, T.-T., Harrison, A. G. & Wang, P.-H. Differential roles of RIG-I like receptors in SARS-CoV-2 infection. Milit. Med. Res. 8, 49 (2021).

    CAS  Google Scholar 

  125. Yin, X. et al. MDA5 governs the innate immune response to SARS-CoV-2 in lung epithelial cells. Cell Rep. 34, 108628 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Frazier, M. N. et al. Flipped over U: structural basis for dsRNA cleavage by the SARS-CoV-2 endoribonuclease. Nucleic Acids Res. 50, 8290–8301 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Hackbart, M., Deng, X. & Baker, S. C. Coronavirus endoribonuclease targets viral polyuridine sequences to evade activating host sensors. Proc. Natl Acad. Sci. USA 117, 8094–8103 (2020).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  128. Ancar, R. et al. Physiologic RNA targets and refined sequence specificity of coronavirus EndoU. RNA 26, 1976–1999 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Singh, K. K., Chaubey, G., Chen, J. Y. & Suravajhala, P. Decoding SARS-CoV-2 hijacking of host mitochondria in COVID-19 pathogenesis. Am. J. Physiol. Cell Physiol. 319, C258–C267 (2020).

    PubMed  PubMed Central  Google Scholar 

  130. Schoggins, J. W. et al. Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature 505, 691–695 (2014).

    CAS  PubMed  ADS  Google Scholar 

  131. Sun, L., Wu, J., Du, F., Chen, X. & Chen, Z. J. Cyclic GMP–AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339, 786–791 (2013).

    CAS  PubMed  ADS  Google Scholar 

  132. Rui, Y. et al. Unique and complementary suppression of cGAS-STING and RNA sensing — triggered innate immune responses by SARS-CoV-2 proteins. Signal. Transduct. Target. Ther. 6, 123 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Humphries, F. et al. A diamidobenzimidazole STING agonist protects against SARS-CoV-2 infection. Sci. Immunol. 6, eabi9002 (2021).

    PubMed  PubMed Central  Google Scholar 

  134. Li, M. et al. Pharmacological activation of STING blocks SARS-CoV-2 infection. Sci. Immunol. 6, eabi9007 (2021).

    PubMed  PubMed Central  Google Scholar 

  135. Christgen, S. & Kanneganti, T.-D. Inflammasomes and the fine line between defense and disease. Curr. Opin. Immunol. 62, 39–44 (2020).

    CAS  PubMed  Google Scholar 

  136. Kelley, N., Jeltema, D., Duan, Y. & He, Y. The NLRP3 inflammasome: an overview of mechanisms of activation and regulation. Int. J. Mol. Sci. 2019 20, 3328 (2019).

    CAS  Google Scholar 

  137. Campbell, G. R., To, R. K., Hanna, J. & Spector, S. A. SARS-CoV-2, SARS-CoV-1, and HIV-1 derived ssRNA sequences activate the NLRP3 inflammasome in human macrophages through a non-classical pathway. iScience 24, 102295 (2021).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  138. Pan, P. et al. SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation. Nat. Commun. 12, 4664 (2021).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  139. Xu, H. et al. SARS-CoV-2 viroporin encoded by ORF3a triggers the NLRP3 inflammatory pathway. Virology 568, 13–22 (2022).

    CAS  PubMed  Google Scholar 

  140. Rodrigues, T. S. et al. Inflammasomes are activated in response to SARS-cov-2 infection and are associated with COVID-19 severity in patients. J. Exp. Med. 218, e20201707 (2020).

    PubMed Central  Google Scholar 

  141. Yalcinkaya, M. et al. Modulation of the NLRP3 inflammasome by Sars-CoV-2 Envelope protein. Sci. Rep. 11, 24432 (2021).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  142. Zhang, Y. et al. The ORF8 protein of SARS-CoV-2 mediates immune evasion through down-regulating MHC-Ι. Proc. Natl Acad. Sci. USA 118, e2024202118 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Arshad, N. et al. SARS-CoV-2 accessory proteins ORF7a and ORF3a use distinct mechanisms to down-regulate MHC-I surface expression. Proc. Natl Acad. Sci. USA 120, e2208525120 (2023).

