08-04-2021, 01:10 AM
(This post was last modified: 08-04-2021, 01:25 AM by Relax.
Edit Reason: amendation
)
Virus–host interactions and host response
A successful intracellular coronavirus life cycle invariably relies on critical molecular interactions with host proteins that are repurposed to support the requirements of the virus. This includes host factors required for virus entry (such as the entry receptor and host cell proteases), factors required for viral RNA synthesis and virus assembly (such as ER and Golgi components and associated vesicular trafficking pathways) and factors required for the translation of viral mRNAs (such as critical translational initiation factors)68,124,125,126,127,128,129.
A first systematic expression study of SARS-CoV-2 proteins and subsequent affinity purification followed by mass spectrometry identified more than 300 potential coronavirus–host protein interactions. Although outside the context of a SARS-CoV-2 infection, interactors of individually overexpressed SARS-CoV-2 proteins uncovered several cellular processes reminiscent of those of other coronaviruses that are likely to also be involved in the SARS-CoV-2 life cycle130. Importantly, 69 compounds, either FDA approved or at different stages of clinical development, that target putative SARS-CoV-2 protein interactors were foregrounded, a subset of which efficiently prevented SARS-CoV-2 replication in vitro. These systematic screening approaches of large compound libraries that target host proteins provide means of rapidly identifying antiviral (repurposed) drugs and accelerated clinical availability131. However, a detailed functional characterization of conserved host pathways that promote coronavirus replication will guide the development of efficacious targeted therapeutics against coronavirus infections.
In addition, coronaviruses efficiently evade innate immune responses. Virus–host interactions in this context are multifaceted and include strategies to hide viral pathogen-associated molecular patterns, such as replication intermediates (dsRNA), that may be sensed by cytosolic pattern recognition receptors132,133. DMVs have been proposed to shield dsRNA and sites of viral RNA synthesis; however, experimental proof supporting this idea has not yet been obtained. The coronaviral RTC also contributes to innate immune evasion through several nsp-encoded functions. These include PLpro-mediated deubiquitylation activity134,135, de-ADP-ribosylation by nsp3-encoded macro domains136, RNA-modifying enzymatic activities such as 5′-cap N7-methylation and 2′-O-methylation (nsp14 and nsp16, respectively)74,137,138, and exonuclease139 and endoribonuclease140,141 activities (nsp14 and nsp15, respectively). Although these mechanisms have been elucidated in considerable detail for several prototype coronaviruses, data for SARS-CoV-2 are not yet available.
Besides the well-conserved functions residing in the nsps that comprise the RTC, additional mechanisms to counteract innate immune responses are known for coronaviruses. For example, nsp1 is rapidly proteolytically released from pp1a and pp1ab and affects cellular translation in the cytoplasm to favour viral mRNAs over cellular mRNA, and thereby also decreases the expression of type I and III interferons and of other host proteins of the innate immune response. Indeed, a first structural and functional analysis of SARS-CoV-2 nsp1 showed binding of nsp1 to ribosomes and nsp1-mediated impairment of translation64. Furthermore, several coronavirus accessory proteins are known to affect innate immune responses, most prominently MHV NS2 and MERS-CoV ORF4b proteins, that have 2′,5′-phosphodiesterase activity to antagonize the OAS–RNase L pathway142. Although this activity is not predicted for any accessory protein of SARS-CoV or SARS-CoV-2, the ORF3b, ORF6 and N proteins of SARS-CoV have been shown to interfere at multiple levels of the cellular interferon signalling pathway, thereby efficiently inhibiting innate immune responses103. Interestingly, an initial report recently suggested a similar role of SARS-CoV-2 ORF3b as an effective interferon antagonist99. Although this property remains to be demonstrated in the context of viral infection, these results suggest that SARS-CoV-2 shares some preserved accessory protein activities with SARS-CoV that interfere with antiviral host responses.
Coronavirus biology and COVID-19
Our knowledge on SARS-CoV-2 replication, gene function and host interactions is accumulating at unprecedented speed and it will be important to link those findings to the disease induced by SARS-CoV-2 infection, COVID-19. Thus, there is a need to establish experimental systems, such as representative animal models to study the transmission and pathogenicity of SARS-CoV-2, primary airway epithelial cultures and organoids to study SARS-CoV-2 replication and host responses to infection in relevant cell types, and reverse genetics systems to study the specific gene functions of SARS-CoV-2 (Table 1). These tools will be instrumental to understanding how the molecular biology of SARS-CoV-2 affects the development of COVID-19.