    CAS  PubMed  Google Scholar 

  144. Yoo, J. S. et al. SARS-CoV-2 inhibits induction of the MHC class I pathway by targeting the STAT1-IRF1-NLRC5 axis. Nat. Commun. 12, 6602 (2021).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  145. Menachery, V. D. et al. MERS-CoV and H5N1 influenza virus antagonize antigen presentation by altering the epigenetic landscape. Proc. Natl Acad. Sci. USA 115, E1012–E1021 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Kee, J. et al. SARS-CoV-2 disrupts host epigenetic regulation via histone mimicry. Nature 610, 381–388 (2022).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  147. Kim, Y. M. & Shin, E. C. Type I and III interferon responses in SARS-CoV-2 infection. Exp. Mol. Med. 53, 750–760 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Liu, G. Q. et al. ISG15-dependent activation of the sensor MDA5 is antagonized by the SARS-CoV-2 papain-like protease to evade host innate immunity. Nat. Microbiol. 6, 467–478 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Moustaqil, M. et al. SARS-CoV-2 proteases PLpro and 3CLpro cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species. Emerg. Microbes Infect. 10, 178–195 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Shin, D. et al. Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity. Nature 587, 657–662 (2020).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  151. Zhang, S., Wang, J. & Cheng, G. Protease cleavage of RNF20 facilitates coronavirus replication via stabilization of SREBP1. Proc. Natl Acad. Sci. USA 118, e2107108118 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Miao, G. et al. ORF3a of the COVID-19 virus SARS-CoV-2 blocks HOPS complex-mediated assembly of the SNARE complex required for autolysosome formation. Dev. Cell 56, 427–442.e5 (2021).

    CAS  PubMed  Google Scholar 

  153. Sui, L. et al. SARS-CoV-2 membrane protein inhibits type i interferon production through ubiquitin-mediated degradation of TBK1. Front. Immunol. 12, 662989 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Ren, Y. et al. The ORF3a protein of SARS-CoV-2 induces apoptosis in cells. Cell Mol. Immunol. 17, 881–883 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Zhang, Y. et al. The SARS-CoV-2 protein ORF3a inhibits fusion of autophagosomes with lysosomes. Cell Discov. 7, 31 (2021).

    MathSciNet  CAS  PubMed  PubMed Central  Google Scholar 

  156. Ashour, H. M., Elkhatib, W. F., Md. Rahman, M. & Elshabrawy, H. A. Insights into the recent 2019 novel coronavirus (SARS-CoV-2) in light of past human coronavirus outbreaks. Pathogens 9, 186 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Shang, J. et al. Compositional diversity and evolutionary pattern of coronavirus accessory proteins. Brief. Bioinform 22, 1267–1278 (2021).

    CAS  PubMed  Google Scholar 

  158. Frieman, M. et al. Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane. J. Virol. 81, 9812–9824 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Addetia, A. et al. SARS-CoV-2 ORF6 disrupts bidirectional nucleocytoplasmic transport through interactions with Rae1 and Nup98. mBio 12, e00065–e00121 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Kato, K. et al. Overexpression of SARS-CoV-2 protein ORF6 dislocates RAE1 and NUP98 from the nuclear pore complex. Biochem. Biophys. Res. Commun. 536, 59–66 (2021).

    CAS  PubMed  Google Scholar 

  161. Kimura, I. et al. Sarbecovirus ORF6 proteins hamper induction of interferon signaling. Cell Rep. 34, 108916 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Miorin, L. et al. SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling. Proc. Natl Acad. Sci. USA 117, 28344–28354 (2020).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  163. Miyamoto, Y. et al. SARS-CoV-2 ORF6 disrupts nucleocytoplasmic trafficking to advance viral replication. Commun. Biol. 5, 483 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Kehrer, T. et al. Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis. Cell Host Microbe 31, 1668–1684.e12 (2023).

    CAS  PubMed  Google Scholar 

  165. Zhang, K. et al. Nsp1 protein of SARS-CoV-2 disrupts the mRNA export machinery to inhibit host gene expression. Sci. Adv. 7, eabe7386 (2021).

    MathSciNet  CAS  PubMed  ADS  PubMed Central  Google Scholar 

  166. Schubert, K. et al. Universal features of Nsp1-mediated translational shutdown by coronaviruses. Mol. Cell 83, 3546–3557.e8 (2023).

    CAS  PubMed  Google Scholar 

  167. Baggen, J., Vanstreels, E., Jansen, S. & Daelemans, D. Cellular host factors for SARS-CoV-2 infection. Nat. Microbiol. 6, 1219–1232 (2021).

    CAS  PubMed  Google Scholar 

  168. Baggen, J. et al. Genome-wide CRISPR screening identifies TMEM106B as a proviral host factor for SARS-CoV-2. Nat. Genet. 53, 435–444 (2021).

    CAS  PubMed  Google Scholar 

  169. Daniloski, Z. et al. Identification of required host factors for SARS-CoV-2 infection in human cells. Cell 184, 92–105.e16 (2021).

    CAS  PubMed  Google Scholar 

  170. Wang, R. et al. Genetic screens identify host factors for SARS-CoV-2 and common cold coronaviruses. Cell 184, 106–119.e14 (2021).

    CAS  PubMed  Google Scholar 

  171. Schneider, W. M. et al. Genome-scale identification of SARS-CoV-2 and pan-coronavirus host factor networks. Cell 184, 120–132.e14 (2021).

    CAS  PubMed  Google Scholar 

  172. Baggen, J. et al. TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry. Cell 186, 3427–3442.e22 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Rebendenne, A. et al. Bidirectional genome-wide CRISPR screens reveal host factors regulating SARS-CoV-2, MERS-CoV and seasonal HCoVs. Nat. Genet. 54, 1090–1102 (2022).

    CAS  PubMed  Google Scholar 

  174. Biering, S. B. et al. Genome-wide bidirectional CRISPR screens identify mucins as host factors modulating SARS-CoV-2 infection. Nat. Genet. 54, 1078–1089 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Zhu, Y. et al. A genome-wide CRISPR screen identifies host factors that regulate SARS-CoV-2 entry. Nat. Commun. 12, 961 (2021).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  176. Grodzki, M. et al. Genome-scale CRISPR screens identify host factors that promote human coronavirus infection. Genome Med. 14, 10 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Hoffmann, H. H. et al. Functional interrogation of a SARS-CoV-2 host protein interactome identifies unique and shared coronavirus host factors. Cell Host Microbe 29, 267–280.e5 (2021).

    CAS  PubMed  Google Scholar 

  178. Burkard, C. et al. Coronavirus cell entry occurs through the endo-/lysosomal pathway in a proteolysis-dependent manner. PLoS Pathog. 10, e1004502 (2014).

    PubMed  PubMed Central  Google Scholar 

  179. Schmidt, N. et al. The SARS-CoV-2 RNA–protein interactome in infected human cells. Nat. Microbiol. 6, 339–353 (2020). The authors provide insight into cellular host factors that directly bind SARS-CoV-2 RNA in infected human cells and compare/explain previously described functions.

    PubMed  PubMed Central  Google Scholar 

  180. May, D. G. et al. A BioID-derived proximity interactome for SARS-CoV-2 proteins. Viruses 14, 611 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Ugalde, A. P. et al. Autophagy‐linked plasma and lysosomal membrane protein PLAC8 is a key host factor for SARS‐CoV‐2 entry into human cells. EMBO J. 41, e110727 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. mac Kain, A. et al. Identification of DAXX as a restriction factor of SARS-CoV-2 through a CRISPR/Cas9 screen. Nat. Commun. 13, 2442 (2022).