As we currently understand, SARS and COVID-19 are a consequence of virus-encoded functions and delayed interferon responses and, in severe cases, they are associated with dysregulated immune responses and immunopathologies143,144. Indeed, rapid and uncontrolled viral replication of SARS-CoV has been demonstrated to evade the host innate immune activation during its initial steps. As a consequence, the increase in aberrant pro-inflammatory responses and immune cell infiltration in the lungs provoke tissue damage and contribute to the clinical manifestation of SARS145.
Consistently, host responses, such as cytokine expression, that are known to drive inflammation and immunopathologies have been assessed in studies that revealed that SARS-CoV-2 considerably affects the transcriptional landscape of infected cells by inducing inflammatory cytokine and chemokine signatures38,146,147. Although interferon responses have been shown to potently impair SARS-CoV-2 replication, only moderate induction of type I interferon, type II interferon and interferon-stimulated genes was reported38,147.
Together, these effects may translate into strong and dysregulated pro-inflammatory responses, while cells display low innate antiviral defence activation as revealed by single-cell transcriptomic studies of nasopharyngeal and bronchial patient samples38,146,148,149. In severe COVID-19 cases, as opposed to mild cases, aberrant recruitment of inflammatory macrophages and infiltration of T lymphocytes, including cytotoxic T cells, as well as of neutrophils have been measured in the lung146,149. The accumulating evidence of dysregulated pro-inflammatory responses during SARS-CoV-2 infections has led to the use of immune modulators to inhibit hyperactivated pathogenic immune responses143,144,150,151
Conclusions
In contrast to the SARS-CoV epidemic of almost 20 years ago, improved technologies, such as transcriptomics, proteomics, single-cell RNA sequencing, global single-cell profiling of patient samples, advanced primary 3D cell cultures and rapid reverse genetics, have been valuable tools to understand and tackle SARS-CoV-2 infections. Furthermore, several existing animal models initially established for SARS-CoV are applicable to study SARS-CoV-2 and will help to identify the critical viral and host factors that impact on COVID-19. We need to understand why SARS-CoV-2, in contrast to SARS-CoV, is replicating so efficiently in the upper respiratory tract and which viral and host determinants are decisive on whether COVID-19 patients will develop mild or severe disease152,153,154. Finally, we need to put the first encouraging studies on SARS-CoV-2 into the context of coronavirus biology to develop efficacious strategies to treat COVID-19 and to develop urgently needed vaccines.
References
1. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat. Microbiol. 5, 536–544 (2020). Most recent update of the coronavirus taxonomy by the International Committee on Taxonomy of Viruses after the emergence of SARS-CoV-2. Coined the virus name SARS-CoV-2.
2. Corman, V. M., Muth, D., Niemeyer, D. & Drosten, C. Hosts and sources of endemic human coronaviruses. Adv. Virus Res. 100, 163–188 (2018).
3. Gorbalenya, A. E., Enjuanes, L., Ziebuhr, J. & Snijder, E. J. Nidovirales: evolving the largest RNA virus genome. Virus Res. 117, 17–37 (2006).
4. Perlman, S. & Netland, J. Coronaviruses post-SARS: update on replication and pathogenesis. Nat. Rev. Microbiol. 7, 439–450 (2009).
5. Masters, P. S. The molecular biology of coronaviruses. Adv. Virus Res. 65, 193–292 (2006).
6. Liu, D. X., Fung, T. S., Chong, K. K. L., Shukla, A. & Hilgenfeld, R. Accessory proteins of SARS-CoV and other coronaviruses. Antivir. Res. 109, 97–109 (2014).
7. Schalk, A. & Hawn, M. C. An apparently new respiratory disease of baby chicks. J. Am. Vet. Med. Assoc. 78, 413–423 (1931).
8. Hamre, D. & Procknow, J. J. A new virus isolated from the human respiratory tract. Proc. Soc. Exp. Biol. Med. 121, 190–193 (1966).