    ADS  Google Scholar 

  183. Brown, M. S. & Goldstein, J. L. A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc. Natl Acad. Sci. USA 96, 11041–11048 (1999).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  184. Kratzel, A. et al. A genome-wide CRISPR screen identifies interactors of the autophagy pathway as conserved coronavirus targets. PLoS Biol. 19, e3001490 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Li, Y. E. et al. TMEM41B and VMP1 are scramblases and regulate the distribution of cholesterol and phosphatidylserine. J. Cell Biol. 220, e202103105 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Lee, S. et al. The SARS-CoV-2 RNA interactome. Mol. Cell 81, 2838–2850.e6 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Labeau, A. et al. Characterization and functional interrogation of the SARS-CoV-2 RNA interactome. Cell Rep. 39, 110744 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Flynn, R. A. et al. Discovery and functional interrogation of SARS-CoV-2 RNA-host protein interactions. Cell 184, 2394–2411.e16 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Kamel, W. et al. Global analysis of protein–RNA interactions in SARS-CoV-2-infected cells reveals key regulators of infection. Mol. Cell 81, 2851–2867.e7 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Chen, Z. et al. Interactomes of SARS-CoV-2 and human coronaviruses reveal host factors potentially affecting pathogenesis. EMBO J. 40, e107776 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Kruse, T. et al. Large scale discovery of coronavirus-host factor protein interaction motifs reveals SARS-CoV-2 specific mechanisms and vulnerabilities. Nat. Commun. 12, 6761 (2021).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  192. Zheng, Z.-Q., Wang, S.-Y., Xu, Z.-S., Fu, Y.-Z. & Wang, Y.-Y. SARS-CoV-2 nucleocapsid protein impairs stress granule formation to promote viral replication. Cell Discov. 7, 38 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Kumar, A. et al. SARS-CoV-2 nonstructural protein 1 inhibits the interferon response by causing depletion of key host signaling factors. J. Virol. 95, e0026621 (2021).

    PubMed  Google Scholar 

  194. Xu, Z. et al. SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation. Proc. Natl Acad. Sci. USA 119, e2204539119 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Alhammad, Y. M. O. et al. The SARS-CoV-2 conserved macrodomain is a mono-ADP-ribosylhydrolase. J. Virol. 95, e01969–e02020 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Liu, Y. et al. SARS-CoV-2 Nsp5 demonstrates two distinct mechanisms targeting RIG-I and MAVS to evade the innate immune response. mBio 12, e0233521 (2021).

    PubMed  Google Scholar 

  197. Zheng, Y. et al. SARS-CoV-2 NSP5 and N protein counteract the RIG-I signaling pathway by suppressing the formation of stress granules. Signal. Transduct. Target. Ther. 7, 22 (2022).

    Google Scholar 

  198. Bhardwaj, T. et al. Amyloidogenic proteins in the SARS-CoV and SARS-CoV-2 proteomes. Nat. Commun. 14, 945 (2023).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  199. Fung, S. Y. et al. SARS-CoV-2 NSP13 helicase suppresses interferon signaling by perturbing JAK1 phosphorylation of STAT1. Cell Biosci. 12, 36 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Hsu, J. C.-C., Laurent-Rolle, M., Pawlak, J. B., Wilen, C. B. & Cresswell, P. Translational shutdown and evasion of the innate immune response by SARS-CoV-2 NSP14 protein. Proc. Natl Acad. Sci. USA 118, e2101161118 (2021).

    PubMed  PubMed Central  Google Scholar 

  201. Ricardo-Lax, I. et al. Replication and single-cycle delivery of SARS-CoV-2 replicons. Science 374, 1099–1106 (2021).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  202. Benton, D. J. et al. Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion. Nature 588, 327–330 (2020).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  203. Freitas, R. S., Crum, T. F. & Parvatiyar, K. SARS-CoV-2 spike antagonizes innate antiviral immunity by targeting interferon regulatory factor 3. Front. Cell. Infect. Microbiol. 11, 789462 (2022).

    PubMed  PubMed Central  Google Scholar 

  204. Zhang, Q. et al. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) membrane (M) and spike (S) proteins antagonize host type I interferon response. Front. Cell Infect. Microbiol. 11, 1242 (2021).

    Google Scholar 

  205. Fu, Y.-Z. et al. SARS-CoV-2 membrane glycoprotein M antagonizes the MAVS-mediated innate antiviral response. Cell Mol. Immunol. 18, 613–620 (2021).

    CAS  PubMed  Google Scholar 

  206. Luo, L. et al. SARS-CoV-2 nucleocapsid protein phase separates with G3BPs to disassemble stress granules and facilitate viral production. Sci. Bull. 66, 1194–1204 (2021).

    CAS  Google Scholar 

  207. Wang, S. et al. Targeting liquid–liquid phase separation of SARS-CoV-2 nucleocapsid protein promotes innate antiviral immunity by elevating MAVS activity. Nat. Cell Biol. 23, 718–732 (2021).

    CAS  PubMed  Google Scholar 

  208. Gori Savellini, G., Anichini, G., Gandolfo, C. & Cusi, M. G. SARS-CoV-2 N protein targets TRIM25-mediated RIG-I activation to suppress innate immunity. Viruses 13, 1439 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Oh, S. J. & Shin, O. S. SARS-CoV-2 nucleocapsid protein targets RIG-I-like receptor pathways to inhibit the induction of interferon response. Cells 10, 530 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Chen, K. et al. SARS-CoV-2 nucleocapsid protein interacts with RIG-I and represses RIG-mediated IFN-β production. Viruses 13, 47 (2020).

    PubMed  PubMed Central  Google Scholar 

  211. Mu, J. et al. SARS-CoV-2 N protein antagonizes type I interferon signaling by suppressing phosphorylation and nuclear translocation of STAT1 and STAT2. Cell Discov. 6, 65 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Kern, D. M. et al. Cryo-EM structure of SARS-CoV-2 ORF3a in lipid nanodiscs. Nat. Struct. Mol. Biol. 28, 573–582 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Wang, R. et al. ORF3a protein of severe acute respiratory syndrome coronavirus 2 inhibits interferon-activated Janus kinase/signal transducer and activator of transcription signaling via elevating suppressor of cytokine signaling 1. Front. Microbiol. 12, 2871 (2021).

    Google Scholar 

  214. Qu, Y. et al. ORF3a-mediated incomplete autophagy facilitates severe acute respiratory syndrome coronavirus-2 replication. Front. Cell Dev. Biol. 9, 716208 (2021).

    PubMed  PubMed Central  Google Scholar 

  215. Stewart, H. et al. The SARS-CoV-2 protein ORF3c is a mitochondrial modulator of innate immunity. iScience 26, 108080 (2023).

    PubMed  ADS  PubMed Central  Google Scholar 

  216. Cao, Z. et al. Ubiquitination of SARS-CoV-2 ORF7a promotes antagonism of interferon response. Cell Mol. Immunol. 18, 746–748 (2021).

    CAS  PubMed  Google Scholar 

  217. Wu, J. et al. SARS-CoV-2 ORF9b inhibits RIG-I-MAVS antiviral signaling by interrupting K63-linked ubiquitination of NEMO. Cell Rep. 34, 108761 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Gao, X. et al. Crystal structure of SARS-CoV-2 Orf9b in complex with human TOM70 suggests unusual virus–host interactions. Nat. Commun. 12, 2843 (2021).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  219. Han, L. et al. SARS‐CoV‐2 ORF9b antagonizes type I and III interferons by targeting multiple components of the RIG‐I/MDA‐5–MAVS, TLR3–TRIF, and cGAS–STING signaling pathways. J. Med. Virol. 93, 5376–5389 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Focosi, D. & Maggi, F. Recombination in coronaviruses, with a focus on SARS-CoV-2. Viruses 14, 1239 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Amoutzias, G. D. et al. The remarkable evolutionary plasticity of coronaviruses by mutation and recombination: insights for the COVID-19 pandemic and the future evolutionary paths of SARS-CoV-2. Viruses 14, 78 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. Nikolaidis, M., Markoulatos, P., van de Peer, Y., Oliver, S. G. & Amoutzias, G. D. The neighborhood of the spike gene is a hotspot for modular intertypic homologous and nonhomologous recombination in coronavirus genomes. Mol. Biol. Evol. 39, msab292 (2022).

    CAS  PubMed  Google Scholar 

  223. Müller, N. F., Kistler, K. E. & Bedford, T. A Bayesian approach to infer recombination patterns in coronaviruses. Nat. Commun. 13, 4186 (2022).

    PubMed  ADS  PubMed Central  Google Scholar 

  224. Gribble, J. et al. The coronavirus proofreading exoribonuclease mediates extensive viral recombination. PLoS Pathog. 17, e1009226 (2021). This article provides a functional link between the proofreading exoribonuclease and coronavirus recombination.

    CAS  PubMed  PubMed Central  Google Scholar 

  225. Turakhia, Y. et al. Pandemic-scale phylogenomics reveals the SARS-CoV-2 recombination landscape. Nature 609, 994–997 (2022).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  226. Threat assessment brief: implications for the EU/EEA of the spread of the SARS-CoV-2 Omicron XBB.1.5 sub-lineage. ECDC https://www.ecdc.europa.eu/en/publications-data/covid-19-threat-assessment-brief-implications-spread-omicron-xbb (2023).