9. McIntosh, K., Dees, J. H., Becker, W. B., Kapikian, A. Z. & Chanock, R. M. Recovery in tracheal organ cultures of novel viruses from patients with respiratory disease. Proc. Natl Acad. Sci. USA 57, 933–940 (1967).
10. Tortorici, M. A. & Veesler, D. Structural insights into coronavirus entry. Adv. Virus Res. 105, 93–116 (2019).
11. Li, F. Structure, function, and evolution of coronavirus spike proteins. Annu. Rev. Virol. 3, 237–261 (2016).
12. Letko, M., Marzi, A. & Munster, V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat. Microbiol. 5, 562–569 (2020). First functional assessment of the interaction of the SARS-CoV-2 Spike protein receptor binding domain with the cellular receptor ACE2.
13. Li, W. et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 426, 450–454 (2003).
14. Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020).
15. 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 (2020). Functional assessment of SARS-CoV-2 entry into host cells highlighting the importance of the ACE2 receptor and the cellular protease TMPRSS2 as entry factors.
16. Walls, A. C. et al. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 181, 281–292 (2020). Recommended resource describing key aspects of SARS-CoV-2 Spike features.
17. Li, F., Li, W., Farzan, M. & Harrison, S. C. Structural biology: structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science 309, 1864–1868 (2005).
18. Li, W. et al. Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2. EMBO J. 24, 1634–1643 (2005)...........................
...................33. Hamming, I. et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J. Pathol. 203, 631–637 (2004).
34.
Shieh, W. J. et al. Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan. Hum. Pathol. 36, 303–309 (2005)....................
................ 94. Cai, Q. et al. Experimental treatment with favipiravir for COVID-19: an open-label control study. Engineering https://doi.org/10.1016/j.eng.2020.03.007 (2020).
95. Stertz, S. et al. The intracellular sites of early replication and budding of SARS-coronavirus. Virology 361, 304–315 (2007)...............
.................[NB: see link for another 105 Scientific References]
[NB: Published: 28 October 2020
Coronavirus biology and replication: implications for SARS-CoV-2
Philip V’kovski, Annika Kratzel, Silvio Steiner, Hanspeter Stalder & Volker Thiel
Glossary
Nested set
Refers to the nested set of coronavirus 5′-coterminal and 3′-coterminal RNAs. Most nidoviruses (Nidus, nest, latin) share this mechanism of transcription and are grouped into the order Nidovirales.
Zoonotic pathogens
Animal pathogens that can infect and replicate in humans.
Recombination breakpoints
Distinct sites in the viral genome that are associated with a high frequency of exchange of genetic material between related viruses during co-infection of the same host cell.
Integrins
Proteins that bind carbohydrate moieties found on proteins of the extracellular matrix or on cell-surface glycoproteins.
Hybridoma
Clonal cells resulting from the fusion of B lymphoblasts and lymphoid myeloma cells. Hybridoma cells are used for the production of monoclonal antibodies.
Escape mutations
Nucleotide changes that enable evasion from a selective pressure. Frequently used to describe changes in the viral genome that impair the efficiency of antibodies or antiviral compounds.
Transcription regulatory sequences
(TRSs). Direct the leader-body junction during synthesis of coronavirus subgenomic RNAs.
Accessory genes
Sets of coronavirus genes that encode proteins that are neither the non-structural proteins 1–16 (encoded in ORF1a/b and composing the replication and transcription complex) nor the canonical coronavirus structural proteins S, E, M and N. Usually dispensable in cell culture.
Major histocompatibility complex
Major histocompatibility complex (MHC) molecules are cell-surface proteins that present a repertoire of proteins currently being expressed in the cell or proteins that have been uptaken by the cell in the form of MHC-bound peptides (called epitopes). T cells can recognize the MHC–peptide complexes and are stimulated to exert their immune functions upon recognition of MHC-bound pathogen-derived peptides.
Double-membrane vesicles
(DMVs). DMVs are characteristic membranous structures induced by coronaviruses and many other positive-sense RNA viruses. They anchor the replication and transcription complex and support viral replication and RNA synthesis.
OAS–RNase L pathway
There are several cellular 2′,5′-oligoadenylate synthetases that produce 2′,5′-oligoadenylates upon stimulation by double-stranded RNA. 2′,5′-oligoadenylates can stimulate the cellular ribonuclease RNase L that degrades cellular and viral RNAs as part of the antiviral host defence.
https://www.nature.com/articles/s41579-020-00468-6
A successful intracellular coronavirus life cycle invariably relies on critical molecular interactions with host proteins that are repurposed to support the requirements of the virus. This includes host factors required for virus entry (such as the entry receptor and host cell proteases), factors required for viral RNA synthesis and virus assembly (such as ER and Golgi components and associated vesicular trafficking pathways) and factors required for the translation of viral mRNAs (such as critical translational initiation factors)68,124,125,126,127,128,129.
A first systematic expression study of SARS-CoV-2 proteins and subsequent affinity purification followed by mass spectrometry identified more than 300 potential coronavirus–host protein interactions. Although outside the context of a SARS-CoV-2 infection, interactors of individually overexpressed SARS-CoV-2 proteins uncovered several cellular processes reminiscent of those of other coronaviruses that are likely to also be involved in the SARS-CoV-2 life cycle130. Importantly, 69 compounds, either FDA approved or at different stages of clinical development, that target putative SARS-CoV-2 protein interactors were foregrounded, a subset of which efficiently prevented SARS-CoV-2 replication in vitro. These systematic screening approaches of large compound libraries that target host proteins provide means of rapidly identifying antiviral (repurposed) drugs and accelerated clinical availability131. However, a detailed functional characterization of conserved host pathways that promote coronavirus replication will guide the development of efficacious targeted therapeutics against coronavirus infections.
In addition, coronaviruses efficiently evade innate immune responses. Virus–host interactions in this context are multifaceted and include strategies to hide viral pathogen-associated molecular patterns, such as replication intermediates (dsRNA), that may be sensed by cytosolic pattern recognition receptors132,133. DMVs have been proposed to shield dsRNA and sites of viral RNA synthesis; however, experimental proof supporting this idea has not yet been obtained. The coronaviral RTC also contributes to innate immune evasion through several nsp-encoded functions. These include PLpro-mediated deubiquitylation activity134,135, de-ADP-ribosylation by nsp3-encoded macro domains136, RNA-modifying enzymatic activities such as 5′-cap N7-methylation and 2′-O-methylation (nsp14 and nsp16, respectively)74,137,138, and exonuclease139 and endoribonuclease140,141 activities (nsp14 and nsp15, respectively). Although these mechanisms have been elucidated in considerable detail for several prototype coronaviruses, data for SARS-CoV-2 are not yet available.
Besides the well-conserved functions residing in the nsps that comprise the RTC, additional mechanisms to counteract innate immune responses are known for coronaviruses. For example, nsp1 is rapidly proteolytically released from pp1a and pp1ab and affects cellular translation in the cytoplasm to favour viral mRNAs over cellular mRNA, and thereby also decreases the expression of type I and III interferons and of other host proteins of the innate immune response. Indeed, a first structural and functional analysis of SARS-CoV-2 nsp1 showed binding of nsp1 to ribosomes and nsp1-mediated impairment of translation64. Furthermore, several coronavirus accessory proteins are known to affect innate immune responses, most prominently MHV NS2 and MERS-CoV ORF4b proteins, that have 2′,5′-phosphodiesterase activity to antagonize the OAS–RNase L pathway142. Although this activity is not predicted for any accessory protein of SARS-CoV or SARS-CoV-2, the ORF3b, ORF6 and N proteins of SARS-CoV have been shown to interfere at multiple levels of the cellular interferon signalling pathway, thereby efficiently inhibiting innate immune responses103. Interestingly, an initial report recently suggested a similar role of SARS-CoV-2 ORF3b as an effective interferon antagonist99. Although this property remains to be demonstrated in the context of viral infection, these results suggest that SARS-CoV-2 shares some preserved accessory protein activities with SARS-CoV that interfere with antiviral host responses.
Coronavirus biology and COVID-19
Our knowledge on SARS-CoV-2 replication, gene function and host interactions is accumulating at unprecedented speed and it will be important to link those findings to the disease induced by SARS-CoV-2 infection, COVID-19. Thus, there is a need to establish experimental systems, such as representative animal models to study the transmission and pathogenicity of SARS-CoV-2, primary airway epithelial cultures and organoids to study SARS-CoV-2 replication and host responses to infection in relevant cell types, and reverse genetics systems to study the specific gene functions of SARS-CoV-2 (Table 1). These tools will be instrumental to understanding how the molecular biology of SARS-CoV-2 affects the development of COVID-19.
As we currently understand, SARS and COVID-19 are a consequence of virus-encoded functions and delayed interferon responses and, in severe cases, they are associated with dysregulated immune responses and immunopathologies143,144. Indeed, rapid and uncontrolled viral replication of SARS-CoV has been demonstrated to evade the host innate immune activation during its initial steps. As a consequence, the increase in aberrant pro-inflammatory responses and immune cell infiltration in the lungs provoke tissue damage and contribute to the clinical manifestation of SARS145.
Consistently, host responses, such as cytokine expression, that are known to drive inflammation and immunopathologies have been assessed in studies that revealed that SARS-CoV-2 considerably affects the transcriptional landscape of infected cells by inducing inflammatory cytokine and chemokine signatures38,146,147. Although interferon responses have been shown to potently impair SARS-CoV-2 replication, only moderate induction of type I interferon, type II interferon and interferon-stimulated genes was reported38,147.
Together, these effects may translate into strong and dysregulated pro-inflammatory responses, while cells display low innate antiviral defence activation as revealed by single-cell transcriptomic studies of nasopharyngeal and bronchial patient samples38,146,148,149. In severe COVID-19 cases, as opposed to mild cases, aberrant recruitment of inflammatory macrophages and infiltration of T lymphocytes, including cytotoxic T cells, as well as of neutrophils have been measured in the lung146,149. The accumulating evidence of dysregulated pro-inflammatory responses during SARS-CoV-2 infections has led to the use of immune modulators to inhibit hyperactivated pathogenic immune responses143,144,150,151
Conclusions
In contrast to the SARS-CoV epidemic of almost 20 years ago, improved technologies, such as transcriptomics, proteomics, single-cell RNA sequencing, global single-cell profiling of patient samples, advanced primary 3D cell cultures and rapid reverse genetics, have been valuable tools to understand and tackle SARS-CoV-2 infections. Furthermore, several existing animal models initially established for SARS-CoV are applicable to study SARS-CoV-2 and will help to identify the critical viral and host factors that impact on COVID-19. We need to understand why SARS-CoV-2, in contrast to SARS-CoV, is replicating so efficiently in the upper respiratory tract and which viral and host determinants are decisive on whether COVID-19 patients will develop mild or severe disease152,153,154. Finally, we need to put the first encouraging studies on SARS-CoV-2 into the context of coronavirus biology to develop efficacious strategies to treat COVID-19 and to develop urgently needed vaccines.
References
1. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat. Microbiol. 5, 536–544 (2020). Most recent update of the coronavirus taxonomy by the International Committee on Taxonomy of Viruses after the emergence of SARS-CoV-2. Coined the virus name SARS-CoV-2.
2. Corman, V. M., Muth, D., Niemeyer, D. & Drosten, C. Hosts and sources of endemic human coronaviruses. Adv. Virus Res. 100, 163–188 (2018).
3. Gorbalenya, A. E., Enjuanes, L., Ziebuhr, J. & Snijder, E. J. Nidovirales: evolving the largest RNA virus genome. Virus Res. 117, 17–37 (2006).
4. Perlman, S. & Netland, J. Coronaviruses post-SARS: update on replication and pathogenesis. Nat. Rev. Microbiol. 7, 439–450 (2009).
5. Masters, P. S. The molecular biology of coronaviruses. Adv. Virus Res. 65, 193–292 (2006).
6. Liu, D. X., Fung, T. S., Chong, K. K. L., Shukla, A. & Hilgenfeld, R. Accessory proteins of SARS-CoV and other coronaviruses. Antivir. Res. 109, 97–109 (2014).
7. Schalk, A. & Hawn, M. C. An apparently new respiratory disease of baby chicks. J. Am. Vet. Med. Assoc. 78, 413–423 (1931).
8. Hamre, D. & Procknow, J. J. A new virus isolated from the human respiratory tract. Proc. Soc. Exp. Biol. Med. 121, 190–193 (1966).
9. McIntosh, K., Dees, J. H., Becker, W. B., Kapikian, A. Z. & Chanock, R. M. Recovery in tracheal organ cultures of novel viruses from patients with respiratory disease. Proc. Natl Acad. Sci. USA 57, 933–940 (1967).
10. Tortorici, M. A. & Veesler, D. Structural insights into coronavirus entry. Adv. Virus Res. 105, 93–116 (2019).
11. Li, F. Structure, function, and evolution of coronavirus spike proteins. Annu. Rev. Virol. 3, 237–261 (2016).
12. Letko, M., Marzi, A. & Munster, V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat. Microbiol. 5, 562–569 (2020). First functional assessment of the interaction of the SARS-CoV-2 Spike protein receptor binding domain with the cellular receptor ACE2.
13. Li, W. et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 426, 450–454 (2003).
14. Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020).
15. 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 (2020). Functional assessment of SARS-CoV-2 entry into host cells highlighting the importance of the ACE2 receptor and the cellular protease TMPRSS2 as entry factors.
16. Walls, A. C. et al. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 181, 281–292 (2020). Recommended resource describing key aspects of SARS-CoV-2 Spike features.
17. Li, F., Li, W., Farzan, M. & Harrison, S. C. Structural biology: structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science 309, 1864–1868 (2005).
18. Li, W. et al. Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2. EMBO J. 24, 1634–1643 (2005)...........................
...................33. Hamming, I. et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J. Pathol. 203, 631–637 (2004).
34.
Shieh, W. J. et al. Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan. Hum. Pathol. 36, 303–309 (2005)....................
................ 94. Cai, Q. et al. Experimental treatment with favipiravir for COVID-19: an open-label control study. Engineering https://doi.org/10.1016/j.eng.2020.03.007 (2020).
95. Stertz, S. et al. The intracellular sites of early replication and budding of SARS-coronavirus. Virology 361, 304–315 (2007)...............
.................[NB: see link for another 105 Scientific References]
[NB: Published: 28 October 2020
Coronavirus biology and replication: implications for SARS-CoV-2
Philip V’kovski, Annika Kratzel, Silvio Steiner, Hanspeter Stalder & Volker Thiel
Glossary
Nested set
Refers to the nested set of coronavirus 5′-coterminal and 3′-coterminal RNAs. Most nidoviruses (Nidus, nest, latin) share this mechanism of transcription and are grouped into the order Nidovirales.
Zoonotic pathogens
Animal pathogens that can infect and replicate in humans.
Recombination breakpoints
Distinct sites in the viral genome that are associated with a high frequency of exchange of genetic material between related viruses during co-infection of the same host cell.
Integrins
Proteins that bind carbohydrate moieties found on proteins of the extracellular matrix or on cell-surface glycoproteins.
Hybridoma
Clonal cells resulting from the fusion of B lymphoblasts and lymphoid myeloma cells. Hybridoma cells are used for the production of monoclonal antibodies.
Escape mutations
Nucleotide changes that enable evasion from a selective pressure. Frequently used to describe changes in the viral genome that impair the efficiency of antibodies or antiviral compounds.
Transcription regulatory sequences
(TRSs). Direct the leader-body junction during synthesis of coronavirus subgenomic RNAs.
Accessory genes
Sets of coronavirus genes that encode proteins that are neither the non-structural proteins 1–16 (encoded in ORF1a/b and composing the replication and transcription complex) nor the canonical coronavirus structural proteins S, E, M and N. Usually dispensable in cell culture.
Major histocompatibility complex
Major histocompatibility complex (MHC) molecules are cell-surface proteins that present a repertoire of proteins currently being expressed in the cell or proteins that have been uptaken by the cell in the form of MHC-bound peptides (called epitopes). T cells can recognize the MHC–peptide complexes and are stimulated to exert their immune functions upon recognition of MHC-bound pathogen-derived peptides.
Double-membrane vesicles
(DMVs). DMVs are characteristic membranous structures induced by coronaviruses and many other positive-sense RNA viruses. They anchor the replication and transcription complex and support viral replication and RNA synthesis.
OAS–RNase L pathway
There are several cellular 2′,5′-oligoadenylate synthetases that produce 2′,5′-oligoadenylates upon stimulation by double-stranded RNA. 2′,5′-oligoadenylates can stimulate the cellular ribonuclease RNase L that degrades cellular and viral RNAs as part of the antiviral host defence.
https://www.nature.com/articles/s41579-020-00468-6