  227. Ogando, N. S. et al. SARS-coronavirus-2 replication in Vero E6 cells: replication kinetics, rapid adaptation and cytopathology. J. Gen. Virol. 101, 925–940 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. Sasaki, M. et al. SARS-CoV-2 variants with mutations at the S1/S2 cleavage site are generated in vitro during propagation in TMPRSS2-deficient cells. PLoS Pathog. 17, e1009233 (2021). The importance of the S1/S2 furin cleavage site and its rapid loss after in vitro virus passages is demonstrated.

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Hou, Y. J. et al. SARS-CoV-2 D614G variant exhibits efficient replication ex vivo and transmission in vivo. Science 370, 1464–1468 (2020).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  230. Han, Y., Yang, L., Lacko, L. A. & Chen, S. Human organoid models to study SARS-CoV-2 infection. Nat. Methods 19, 418–428 (2022).

    CAS  PubMed  Google Scholar 

  231. Hui, K. P. Y. et al. SARS-CoV-2 Omicron variant replication in human bronchus and lung ex vivo. Nature 603, 715–720 (2022).

    CAS  PubMed  ADS  Google Scholar 

  232. Zhou, B. et al. SARS-CoV-2 spike D614G change enhances replication and transmission. Nature 592, 122–127 (2021).

    CAS  PubMed  ADS  Google Scholar 

  233. Chu, H., Chan, J. F. W. & Yuen, K. Y. Animal models in SARS-CoV-2 research. Nat. Methods 19, 392–394 (2022).

    CAS  PubMed  Google Scholar 

  234. Dinnon, K. H. et al. A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures. Nature 586, 560–566 (2020). These authors created a mouse-adapted SARS-CoV-2, which models COVID-19 pathogenesis in mice and serves as an important model system for in vivo evaluation of therapeutics and vaccines.

    PubMed  ADS  PubMed Central  Google Scholar 

  235. Corbett, K. S. et al. Evaluation of the mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates. N. Engl. J. Med. 383, 1544–1555 (2020).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank all our colleagues in the field of coronaviruses, who have helped to increase our knowledge of this virus family since its discovery. Owing to the scope and focus of this manuscript, they have primarily focused on recent publications working with SARS-CoV-2; however, we appreciate that many of these insights are built on a strong foundation of research on previous coronaviruses during the past decades. Work in the authors’ laboratory was supported by the Swiss National Science Foundation (grants 310030B_201278 and NCCR ‘RNA & Disease’ grant 205601).

Author information

Authors and Affiliations

Authors

Contributions

S.S., A.K., G.T.B., R.M.L., J.N.K., E.A.M. and V.T. researched the data for the article. S.S., A.K., G.T.B., R.M.L., J.N.K. and V.T. wrote the manuscript. S.S., A.K., G.T.B. and R.M.L. prepared the figures, under the supervision of V.T. L.T. contributed to writing and revising the text.

Corresponding author

Correspondence to Volker Thiel.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Microbiology thanks Luis Enjuanes, who co-reviewed with Sonia Zuñiga; Timothy Sheahan, who co-reviewed with Meghan Diefenbacher; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Cis-acting elements

RNA elements found in RNA viruses that regulate processes such as viral transcription, replication, packaging or expression of genes on the same RNA.

Double-membrane vesicles

Virus-induced organelles that are delimited by two membrane bilayers and dedicated to replication or transcription of the viral RNA.

Internal ribosomal entry sites

RNA elements that allow binding of ribosomes and initiation of translation in a cap-independent manner.

Lipid droplets

Cellular lipid depositories that regulate lipid storage and metabolism.

Liquid–liquid phase separation

A process that establishes two distinct phases from a homogeneous solution; in the context of macromolecules, it is often related to the formation of membrane-less condensates of proteins and RNA.

Monocistronic

Refers to messenger RNA molecules that encode a single gene product.

Polycistronic

Refers to mRNA molecules that encode more than one gene product.

Viroporin

A viral protein with hydrophobic region that can assemble into ion channels or molecular pores on membranes.

Rights and permissions

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.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Steiner, S., Kratzel, A., Barut, G.T. et al. SARS-CoV-2 biology and host interactions. Nat Rev Microbiol 22, 206–225 (2024). https://doi.org/10.1038/s41579-023-01003-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41579-023-01003-z

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing